Optimizing the Management of Acute Myeloid : Individualized Therapy

Optimizing the Management of : Individualized Therapy

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Learning Objectives

• Describe diagnostic testing for risk stratification in AML and the role of cytogenetic and molecular factors in treatment selection • Identify individualized AML treatment approaches based on efficacy and safety data, as well as patient- and disease-related characteristics • Implement strategies to recognize, monitor, and manage toxicities associated with new agents used in the treatment of AML

AML = acute myeloid leukemia. 2 2

AML: Most Common Form of Acute Leukemia in Adults

• Heterogeneous hematologic malignancy ‒ Accounts for largest number of annual deaths from leukemia in the United States ‒ Survival influenced by biological features of the disease and patient age Estimated New 5 Cases in 2020 19,940 New cases 5-Year Survival (2009-2015) % of All New 1.2% Cancer Cases 28.3% Deaths Estimated Deaths in 2020 11,180 per Number 100,000 Persons 100,000 0 % of All 1.8% Cancer Deaths 1992 2003 2016 Year

American Cancer Society. www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed Mar 20, 2020; National Cancer Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 3 3

2020 Spring PCE Oncology Series 1 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

AML Incidence Increases With Age

• Most frequently diagnosed in people aged 65 to 74 New AML Cases by Age Group years 30 25.1% ‒ Median age at diagnosis: 68 years 25 ‒ ~1/3 of patients with newly diagnosed AML are 22.7% ≥75 years of age 20 16.8% • Slightly more common in men than in women 15 • Lifetime risk: ~0.5% in both sexes 11.0% ‒ De novo 10 9.1% New Cases (%) Cases New ‒ Secondary 5.7% 5.3% 5 4.5% • AML-MRC • Therapy-related 0 <20 20-34 35-44 45-54 55-64 65-74 75-84 >84 • Poor prognosis in people aged 75 to 84 years due Age, Years to adverse patient characteristics and comorbidities

AML-MRC = AML with myelodysplasia-related changes. Granfeldt Østgård LS, et al. J Clin Oncol. 2015;31:3641-3649; Klepin HD, et al. Am Soc Clin Oncol Educ Book. 2019;39:421-432; National Cancer Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; Vardiman JW, et al. Blood. 2009;114:937-951. 4 4

AML Treatment Paradigm and Goals

Risk Stratify Induction Therapy Consolidation Allogeneic HSCT • Performance Goal: Relapse Goal status, age, • Achieve CR Goals: • Cure comorbidities • Prevent recurrence • Preexisting • Bridge to transplant myelodysplasia Risk Stratify • Prior cytotoxic • Performance status, age, comorbidities therapy • Cytogenetics • Cytogenetics Relapse (6-9 months) • Genomic mutations • Genomic mutations or Refractory

Low Intensity Therapy R/R Therapy/ Goal: Goal: Achieve CR • Achieve CR or Nonintensive Therapy stable disease Goals: • Stable disease • Slow disease progression CR = complete response; R/R = relapsed or refractory. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 5 5

Allogeneic HSCT

• Allogeneic HSCT is a potentially curative therapy that may be used in patients with intermediate- or high-risk AML who have a suitable donor source and are considered to be good candidates • Historically, older patients with AML have not been considered for allogeneic HSCT due to the presence of comorbidities and the perceived risk of increased mortality • Reduced intensity and non-myeloablative conditioning regimens have enabled the use of allogeneic HSCT in a greater number of older patients with AML • Recent data support the use of allogeneic HSCT in selected, fit, older patients with AML after intensive chemotherapy; however, the number of older patients who receive allogeneic HSCT remains low

Lipof JJ, et al. Cancers. 2018;10:179. 6 6

2020 Spring PCE Oncology Series 2 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Individualizing Treatment Goals in AML

EXAMPLE: • Novel low-intensity induction regimens may provide patients ≥75 years old and those who have comorbidities with the goal of a complete response BUT: • Stable disease may be a reasonable therapeutic goal for some patients such as those who are elderly and/or frail BUT: • Patients may request high-intensity induction regimens and/or potentially curative, allogeneic HSCT regardless of age, performance status, and comorbidities

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 7 7

Recently Approved for AML

Drug Description Indication Multikinase inhibitor with inhibitory • Adults with newly diagnosed FLT3-mutated AML activity against FLT3-ITD and FLT3- in combination with standard cytarabine and TKD mutations daunorubicin induction therapy and cytarabine consolidation therapy Inhibitor of multiple receptor tyrosine • Adults with R/R FLT3-mutated AML kinases, including FLT3 Oral IDH2 inhibitor • Adults with R/R IDH2-mutated AML Oral IDH1 inhibitor • AML with a susceptible IDH1 mutation in: ⎻ Adults with newly diagnosed AML who are aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy ⎻ Adults with R/R AML

TKD = domain. Idhifa [prescribing information]. Celgene Corporation; 2019; Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; Tibsovo [prescribing information]. Agios Pharmaceuticals, Inc; 2019; Xospata [prescribing information]. Astellas Pharma US, Inc.;2019. 8 8

Recently Approved Novel Agents for AML

Drug Description Indication Gemtuzumab CD33-directed antibody- • Adults with newly diagnosed CD33-positive AML (in combination with ozogamicin drug conjugate daunorubicin and cytarabine or as a single-agent regimen) • R/R CD33-positive AML in adults and in pediatric patients aged ≥2 years Hedgehog pathway • Newly diagnosed AML in combination with LDAC in adults who are inhibitor aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy BCL-2 inhibitor • Newly diagnosed AML in combination with azacitidine, decitabine, or LDAC in adults who are aged ≥75 years or who have comorbidities that preclude intensive induction chemotherapy CPX-351 Liposomal combination of • Adults with newly diagnosed therapy-related AML or AML-MRC daunorubicin and cytarabine

BCL-2 = B-cell 2; LDAC = low-dose cytarabine. Daurismo [prescribing information]. Pfizer Inc; 2020; Mylotarg [prescribing information]. Pfizer Inc; 2018; Venclexta [prescribing information]. AbbVie Inc; 2019; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019. 9 9

2020 Spring PCE Oncology Series 3 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Case Study 1: Tom, 58 Years Old

• Presents to ED complaining of • Laboratory results: extreme fatigue and abrupt onset of – WBCs: 120,000 cells/mm3 shortness of breath – Hgb: 6.9 g/dL • 2-week history of worsening exercise – Platelets: 27,000/mm3 tolerance – Blasts: 47% • No significant past medical history • Admitted to hospital for further • Enjoys bicycling, swimming, and testing painting

Hgb = hemoglobin. 10 10

Diagnostic Testing and Karyotyping for Risk Stratification

• core biopsy and aspirate analysis, including immunophenotyping and cytochemistry • Molecular analyses: FLT3 (ITD and TKD), NPM1, CEBPA, IDH1, IDH2, TP53, c-KIT, RUNX1, ASXL1 • Karyotyping is an important prognostic factor for predicting remission rates, relapse risk, and OS ‒ Complex karyotype: independent unfavorable risk factor • With each additional karyotype abnormality, the risk of failing to achieve CR increases • SWOG analysis: • Complex cytogenetics without involvement of chromosome 5 or 7: CR 50%; OS 20% • Complex cytogenetics + involvement of chromosome 5 or 7: CR 37%; OS 3% ‒ Monosomal karyotype: very poor prognosis • 4-year OS 4%

OS = overall survival; SWOG = Southwest Oncology Group. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Orozco JJ, et al. Oncology (Williston Park). 2012;26:706-712; Slovak ML, et al. Blood. 2000;96:4075-4083; Xu J, et al. Turk J Haematol. 2017;34:126-130. 11 11

AML Disease Prognosis Influenced by Genetic Abnormalities

Risk Category Genetic Abnormality 5-Year Survival • t(8;21)(q22;q22.1); RUNX1-RUNX1T1 • inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Favorable 34% to 65% • Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow • Biallelic mutated CEBPA

• Mutated NPM1 and FLT3-ITDhigh • Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions) Intermediate 13% to 41% • t(9;11)(p21.3;q23.3); MLLT3-KMT2A • Cytogenetic abnormalities not classified as favorable or adverse

• t(6;9)(p23;q34.1); DEK-NUP214 • t(v;11q23.3); KMT2A rearranged high • t(9;22)(q34.1;q11.2); BCR-ABL1 • Wild-type NPM1 and FLT3-ITD • Mutated RUNX1 • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); Poor/Adverse • Mutated ASXL1 2% to 14% GATA2,MECOM(EVI1) Mutated TP53 • –5 or del(5q); –7; –17/abn(17p) • Complex karyotype, monosomal karyotype

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 12 12

2020 Spring PCE Oncology Series 4 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

MRCs in AML

• MRCs are characterized by a history of (MDS), significant morphologic dysplasia, or MDS-related cytogenetic features • Patients with MRCs have a worse prognosis • Can occur in patients with or without a history of MDS or myeloproliferative neoplasms (MPN) • Also includes AML with morphologic features or cytogenetic abnormalities characteristic of MDS

National Cancer Institute. www.cancer.gov/publications/dictionaries/cancer-terms/def/aml-mrc. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. 13 13

Optimizing Testing

• Communication between clinician and pathologist ensures necessary testing ‒ Pertinent patient history • Prior hematologic disorder or known predisposing conditions • Prior malignancy • Exposure to cytotoxic therapy, immunotherapy, radiotherapy, or other possibly toxic substances • Presence or absence of MRC ‒ Comprehensive genomic profiling at diagnosis for disease classification, risk stratification, prognosis, and treatment selection

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. Waterhouse M, et al. Biol Blood Marrow Transplant. 2011;17:1450-1459. 14 14

Case Study (cont’d): Tom’s Test Results

• ECOG PS: 1 • Cytogenetics: diploid karyotype 46,XY[20] • Bone marrow core biopsy: hypercellular marrow (90% cellularity) with 56% myeloblasts • Flow cytometry: CD33+/CD117+/HLA-DR+/MPO+/CD34− • Molecular studies: ‒ Wild-type CEBPA and NPM1 ‒ FLT3-ITD/wildtype allelic ratio of 0.55

ECOG PS = Eastern Cooperative Oncology Group performance status. 15 15

2020 Spring PCE Oncology Series 5 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

RATIFY: Frontline Standard 7+3 ± Midostaurin in FLT3-ITD and FLT3-TKD Mutated Disease

Median OS: Months (95% CI) Midostaurin Placebo 100 Complete remission by day 60 59% 53% 80 Midostaurin 74.7 (31.5-NR) Placebo 25.6 (18.6-42.9) Event-free survival (EFS) 8 months 3 months 60 4-year OS 51% 44%

40 Midostaurin is indicated for use in patients with 20 FLT3-mutated AML in combination with standard 1-sided P = .009 by stratified log-rank test cytarabine and daunorubicin induction therapy rbblt fSria (%) Survivalof Probability 0 and cytarabine consolidation therapy. 012 24 36 48 60 72 84 90

Patients at Risk, n Months Midostaurin 360 269 208 181 151 97 37 1 Placebo 357 221 163 147 129 80 30 1

CI = confidence interval; NR = not reported. Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; Stone RM, et al. N Engl J Med. 2017;377:454-464. 16 16

Case Study (cont’d)

• Because Tom has a FLT3-ITD mutation, induction chemotherapy is initiated with 7+3 (daunorubicin 60 mg/m2) and midostaurin 50 mg orally twice a day on days 8 to 21

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Standard 7+3 ± Midostaurin: AEs

• No statistically significant differences in grade 5 AEs between midostaurin and placebo ‒ Significantly more grade ≥3 anemia and rash vs placebo ‒ Significantly more nausea with placebo • AEs with 7+3 and midostaurin: febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection • Administer prophylactic antiemetics before treatment with midostaurin • Instruct patients to take with food; do not open or crush capsules • Consider interval assessments of QT if taken concurrently with that can prolong the QT interval

AE = adverse event. Cessna MH, et al. www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Rydapt [prescribing Information]. Novartis; 2019; Stone RM, et al. Blood. 2015;126:6; Stone RM, et al. N Engl J Med. 2017;377:454-464. 18 18

2020 Spring PCE Oncology Series 6 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Gemtuzumab Ozogamicin + Chemotherapy: OS by Risk Category

Annual event rates: Years 1 to 5 Years 6+ • Approved for newly diagnosed and R/R GO 5.8% SD 1.1 2.3% SD 1.3 CD33+ AML No GO 14.1% SD 1.9 0.0% SD 0.0 ‒ May be used in combination with 7+3 100

or as monotherapy in certain patients 77.5% 80 75.5% • Meta-analysis of 5 randomized controlled trials (N = 3325) 60 • Absolute survival benefit at 6 years 55.0% 54.8% 40 especially apparent in patients with

Estimated % Still Still % Alive Estimated 20 favorable cytogenetic characteristics – allocated GO (% ± SD) 20.7% SD 6.5 – allocated No GO (% ± SD) (log-rank P = .0006) 0 0 1 2 3 4 5 6+ Years Deaths/person-years: Favorable cytogenics GO 12/117 7/104 6/93 1/81 1/70 3/129 No GO 20/109 18/93 10/76 5/61 1/45 0/84

GO = ; SD = standard deviation. Hill RK, et al. Lancet Oncol. 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018. 19 19

Gemtuzumab Ozogamicin: AEs

• Prescribing information carries a boxed warning for hepatotoxicity, including severe or fatal VOD, also known as sinusoidal obstruction syndrome • VOD risk higher in patients: ‒ With moderate or severe hepatic impairment prior to receiving gemtuzumab ozogamicin ‒ Treated with gemtuzumab ozogamicin before or after HSCT • Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose • After treatment, monitor frequently for VOD signs/symptoms ‒ Elevations in ALT, AST, and total bilirubin ‒ Hepatomegaly ‒ Rapid weight gain ‒ Ascites

ALT = alanine transaminase; AST = aspartate aminotransferase; VOD = veno-occlusive disease. Hill RK, et al. Lancet Oncol. 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018. 20 20

CPX-351: Median OS in Newly Diagnosed Older Patients With High-risk Secondary AML

Events/No. Median survival • Approved for newly diagnosed, therapy- 100 of patients (95% Cl), months CPX-351 104/153 9.56 (6.60 to 11.86) related, or AML-MRC 7+3 132/156 5.95 (4.99 to 7.75) 80 HR, 0.69 One-sided P = .003 • Improved OS vs standard 7+3 in older

60 patients with high-risk secondary AML • Better outcomes after allogeneic HSCT 40 OS(%) in older patients with high-risk AML, 20 including 53% fewer deaths within 100 days of transplant

0 3 6 9 12 15 18 21 24 27 30 33 36 Time Since Random Assignment (months) No. at risk CPX-351 153 122 92 79 62 46 34 21 16 11 5 1 7+3 156 110 77 56 43 31 20 12 7 3 2 0

Lancet JE, et al. J Clin Oncol. 2018;36:2684-2692. 21 21

2020 Spring PCE Oncology Series 7 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

CPX-351: AEs

• Reported AEs are generally consistent with the known safety profile of cytarabine and daunorubicin therapy • Boxed warning against interchanging with other products containing daunorubicin or cytarabine • Associated with delayed neutrophil and platelet count recovery of 6 to 7 days • Administered as 90-minute infusion; potential to be given in outpatient setting

Lancet JE, et al. Blood. 2016;128:906; Lancet JE, et al. J Clin Oncol. 2016;34(15 Suppl):7000. US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm569883.htm. Accessed March 20, 2020; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019. 22 22

Case Conclusion

• After treatment with 7+3 and midostaurin, Tom achieves a CR as assessed by repeat bone marrow biopsy following recovery of blood count • Manageable side effects − Myelosuppression managed with transfusions, growth factors − Nausea and vomiting managed with antiemetic combinations • Tom is sent for allogeneic HSCT

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Case Study 2: Edith, 68 Years Old

• History of AML ‒ CR 4 months ago following 1 cycle of cytarabine with idarubicin and 3 cycles of intermediate-dose cytarabine for consolidation • Presents with extreme fatigue and pallor, sudden onset of shortness of breath ‒ ECOG PS: 2 ‒ Comorbid COPD • Complete blood count: ‒ WBCs: 1300 cells/mm3; absolute neutrophils: 570 cells/mcL; Hgb: 8.3 g/dL; platelets: 95,000/mm3 • Bone marrow biopsy consistent with relapse ‒ 80% cellular with 16% myeloblasts

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2020 Spring PCE Oncology Series 8 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Case Study (cont’d): Edith’s Test Results

• Molecular studies: ‒ IDH1 mutation-positive ‒ FLT3 negative ‒ NPM1 negative • Cytogenetics: 46,XX[20]

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Targeting IDH Mutations: Ivosidenib and Enasidenib in R/R AML

Ivosidenib Enasidenib • First-in-class oral targeted IDH1 inhibitor for R/R AML • First-in-class oral targeted IDH2 inhibitor for R/R AML • Also approved for newly diagnosed adults aged ≥75 years or • Single-arm trial in adult patients with R/R AML and with comorbidities precluding intensive induction chemotherapy IDH2 mutation • Single-arm trial in adult patients with R/R AML and • 19.3% of 176 patients achieved CR IDH1 mutation − 6.8% experienced CRp/CRi • 24.7% of 174 patients achieved CR • Boxed warning: IDH-DS ‒ 8.0% experienced CRh • Most common AEs of any grade: • Boxed warning: IDH-DS − Nausea, vomiting, diarrhea, elevated bilirubin, decreased • Most common AEs of any grade: appetite ‒ Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, ECG QT prolongation, rash, pyrexia, cough, constipation

CRh = complete remission with partial hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRp = complete remission with incomplete platelet recovery. DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Idhifa [prescribing information]. Celgene Corporation; 2019; Stein EM, et al. Blood. 2017;130:722-731; Tibsovo [prescribing information]. Agios Pharmaceuticals; 2019. 26 26

Case Study (cont’d): Edith’s Second-line Therapy

• You start Edith on ivosidenib for her relapsed AML • 4 weeks later, she is admitted to the hospital with shortness of breath, cough, diarrhea, and rapid weight gain despite loss of appetite • She believes the therapy is making her sicker and asks to discontinue treatment

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2020 Spring PCE Oncology Series 9 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

IDH-DS: Signs and Symptoms

• Leukocytosis, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, azotemia • Monitor closely when diagnosis is uncertain, as patients can rapidly deteriorate • For severe or rapidly progressing IDH-DS, hospitalize patient for management

DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Stein EM, et al. Blood. 2017;130:722-731. 28 28

Clinical Management of IDH-DS

• Promptly initiate corticosteroids when IDH-DS is first suspected; upon improvement, progressively reduce steroid dose ‒ Interrupt IDH inhibitor therapy at clinician’s discretion or if severe pulmonary symptoms and/or renal dysfunction persist after 48 hours of treatment ‒ Resume therapy when symptoms improve • In patients with elevated WBC count, promptly initiate hydroxyurea • Furosemide may be used for substantial fluid accumulations • Monitor patients with rapidly increasing peripheral blood cells for disseminated intravascular coagulopathy and hemorrhage

DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Fathi AT. ASCO 2017; Stein EM, et al. Blood. 2017;130:722-731. 29 29

Case Study (cont’d)

• 10 mg is initiated • Differentiation syndrome resolves after 48 hours of therapy • Edith agrees to continue ivosidenib • CR is achieved after 5 months of treatment

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2020 Spring PCE Oncology Series 10 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Venetoclax: CR/CRi and OS in Elderly or Frail Patients

BCL-2 inhibitor for newly diagnosed AML in adults age ≥75 or with comorbidities that preclude intensive induction therapy in combination with azacitidine, decitabine, or LDAC

Multicenter, Phase 1b Dose-escalation and Expansion Study

Composite Response Overall Response Rate Median Duration of Median OS Cohort N Rate, (CR + CRi) n (%) (CR + CRi + PR) n (%) CR + CRi (95% CI) (95% CI) All patients 145 97 (67) 99 (68) 11.3 (8.9-NR) 17.5 (12.3-NR) VEN 400 mg + HMA 60 44 (73) 44 (73) 12.5 (7.8-NR) NR (11.0-NR) VEN 800 mg + HMA 74 48 (65) 50 (68) 11.0 (6.5-12.9) 17.5 (10.3-NR)

• Common AEs (>30%): nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased WBC count • FDA warning of increased risk of death in investigational use in R/R multiple myeloma but not in approved indications

HMA = hypomethylating agent; VEN = venetoclax. DiNardo CD, et al. Blood. 2019;133:7-17; US Food and Drug Administration. www.fda.gov/Drugs/DrugSafety/ucm634120.htm. Accessed Mar 20, 2020. 31 31

Phase 1b/2 Study: Venetoclax + Low-dose Cytarabine in Previously Untreated Patients With AML

• Median OS = 10.1 months • Common grade ≥3 AEs: • Median DOR = 8.1 months – Febrile neutropenia (42%) • 54% of patients achieved CR/CRi – Thrombocytopenia (38%) • Patients without prior HMA exposure – Decreased WBC count (34%) – CR/CRi = 62% – Median DOR = 14.8 months – Median OS = 13.5 months

DOR = duration of response. Wei AH, et al. J Clin Oncol. 2019;37:1277-1284. 32 32

BRIGHT: Glasdegib in Elderly or Frail Newly Diagnosed Patients

Hedgehog pathway inhibitor; for newly diagnosed AML in adults aged ≥75 years or with comorbidities • CR that preclude intensive induction therapy − Glasdegib/LDAC: 17.0% (15/88) of • In combination with LDAC patients vs LDAC: 2.3% (1/44 ) of patients (P <.05) Randomized, International, Phase 2 BRIGHT 1003 Trial • Most common AEs (>20%) − Anemia, fatigue, hemorrhage, febrile 1.0 Median OS, months (80%) neutropenia, musculoskeletal pain, Glasdegib/LDAC 8.8 (6.9-9.9) 0.8 LDAC 4.9 (3.5-6.0) nausea, edema, thrombocytopenia, HR = 0.513 dyspnea, decreased appetite, 0.6 80% CI: 0.394-0.666, P = .0004 dysgeusia, mucositis, constipation, rash 0.4 • Boxed warning Glasdegib/LDAC 0.2 − Embryo-fetal death or severe birth

Survival Probability Survival LDAC defects when administered to pregnant 0.0 women 0 5 10 15 20 25 30 35 40 Time (months) HR = hazard ratio. Cortes JE, et al. Leukemia. 2019;33:379-389. 33 33

2020 Spring PCE Oncology Series 11 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

ADMIRAL: Gilteritinib vs Salvage Chemotherapy

Kinase inhibitor for R/R FLT3+ AML

Phase 3, open-label, multicenter, randomized trial Patients with FLT3-ITD or -TKD mutations randomized to gilteritinib (n = 347) or SC (n = 124) • Efficacy: ‒ OS: 9.3 months GIL; 5.6 SC (HR for death = 0.637; P = .0007) ‒ CR/CRh rate: 34.0% GIL; 15.3% SC (P = .0001) ‒ Median EFS: 2.8 months GIL; 0.7 months SC (HR 0.793; P = .0830) • Common grade ≥3 AEs for GIL: anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), decreased platelet count (12.2%) ‒ Serious treatment-emergent AEs less common with GIL (7.1%) vs SC (9.2%) • Boxed warning for GIL: differentiation syndrome

GIL = gilteritinib; SC = salvage chemotherapy (LDAC, azacitidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/GCSF/idarubicin). Perl AE, et al. AACR 2019. Abstract CT184; Xospata [prescribing information]. Astellas Pharma US, Inc; 2019. 34 34

AML and Patient Counseling

• In one survey, 67% of patients aged ≥60 years did not realize that there was more than one treatment option ‒ Respondents failed to understand their chances of cure, 1-year survival, or treatment-related mortality, regardless of final treatment choice • Educate patients and families on all appropriate treatments: risks and benefits, length of treatment, AE management, treatment expectations and perceptions ‒ Compared with chemotherapy, patients take longer to achieve CR on biologics such as enasidenib • Address any misconceptions and specific needs ‒ Financial assistance available for many therapies ‒ Current evidence on allogeneic HSCT in elderly patients with AML

Devillier R. https://ashpublications.org/blood/article/132/Supplement%201/209/261662/Allogeneic-Hematopoietic-Stem-Cell-Transplantation. Accessed March 20, 2020; LeBlanc TW, et al. J Clin Oncol. 2019;37(suppl):7040; Sekeres MA, et al. Leukemia. 2004;18:809-816; Stein EM, et al. Blood. 2017;130:722-731. 35 35

Case Conclusion

• Edith continues ivosidenib • Following blood count recovery, she proceeds to allogeneic HSCT

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2020 Spring PCE Oncology Series 12 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

Investigational Treatment Approaches in AML

• Second-generation FLT3 inhibitors • Immunotherapeutic agents − Crenolanib ‒ Bispecific T-cell engager − ‒ Dual affinity retargeting − CG-806 ‒ PD-1 inhibitors ‒ CTLA-4 inhibitors ‒ Chimeric antigen receptor therapies

PD-1 = programmed cell death protein 1. Broderick JM. www.onclive.com/web-exclusives/fda-panel-votes-against-quizartinib-approval-for-aml. Accessed Mar 20, 2020; Cortes JE, et al. Leukemia. 2019;33:379-389; Lichtenegger FS, et al. J Hematol Oncol. 2017;10:142; Liu H, et al. Front Immunol. 2017;8:38; Montesinos P, et al. J Clin Oncol. 2019;37(15 suppl):TPS7063. Papayannidis C, et al. Int J Mol Sci. 2019;20:e2721; Ternyila D. www.targetedonc.com/news/daver- investigates-combination-therapy-in-tp53-flt3mutated-aml. Accessed Mar 20, 2019; Zhang H, et al. AACR 2019. 37 37

QUAZAR AML Maintenance Trial: Design and Methods

• Randomized, double-blind, placebo-controlled trial investigating the epigenetic modifier CC-486 (oral formulation of azacitidine) in patients aged ≥55 years with AML in first remission following induction chemotherapy • Primary endpoint ‒ OS • Secondary endpoints ‒ RFS, health-related quality of life, safety • Patients randomized to receive CC-486 300 mg or placebo once daily on days 1 to 14 of repeated 28-day treatment cycles

RFS = relapse-free survival. Roboz GJ, et al. Future Oncol. 2016;12(3):293-301; Wei AH, et al. Blood. 2019;134(suppl 2):LBA-3. 38 38

QUAZAR AML Maintenance Trial: Results

• 472 patients (median age, 68 years) were randomized to receive CC-486 (n = 238) or placebo (n = 234) ‒ At median follow-up of 42 months, median OS from time of randomization with CC-486 and placebo was 24.7 months vs 14.8 months, respectively ‒ Median RFS with CC-486 and placebo was 10.2 months vs 4.8 months, respectively ‒ Most common grade 3/4 AEs: neutropenia (CC-486, 41%; placebo, 24%), thrombocytopenia (23% and 22%, respectively), and anemia (14% and 13%, respectively)

Roboz GJ, et al. Future Oncol. 2016;12(3):293-301; Wei AH, et al. Blood. 2019;134(suppl 2):LBA3. 39 39

2020 Spring PCE Oncology Series 13 Optimizing the Management of Acute Myeloid Leukemia: Individualized Therapy

CC-486 Maintenance Trial After Allogeneic HSCT: Design and Methods

• Phase 1/2 dose-finding study of CC-486 maintenance therapy after allogeneic HSCT in patients with AML or MDS who were in morphologic CR at the time of treatment initiation • Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles • Endpoints: safety, pharmacokinetics, incidence of graft-versus-host disease, relapse/progression rate, and survival

de Lima M, et al. Biol Blood Marrow Transplant. 2018;24:2017-2024. 40 40

CC-486 Maintenance Trial After Allogeneic HSCT: Results

• The intention-to-treat population consisted of 30 patients (median age, 64.5 years) who received ≥1 dose of CC-486 between July 2013 and November 2015 • At 19-month follow-up, median OS was not reached 1.0 Median OS was not reached 0.9 (NR, 95% CI 15.1 months, NR) in any dosing cohort; the range for all patients was 0.8 86 to 1324 days 0.7 • Rate of relapse or progressive disease during 0.6 treatment in 28 assessable patients: 21% 0.5 0.4 • 1-year cumulative incidence of acute or chronic 0.3 graft-versus-host disease: 50% Censored Survival Probability Survival 0.2 • Grade 3/4 AEs were uncommon and occurred with 0.1 similar frequency across the dosing regimens 0.0 0 6 12 18 24 30 36 42 48 Patients 30 25 23 19 12 5 3 1 at Risk Time (months)

de Lima M, et al. Biol Blood Marrow Transplant. 2018;24:2017-2024. 41 41

PCE Action Plan

 Consider patient factors and preferences when establishing treatment goals for AML  Risk-stratify patients by karyotype and genetic abnormalities in order to help predict remission, relapse, and OS  Order comprehensive genomic profiling at both diagnosis and relapse, as genomic alterations can evolve throughout the disease course  Enhance shared decision-making by addressing patient and family perceptions and knowledge of all appropriate treatments

PCE Promotes Practice Change

42 42

2020 Spring PCE Oncology Series 14 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

1

Learning Objectives

• Identify novel agents used in the treatment of relapsed/refractory (RR) multiple myeloma (MM) and guideline recommendations for their use • Apply established criteria to identify patients who have developed RRMM and individualize therapy based on relevant patient- and disease-related characteristics • Use current recommendations for monitoring and managing treatment-related AEs in patients with RRMM

AE = adverse event. 2 2

Multiple Myeloma

• B-cell–derived plasma cell disorder ‒ Clonal proliferation of immunoglobulin (Ig)-secreting malignant plasma cells in bone marrow ‒ Secretion of M-protein into blood or urine • Abnormal Ig or Ig fragment; also called monoclonal protein, myeloma protein, or paraprotein ‒ Associated end-organ dysfunction • 32,270 new cases expected in the United States in 2020 • Median age at diagnosis is ~69 years, but 37% of patients are aged <65 years • Novel treatments have improved survival for newly diagnosed MM, but relapse is still expected ‒ 2-year survival rate (all patients): 87.1% in 2012, up from 69.9% in 2006 ‒ 5-year survival rate (all patients): 54% in 2009-2015, up from 27% in 1987-1989 • Important to use the best therapies in front-line treatment: treatment-free intervals are shorter with each subsequent line of therapy American Cancer Society. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html. Accessed Mar 23, 2020; Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020; Fonseca R, et al. Leukemia. 2017;31:1915-1921; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020; Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060; Yong K, et al. Br J Haematol. 2016;175:252-254. 3 3

2020 PCE Spring Oncology Series 1 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Progress in Treating Multiple Myeloma

Preclinical and Clinical Studies Leading to FDA Approvals in MM

2006 2012,2012, 20152015 2015 2020 Improvement in OS From Median Thalidomide CarfilzomibCarfilzomib Panobinostat of 3 to 8 to 10 Years 1.0 1960-65 0.9 2005 2010 2015 2020 1965-70 1970-75 0.8 1975-80 0.7 1980-85 2003, 2005, 2008 2007 2013, 2015 2019 1985-90 Bortezomib (BTZ) (BTZ) Doxil + Pomalidomide Selinexor 0.6 1990-95 BTZ 1995-00 0.5 2015 2000-05 Ixazomib 2005-10 Ixazomib 0.4

2006, 2014 2015 2015 0.3 Lenalidomide rprin SurvivingProportion 0.2

0.1 Immunomodulatory agent Proteasome inhibitor XPO1 inhibitor 0.0 HDAC inhibitor 0 2 4 6 8 10 12 14 16 18 20

OS = overall survival; XPO1 = exportin 1. Follow-up From Diagnosis (years) Adapted with permission from Anderson KC. Clin Cancer Res. 2016;22:5419-5427. 4 4

Myeloma Can Be Treated, But Not Cured

Asymptomatic Symptomatic Relapsing Refractory Disease may respond or become refractory at any point

Active Relapse → myeloma

Relapse MGUS or

M-Protein Level Level M-Protein indolent myeloma Remission 1st-line 2nd- or 3rd- 4th-line 4th-20th-line therapy line therapy therapy therapy ← 2-3 years ← 1-2 years ← 1-2 years ← 6 months-1 year → → → →

MGUS = monoclonal gammopathy of unknown significance. Adapted from: Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020. 5 5

Response and Survival in RRMM

12 Response Duration With Subsequent 100 Survival Outcomes Lines of Treatment Median, Months 10 80 Events, n/N (range) OS 170/286 9 (7-11) 8 217/286 5 (4-6) 60 EFS

6 40

4 (%) Patients 20 2

0 0 First Second Third Fourth Fifth Sixth 0 12 24 36 48 60 Median Response Duration (months) ResponseDuration Median Treatment Regimen Months

EFS = event-free survival. Kumar SK, et al. Leukemia. 2012;26:149-157; Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. 6 6

2020 PCE Spring Oncology Series 2 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

International Myeloma Working Group: Standard Response Criteria

Criteria Definition MRD-negative In patients who have achieved ≥CR, MRD negative in bone marrow by NGS plus disappearance of areas of disease previously seen on FPG-PET/CT Stringent CR CR and normal FLC ratio, absence of clonal cells in bone marrow biopsy by IHC CR Negative immunofixation on serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirate VGPR Serum and urine M-protein detectable on immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 h

PR ≥50% reduction of serum M-protein plus ≥90% reduction in urine M-protein or to <200 mg/24 h

Minimal response ≥25% but ≤49% reduction in serum M-protein and reduction in 24 h urine M-protein of 50% to 89%

Stable disease No evidence of disease response or progression

CR = complete response; FDG PET/CT = fluorodeoxyglucose positron emission tomography-computed tomography; FLC = free light chain; IHC = immunohistochemistry; MRD = minimal residual disease; NGS = next-generation sequencing; PR = partial response; VGPR = very good partial response. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 7 7

Major Classes of Treatment Used in Multiple Myeloma

IMiDs PIs mAbs Others Agents in • Lenalidomide (R) • Bortezomib (V) • Daratumumab (D) • HDI: Panobinostat (F) class • Pomalidomide (P) • Carfilzomib (K) • Isatuximab • XPO1: Selinexor (abbreviation) • Thalidomide (T) • Ixazomib (N, I) • Elotuzumab (E)

Mechanism of • Antiangiogenic and • Promote • Daratumumab • Panobinostat: action anti-inflammatory • Inhibit osteoclast and Isatuximab: Damages DNA and properties formation CD38-mediated upregulates apoptosis- • CD-4+/CD-8+ T-cell • Increase osteoblast apoptosis promoting proteins enhancement creation and • Elotuzumab: • Selinexor: Inhibits • NK cell function SLAMF7-mediated growth and promotes augmentation NK cell apoptosis by blocking enhancement actions of XPO1

HDI = histone deacetylase inhibitor; mAbs = monoclonal antibodies; NK = natural killer; PI = protease inhibitor; SLAMF7 = signaling activation molecule F7. Bahlis NJ, et al. Blood. 2018;132:2546-2554; Cook G, et al. Crit Rev Oncol Hematol. 2018;121:74-89; Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060. 8 8

Current Treatment Paradigm for Active Myeloma

SCT Eligible Induction SCT/Consolidation Maintenance

Diagnosis Managing and Risk Relapse Stratification SCT Induction Followed by Ineligible Continuous Maintenance Therapy

Tumor Burden

SCT = stem-cell transplant. 9 9

2020 PCE Spring Oncology Series 3 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Case Study 1: Jean, 68 Years Old

History • Diagnosed with MM 4 years ago • Standard-risk cytogenetics: t(6;14) • Front-line treatment ‒ Bortezomib/lenalidomide/low-dose dexamethasone (VRd): achieved VGPR ‒ Successful ASCT with melphalan 200 mg/m2: achieved CR ‒ Lenalidomide 10 mg maintenance treatment

Finding 4 Months Ago 2 Months Ago Serum M-protein 0.1 g/dL 0.2 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL Hgb 12.5 g/dL 10.9 g/dL Bone lesions None None

ASCT = autologous stem-cell transplant; Hgb = hemoglobin. 10 10

Case Study (cont’d): Today’s Visit

• 20 months after starting lenalidomide maintenance, Jean presents with pain in her ribs and back • Otherwise good health, but has residual PN from VRd; Jean says it is still slowly improving • Bone marrow biopsy: 14% bone marrow plasma cells, 50% increase over last biopsy • ECOG PS = 1

Finding 4 Months Ago 2 Months Ago Today Serum M-protein 0.1 g/dL 0.2 g/dL 0.9 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL 2.0 mg/dL Hgb 12.5 g/dL 10.9 g/dL 9.5 g/dL Bone lesions None None Osteolytic lesions on X-ray

ECOG PS = Eastern Cooperative Oncology Group performance status; PN = peripheral neuropathy. 11 11

MM Cytogenetic Changes Over Time May Impact Prognosis

• Myeloma evolves over time in response to treatment, epigenetics, and other factors • Presence of high-risk cytogenetics at diagnosis is associated with higher rates of clonal evolution • High-risk clones can develop de novo after successful front-line therapy and ASCT ‒ High-risk deletion 17p and gain 1q21 mutations • Development of high-risk mutations associated with poor prognosis • Acquired del17p associated with significantly shorter PFS and OS ‒ Lower-risk translocations; eg, t(11;14) or t(6;14) (rare)

PFS = progression-free survival. Bianchi G, Ghobrial M. Curr Cancer Ther Rev. 2014;10:70-79; Lakshman A, et al. Blood Adv. 2019;3:1930-1938; Merz M, et al. Haematologica. 2017;102:1432-1438. 12 12

2020 PCE Spring Oncology Series 4 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

mSMART: Risk Classification of MM

Standard Risk High Risk** • All others, including: High-risk genetic • RISS stage 3 – Trisomies abnormalities by FISH or • High plasma-cell S phase equivalent – t(11:14)* • Gene expression profiling: • t(4:14) – t(6:14) High-risk signature • t(14:16) Jean now • Double-hit: any 2 high-risk Jean at diagnosis • t(14:20) genetic abnormalities • del(17p) • Triple-hit: ≥3 high-risk • p53 mutation genetic abnormalities • 1qgain

*t(11;14) may be associated with plasma cell leukemia; **Trisomies may ameliorate risk. FISH = fluorescent in situ hybridization; mSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; RISS = Revised International Staging System. Mayo Clinic.static1.squarespace.com/static/5b44f08ac258b493a25098a3/t/5b802d8270a6adbc6a79a678/ 1535126914646/Risk+Strat+3.0rev_svr.pdf. Accessed Mar 23, 2020. 13 13

Relapse Patterns in Multiple Myeloma

Clinically symptomatic disease with increase Extramedullary disease in M-protein

Four patterns of relapse

Plasma cell leukemia Asymptomatic disease characterized by increase in M-protein

Alegre, et al. Haemotologica. 2002; 87:609-614. 14 14

Biochemical Relapse: IMWG Criteria

Biochemical relapse identified due to improved monitoring can catch progression before development of clinical symptoms • 25% increase from the lowest response value in ≥1of the following: ‒ Serum M-protein • Absolute increase ≥0.5 g/dL or • Increase ≥1 g/dL if the lowest M-protein level was ≥5 g/dL ‒ Urine M-protein: absolute increase ≥200 mg/24 hours ‒ For patients without measurable serum or urine M-protein levels • Difference between involved and uninvolved FLC levels: absolute increase >10 mg/dL • Absolute increase >10% in percentage of bone marrow plasma cells • Development of new lesions, increase in size of existing lesions,* or ≥50% increase in circulating plasma cells (minimum 200 cells/mcL) if only measure of disease

*50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in the short axis. IMWG = International Myeloma Working Group; SPD = sum of the products of the maximal perpendicular diameters. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 15 15

2020 PCE Spring Oncology Series 5 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Clinical Relapse: IMWG Criteria

≥1 of the following: CRAB criteria: a mnemonic for myeloma-related organ dysfunction: • CRAB features C = calcium elevation: >11.5 mg/dL • Size* increase in existing (or development R = renal disease: serum Cr >2 mg/dL of new) soft tissue plasmacytomas or A = anemia: Hgb <10 g/dL or >2 g/dL bone lesions (not new osteoporotic fractures) below LLN • Hgb reduction ≥2 g/dL unrelated to MM B = bone lesions: ≥1 osteolytic lesion therapy or other conditions • Serum creatinine increase ≥2 mg/dL attributable to MM • Hyperviscosity related to serum paraprotein

*50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 16 16

IMWG: High-Risk Disease Characteristics in Relapsed or Relapsed/Refractory Disease

• Adverse cytogenetic features • Complex karyotypes

• High β2 microglobulin (>5.5 mg/L) or low albumin (<3.5 mg/dL) • LDH above normal • Circulating plasma cells • Extramedullary disease • Short duration of response (DOR) to prior therapy or progression on current therapy • Aggressive clinical features: rapid symptom onset, extensive disease, CRAB features

LDH = lactate dehydrogenase. Dingli D, et al. Mayo Clin Proc. 2017;92:578-598; Laubach J, et al. Leukemia. 2016;30:1005-1017. 17 17

IMWG: Principles of Treating Progressive Disease

When to Treat • Clinical (symptomatic) relapse: CRAB criteria • Rapidly rising M-protein levels (eg, monoclonal peak doubling time ≤3 months) • Extramedullary disease • Early relapse, high-risk cytogenetics • Threatened organ function (ie, renal dysfunction)

Laubach L, et. al Leukemia. 2016;30:1005-1017. 18 18

2020 PCE Spring Oncology Series 6 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Before Changing or Initiating Therapy

• Make sure the patient has actually progressed − Repeat myeloma lab tests − Don’t compare results from different labs • Characterize the relapse − Asymptomatic biochemical (indolent) vs symptomatic clinical − Slow vs rapid − Early vs late

19 19

Selecting Treatment for RRMM: General Principles

• Duration of initial response informs the biology of RRMM • Regimen: triplet* (eg, KRd) is preferred over doublet ‒ Include ≥1 agent from a new or non-refractory class ‒ Previously used agents may be effective in different combinations • When selecting therapy and optimal doses, consider ‒ Disease risk, ECOG PS, age, comorbidities ‒ Bone marrow biopsy at each relapse to reassess risk ‒ Prior and residual toxicities • Treat to maximum response and maintain on ≥1 agent until progression or intolerability

*Two active classes plus dexamethasone. Laubach L, et al. Leukemia. 2016;30:1005-1017; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020; Sonneveld P, Broijl A. Haematologica. 2016;101:396-406. 20 20

Establish the Goals of Treatment for the Patient

• Balance treatment efficacy with Patient characteristics Prior therapy •Goals of treatment • Prior ASCT? impact on QoL •Age/frailty • Prior IMiDs? PIs? − May not need a regimen with a •Performance status • Depth/DOR high CR rate •Lifestyle/mobility • Time to progression? − Stable disease is an excellent •Comorbidities • Toxicities goal of therapy for many patients with RRMM Disease characteristics ‒ Little difference in clinical • Cytogenetics consequences between stable • CRAB present disease and CR • Extramedullary disease • Aggressive features • Short DOR

QoL = quality of life. 21 21

2020 PCE Spring Oncology Series 7 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Recent FDA Approved Agents and Combinations

≥2 Prior Courses

≥1 or 1 to 3 Prior Courses Daratumumab + pomalidomide + dexamethasone ≥1: Carfilzomib monotherapy (PX-171–003; FOCUS) Isatuximab + pomalidomide + dexamethsone 1-3: Carfilzomib + lenalidomide + dexamethasone (ASPIRE) Elotuzumab + pomalidomide + 1-3: Carfilzomib, dexamethasone (ENDEAVOR) dexamethasone (ELOQUENT-3)

≥1: Daratumumab + either lenalidomide or bortezomib + dexamethasone Pomalidomide + dexamethasone (POLLUX & CASTOR) Panobinostat + bortezomib + ≥1: Ixazomib + lenalidomide + dexamethasone (TOURMALINE-MM1) dexamethasone (PANORAMA-1)

1-3: Elotuzumab + lenalidomide + dexamethasone (ELOQUENT- 2) ≥3 or ≥4 Prior Courses

≥3: Daratumumab monotherapy (SIRIUS)

≥4: Selinexor + dexamethasone (STORM)

Attal M, et al. Lancet. 2019;394:2096-2107; Chari A, et al. Blood. 2017;130:974-981; Chari A, et al. ASH 2018. Abstract 598; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Dimopoulos MA, et al. N Engl J Med. 2016;375:1319-1331; Dimopoulos MA, et al. N Engl J Med 2018; 379:1811-1822; Hájek, et al. Leukemia. 2017;31:107-114; Lonial S, et al. Lancet. 2016;387:1551-1560; Lonial S, et al. N Engl J Med 2015; 373:621-631; Moreau P, et al. N Engl J Med. 2016; 374:1621-1634; Palumbo A, et al. N Engl J Med. 2016; 375:754-766; San-Miguel, et al. Lancet Haematol. 2016;3:e506-e515; Stewart K, et al. N Engl J Med. 2015; 372:142-152; Vij, et al. Br J Haematol. 2012;158:739–748. 22 22

Summary: mSMART Recommended Approaches After First Relapse

On Maintenance* Off Therapy/Unmaintained* Triplet Preferred: Add ≥1 New Agent, or Next Generation Agent Indolent Relapse From Same Class Fit Patients or Frail Patients Indolent Relapse Fit Patients or Frail Patients • KRd • IRd If lenalidomide maintenance: If lenalidomide maintenance: • DaraRd • EloRd • KPomD • DaraVd • PomD • DaraVd • Id + cyclophosphamide If bortezomib maintenance: If bortezomib maintenance: • DaraRd • IRd • DaraRd

*Consider salvage ASCT in eligible patients who have not had a previous ASCT. Consider second ASCT in eligible patients if response has been >18 months (unmaintained) or >36 months (maintained). DaraRd = daratumumab, lenalidomide, dexamethasone; DaraVd = daratumumab, bortezomib, dexamethasone; EloRd = elotuzumab, lenalidomide, dexamethasone; Id = isatuximab, dexamethasone; IRd = isatuximab, lenalidomide, dexamethasone; K/PomD = carfilzomib, pomalidomide, dexamethasone; PomD = pomalidomide, dexamethasone. Dingli D, et al. Mayo Clin Proc. 2018;92:578-598. 23 23

Ranking of Treatments Based on Meta-analysis Results

Botta C, et al. Blood Adv. 2017;1:455-466. 24 24

2020 PCE Spring Oncology Series 8 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Case Study (cont’d)

• Jean was retreated with VRd and achieved a partial response at 6 months; she presents now with complaints of persistent fatigue, shortness of breath, swelling of ankles, and bone pain in lower legs • Updated cytogenetics: unchanged—still high-risk del(17p) • Current laboratory measurements

Finding At Diagnosis 6 Months Ago Today Serum M-protein 0.9 g/dL 0.6 g/dL 1.2 g/dL Serum creatinine 2.0 mg/dL 1.6 mg/dL 2.1 mg/dL Serum calcium — 10.2 mg/dL 11.6mg/dL Hgb 11.0 g/dL 11.0 g/dL 10.2 g/dL Bone marrow — <10% plasma cells 16%plasma cells

25 25

Relapsed vs Refractory Disease

• Relapsed/refractory MM: progression on therapy after achieving at least minor response or progression within 60 days of most recent therapy • Primary refractory MM: progression on therapy without achieving at least minor response • Relapsed MM: meets IMWG criteria for progressive disease but does not fit definition of RR or primary refractory

Nooka AK, et al. Blood. 2015;125:3085-3099. 26 26

Administration Considerations for PIs

Bortezomib (V) Carfilzomib (K) Ixazomib (N, I) Route* SC** IV Oral Select AEs to assess PN Cardiac failure Thrombocytopenia Hypotension Renal insufficiency GI toxicity Cardiac toxicity Pulmonary toxicity, dyspnea Peripheral neuropathy Pulmonary toxicity Hypertension Rash GI toxicity Venous thrombosis Hepatotoxicity Thrombocytopenia Hemorrhage Neutropenia Thrombocytopenia Hepatic toxicity Rate of PN with PI + Rd Any grade: 35% Any grade: 11% Any grade: 28% Grade 3 or 4: 8% Grade ≥3: 2% Grade ≥3: 2% Management Monitor CBC; safe in renal failure, Monitor hydration, cardiopulmonary Reduce dose for hepatic/renal considerations herpes prophylaxis toxicities, herpes prophylaxis disease, herpes prophylaxis

*Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **An IV formulation is available but is not recommended for use. AE = adverse event; CBC = complete blood count; Rd = lenalidomide/low-dose dexamethasone. Kyprolis [prescribing information]. Amgen; 2019; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020; Ninlaro [prescribing information]. Takeda; 2020; Velcade [prescribing information]. Millennium Pharmaceuticals, Inc; 2019. 27 27

2020 PCE Spring Oncology Series 9 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Administration Considerations for mAbs

Daratumumab (D, Dara) and Isatuximab (Isa) Elotuzumab (E, Elo) Route* IV IV

AE prophylaxis Pre/post with corticosteroids, antipyretics, and 60 to 90 min before infusion, administer antihistamines; oral steroid may not be needed after infusion corticosteroids, H1 blocker, H2 blocker, if used in combinations that include dexamethasone acetaminophen ± Inhaled steroids for patients with COPD (Dara) Select AEs to assess Infusion reactions Infusion reactions Interference with cross-matching, red blood cell antibody Infection** screening, and determination of CR Second primary malignancy Infection** Hepatotoxicity Neutropenia, thrombocytopenia Interference with determination of CR Management For infusion reaction risk, pre/post medicate as directed; interrupt infusion if reaction occurs considerations Monitor CBC periodically during treatment with Dara and Isa; monitor during neutropenia for infection; dose delay with Dara or Isa may be required to allow neutrophil recovery Monitor patients during treatment for second primary malignancies, per IMWG guidelines (lsa, Elo)

*Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **Patients should receive varicella zoster virus prophylaxis when receiving daratumumab or elotuzumab. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Sarclisa [prescribing information]. Sanofi-aventis US; 2020. 28 28

Administration Considerations for XPO1 Inhibitor

Selinexor Route and dosage Oral, 80 mg days 1 and 3 of each week when combined with dexamethasone Frequent AEs (>20%) Thrombocytopenia, fatigue, nausea, anemia, decreased appetite/weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and URI Select AEs to assess Thrombocytopenia Neutropenia Considered highly emetogenic; GI adverse reactions, especially nausea Hyponatremia Infections Management Monitor patients for cytopenia, neutropenia, hyponatremia, infections considerations Provide antiemetic prophylaxis May cause dizziness or confusion; optimize hydration, blood counts, and concomitant medications to minimize risk Dose reductions (if needed for hematologic/non-hematologic toxicity) • First: 100 mg once weekly • Second: 80 mg once weekly • Third: 60 mg once weekly (discontinue after third reduction)

URI = upper respiratory infection. Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 29 29

Cardiotoxicity With PIs: Is This a Class Effect?

• Patients with MM are at increased risk for CV complications due to disease factors and comorbidity • Cardiotoxicity increased with irreversible inhibition of ubiquitin-proteasome system ‒ Pre-existing uncontrolled hypertension or left ventricular hypertrophy increase risk for CVAE with carfilzomib • Note: PIs often are used in combination with other agents that also may affect CV function (eg, IMiDs) Bortezomib Carfilzomib Ixazomib • MoA: Reversible PI inhibition • MoA: Irreversible PI inhibition • MoA: Reversible PI inhibition Analysis of 8 myeloma studies (N = 3954), ENDEAVOR (phase 3, N = 929) TOURMALINE Grade ≥3 CVAE: Grade ≥3 with bortezomib: • Grade ≥3 hypertension • N = 361 IRd; 359 Rd patients • HF: 1.3% to 4.7% • 9% carfilzomib, 3% bortezomib • Arrhythmia: 6%; 4% • Arrhythmia: 0.6% to 4.1% • Any grade hypertension • Thromboembolism: <3%; <4% • Ischemic HD: 0.4% to 2.7% • 20.3% carfilzomib, 8.1% bortezomib • HF: 3%; 2% • Cardiac death: 0 to 1.4% • MI: <1%; <2% • No significant differences between bortezomib and placebo patients CV = cardiovascular; CVAE = cardiovascular adverse event (heart failure, hypertension, ischemia, arrhythmia); HD = heart disease; HF = heart failure; MI = myocardial infarction; MoA = mechanism of action; RCT = randomized controlled trial; RR = relative risk of CVAE for patients receiving carfilzomib compared with non–carfilzomib-receiving control patients. Bruno G, et al. Cancers (Basel). 2019;11:pii E622; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Laubach JP, et al. Br J Haematol. 2017;178:547- 560; Li W, et al. JAMA Oncol. 2017;3:980-988; Moreau P, et al. N Engl J Med. 2016;374:1621-1634; Plummer C, et al. Blood Cancer J. 2019;9:26; Waxman AJ, et al. JAMA Oncol. 2018;4:e174519. 30 30

2020 PCE Spring Oncology Series 10 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Assessing for Cardiotoxicity: Proactive Monitoring and Clinical Management of CV Events With Carfilzomib

Strategy Suggestions Baseline CV risk • Assess risk, obtain ECG, and determine need for cardiology consultation assessment and • Control hypertension ongoing monitoring • Review prior history of anthracyclines or other cardiotoxic agents • Consider reduced fluid volume in cycle 1 if high CV risk, and adjust in subsequent cycles Intervention • Withhold carfilzomib for grade 3/4 CVAE until resolved or improved to baseline • Consider restarting carfilzomib therapy at 1 dose level reduction based on a benefit-risk assessment after consulting a cardiologist • When resuming therapy, consider follow-up echocardiograms and/or biomarkers (eg, BNP or NT-proBNP) based on cardiologist recommendations Patient education • Encourage recognition and prompt reporting of symptoms of CV decompensation • Recommend routine BP monitoring, keeping a daily record

BNP = B-type natriuretic peptide; NT-proBNP = N-terminal pro hormone BNP. Jakubowiak AJ, et al. Hematology. 2017;22:585-591; Plummer C, et al. Blood Cancer J. 2019;9:26. 31 31

Factor Patient’s Treatment History and Comorbid Conditions Into Treatment Decisions

• Most patients are older and have preexisting comorbid conditions: up to 69% have preexisting CV disease • Consider response and toxicity with previous lines of therapy • Consider disease factors that increase risk of CV complications, including renal impairment and anemia • Factor possible CV and other toxicities with recommended treatments into treatment decisions

Plummer C, et al. Blood Cancer J. 2019;9:26. 32 32

Case Study (cont’d)

• Jean expresses a preference for oral treatment over repeated infusions ‒ You explain that ixazomib carries a small risk for grade 3 PN that carfilzomib does not have ‒ Jean still would prefer an all-oral regimen • She is prescribed ixazomib + PomD ‒ You recommend loperamide OTC to minimize diarrhea with treatment ‒ You and Jean create a dosing calendar to aid adherence with the dosing schedule of her different medications

33 33

2020 PCE Spring Oncology Series 11 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Example of Calendar for All-Oral Regimen

28-Day Cycle (4-Week Cycle)

Week 1 Week 2 Week 3 Week 4

Treatment Day 1 Days 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 23-28

Ixazomib Yes ✓ No Yes ✓ No Yes ✓ No No No

Pomalidomide Yes ✓ Daily ✓ Yes ✓ Daily ✓ Yes ✓ Daily ✓ No No

Dexamethasone Yes ✓ No Yes ✓ No Yes ✓ No Yes ✓ No

Ninlaro [prescribing information]. Takeda; 2020; Pomalyst [prescribing information]. Celgene; 2019. 34 34

Myelosuppression: Frequent With IMiDs and mAbs*

• Expect cytopenia to occur and manage patient expectations • Increased risk of infection, poorer QoL, and treatment interruption • Use transfusions and growth factors as appropriate

Criteria Lenalidomide Criteria Pomalidomide • Platelets <30K/mcL • Interrupt treatment; • Platelets <25K/mcL • Interrupt treatment; • Recovery ≥30K/mcL follow CBC weekly • Recovery >50K/mcL follow CBC weekly • Resume at next lower • Resume at 3 mg/day dose** • ANC <500/mcL or • Interrupt treatment; • ANC <1K/mcL • Interrupt treatment; febrile neutropenia follow CBC weekly follow CBC weekly • Recovery ≥1K/mcL • Recovery ≥500/mcL • Resume at 3 mg/day • Resume at 25 mg or • Subsequent drops in • Interrupt; with recovery starting dose** platelets or ANC resume at 1 mg less than • Subsequent drops in • Interrupt; with recovery previous dose platelets or ANC resume next lower dose

*Dose modifications for myelosuppression are not indicated with mAbs; **Do not use dose <2.5 mg/day. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Pomalyst [prescribing information]. Celgene; 2019; Revlimid [prescribing information]. Celgene; 2019. 35 35

Toxicity Management

Side Effect Clinical Management Cardiopulmonary • Assess risk at baseline • Provide patients/caregivers with contact info and guidelines for reportable signs/symptoms, along with prevention and treatment strategies Constipation • Hydration, diet, stool softeners/laxatives Diarrhea • Hydration, diet, antidiarrheal agents, dose modify if needed Fatigue • Counsel patients on exercise, sleep, stress reduction; assess and treat for depression, if indicated; review concurrent meds Rash • Treat symptoms with topical agents and antihistamines • Discontinue drug for rare severe drug reactions Peripheral neuropathy • Educate patients on early symptoms and reporting to medical staff • Modify bortezomib dose per prescribing information for peripheral neuropathy grade ≥2

Brigle K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):60-76; Catamero D, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):7-18; Faiman B, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):19-36; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; Noonan K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):37-46; Velcade [prescribing information]. Millennium Pharmaceuticals; 2019. 36 36

2020 PCE Spring Oncology Series 12 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Toxicity Management (cont’d)

Side Effect Clinical Management Thromboembolic events • Baseline risk assessment, including personal and family history Risk factors: • For patients receiving IMiDs: • Older age − Low risk (<2 risk factors): full-dose aspirin • History of thrombotic event − High risk (≥2 risk factors) or IMiD combined with high-dose dexamethasone: • Obese LMWH or full-dose warfarin (target INR 2-3) • Immobilized • Educate patients on preventive strategies and early detection • CV/renal disease • Can consider DOACs, although not well studied in this population • Diabetes

Infusion reactions • Premedicate according to prescribing information • Ensure a hypersensitivity reaction protocol is in place

DOAC = direct oral anticoagulants; INR = international normalized ratio; LMWH = low-molecular-weight heparin. Gleason C, et al. J Adv Pract Oncol. 2016;7(suppl 1):53-57; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Cancer-associated venous thromboembolic disease. www.nccn.org. Accessed Mar 24, 2020; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Noonan K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):37-46. 37 37

Treatment Considerations: Special Populations

Patient Population Considerations Frail, elderly patients • Standard 3-drug regimens; use dose reductions to improve tolerability • Alternate: doublet therapy with Rd or use melphalan/bortezomib/prednisone Renal dysfunction • Bortezomib + IMiD: no dose adjustment needed with pomalidomide; adjust lenalidomide based on CrCl • Other options: bortezomib/daratumumab with high-dose dexamethasone or melphalan/bortezomib/prednisone Cardiac dysfunction • Avoid carfilzomib with preexisting uncontrolled hypertension or advanced HF • Use thromboprophylaxis with IMiD-based therapy Aggressive, high-risk • Consider induction with carfilzomib/Rd disease • Consider VTD-PACE and ASCT for extramedullary disease or PCL Peripheral neuropathy • Administer bortezomib SC using weekly dosing • Treatment with carfilzomib or ixazomib plus Rd

CrCl = creatinine clearance; VTD-PACE = bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; PCL = plasma cell leukemia. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Richter J, et al. Hematol Oncol. 2017;35:246-251. 38 38

Infection Prophylaxis

• Keep current on appropriate vaccinations, including annual flu vaccine ̶ Inactivated vaccines are safe for use • Herpes prophylaxis when receiving PIs or mAbs: acyclovir, famciclovir, valacyclovir ‒ HSV: consider during active therapy, possibly longer ‒ Herpes zoster (VZV): at least 6 to 12 months after ASCT; safe to use inactivated vaccine (Shingrix) in patients with MM • PJP/herpes/antifungal prophylaxis if using high-dose dexamethasone • Pneumococcal vaccine: PCV13, then PPV23 1 year later • IVIG in setting of recurrent, life-threatening infections • Counsel patients to alert treating clinicians to potential infection symptoms, to reduce unnecessary antibiotics

HSV = herpes simplex virus; IVIG = intravenous immunoglobulin; PCV = pneumococcal conjugate vaccine; PJP = Pneumocystis jiroveci pneumonia; PPV = pneumococcal polysaccharide vaccine; VZV = varicella zoster virus. Delforge M, et al. Blood. 2017;129:2359-2367; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; NCCN Guidelines. Infection prevention. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020. 39 39

2020 PCE Spring Oncology Series 13 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Supportive Care for Bone Disease

NCCN: All patients should receive bisphosphonates or denosumab

• Bisphosphonates: pamidronate and zoledronic acid ‒ Similar efficacy, greater ONJ risk with zoledronic acid ‒ Monitor for renal impairment on bisphosphonates • SC denosumab preferred when renal disease is present ‒ May be given monthly; efficacy similar to zoledronic acid • Other supportive care ‒ Baseline dental exam and ONJ monitoring for all patients using a bone-modifying therapy ‒ Orthopedic consult if long-bone fracture present or imminent; consider vertebroplasty or kyphoplasty for vertebral compression fracture

ONJ = osteonecrosis of the jaw. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020 40 40

Other Supportive Care Recommendations

Condition Adjunctive Treatment

Hypercalcemia • Hydration, bisphosphonates (zoledronic acid preferred), denosumab, steroids, and/or calcitonin Anemia • Perform type and screen before using daratumumab if transfusions indicated

Liver function • Monitor for hepatotoxicity with PIs, IMiDs, daratumumab

Renal • Monitor patients on carfilzomib for acute renal failure dysfunction • Monitor renal function in patients on bisphosphonates • Adequate hydration • Plasmapheresis (although not generally useful) • Avoid NSAIDs, intravenous contrast

NSAIDs = nonsteroidal anti-inflammatory drugs. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020 41 41

Assess Toxicity Risk and Implement Management Strategies

• Evaluate patient for unresolved toxicities • Evaluate risk for new or progressive toxicities with continued treatment • Incorporate recommended prophylaxis – Low-dose aspirin for thromboprophylaxis with IMiDs – Herpes prophylaxis prior to PIs or mAbs • Manage and minimize the severity of toxicities as appropriate • Use supportive care for myeloma-related conditions • Educate patients and caregivers about how they can take an active role in managing potential toxicities

Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Trudel S, et al. OncoTargets Ther. 2019;12:5813-5822. 42 42

2020 PCE Spring Oncology Series 14 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

At Each Step, Consider All Possible Treatment Strategies

• Repeat previously effective drugs in new combinations and/or consider totally new combinations • Triple regimens preferred; consider doublets for frail patients • Include next-generation agent from same class or ≥1 new class ‒ Progression on a combination does not necessarily mean the individual drugs will be ineffective in combination with other agents ‒ Treatments that are ineffective alone are often effective when combined • Use drugs to which the patient has not been exposed • Refer patients for clinical trials where appropriate

43 43

Novel Approaches for RRMM

Drug Description FDA Status Clinical Trials Results in RRMM Selinexor Oral nuclear Accelerated approval for Phase 2B trial (STORM): selinexor 80 mg plus dex export protein RRMM after ≥4 prior lines • N = 123 patients refractory to ≥3 prior therapies XPO1 inhibitor of therapy (incl. 2 PIs, 2 • ORR (≥PR) = 26% (including 2 stringent CR) IMiDs, and an anti-CD38 mAB) • AE: fatigue, nausea, grade 3-4 thrombocytopenia Venetoclax for BCL-2 inhibitor Approved in other Phase 3 RCT (BELLINI): venetoclax + Vd vs Vd t(11,14) cancers • N = 291; ≤3 prior therapies translocation • All patients: 61% ≥VGPR (vs 40%), MRD– :13% vs 1% • t(11,14)+ patients: 75% ≥VGPR (vs 27%); MRD– : 25% vs 0 • Grade ≥3 AEs: thrombocytopenia, anemia Isatuximab Anti-CD38 mAb Approved for patients with Phase 3 RCT (ICARIA-MM): Isatuximab + PomD vs PomD ≥2 prior lines of therapy, • N = 307; ≥2 prior therapies including lenalidomide • Improved PFS (primary end point): 11.5 months vs 6.5 months and a PI • Other phase 3 RCT with Kd and VRd ongoing

ORR = overall response rate Attal M. et al. Lancet. 2019;394:2096-2107; Chari A, et al. N Engl J Med. 2019;381:727-738; Kumar S, et al. Blood. 2017;130:2401-2409; Mikhael J, et al. Blood. 2019;134:123-133; Moreau P, et al. ASH 2019: Abstract 653; Richardson PG, et al. Future Oncol. 2018;14:1035-1047; Sarclisa. [prescribing information]. Sanofi-aventis US; 2020; Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 44 44

On the Horizon: BCMA-Targeted Agents in RRMM

Drug Description FDA Status Current Research Results in RRMM Belantamab Immunoconjugate Investigational, Phase 2 (DREAMM-2): dose-ranging (2.5 & 3.4 mg), single agent mafodotin targeting BCMA granted priority review • N = 196; RRMM after ≥3 prior therapies; triple refractory Jan 2020 • Overall RR: 31% with 3.4 mg, 34% with 2.5 mg • Grade ≥3 AE: keratopathy, thrombocytopenia, anemia Phase 1 (DREAMM-1): ≥PR: 60%; median PFS = 12 mo Toxicities: Thrombocytopenia, corneal events: manage with supportive care Idecabtagene BCMA CAR T cell Investigational, Phase 2 (KarMMa): dose-ranging study vicleucel has breakthrough • N = 128; RRMM after ≥3 prior therapies; 84% triple-refractory (ide-cel) therapy designation • Overall RR (all patients) = 73.4% (31.3% CR); 81.5% at highest dose Nov 2017 • Grade ≥3 AEs: CRS (5.5%), neurotoxicity (3.1%) Phase 1: ORR = 85% (45% CR); median PFS = 11.8 mo Toxicities: • CRS: manage with antipyretics, hydration, tocilizumab +/- dex • ICANS: manage with seizure prophylaxis or treatment; monitor for severe symptom development

BCMA = B cell maturation antigen; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; ICANS = immune-effector cell neurotoxicity syndrome. Bristol-Myers Squibb. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-announce-positive-top-li. Accessed Mar 24, 2020; Lonial S, et al. Lancet Oncol. 2020;21:207-221; Mikhael J. Clin Lymphoma Myeloma Leuk. 2019;1:1-7; Raje N, et al. N Engl J Med. 2019;380:1726-1737; Trudel S, et al. Blood Cancer J. 2019;9:37; Wang BY, et al. ASH 2019: Abstract 579; Zhao WH, et al. J Hematol Oncol. 2018;11:141. 45 45

2020 PCE Spring Oncology Series 15 New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Relapsed/Refractory Multiple Myeloma: Summary

• Relapse is still inevitable in MM • Current treatment strategies prolong DOR/PFS at each step of care ‒ Triplet therapies: PI + IMiD + Dex; combinations with PomD and/or mAbs ‒ ASCT for eligible patients, front-line or delayed ‒ Maintenance therapy after consolidation with lenalidomide or bortezomib • Longer survival underscores need to proactively manage disease- and treatment- related toxicities • For patients using oral agents, institute strategies to maintain adherence with sometimes complicated dosing schedules

46 46

PCE Action Plan

 Confirm and characterize a relapse before changing or reinitiating therapy  Choose a regimen based on patient goals as well as balancing efficacy and safety  Consider previous history and be proactive in anticipating issues with subsequent lines of treatment  Evaluate toxicity risk and implement clinical management strategies  Consider all possible treatment strategies, using patient and disease factors to guide subsequent lines of treatment

PCE Promotes Practice Change

47 47

2020 PCE Spring Oncology Series 16 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

1

Learning Objectives

• Summarize the mechanisms of action of available and emerging therapies for TNBC within the context of the underlying tumor biology • Identify the role of new and emerging therapies in the treatment of TNBC • Formulate strategies for the identification and management of toxicities of novel therapies in TNBC

TNBC = triple-negative breast cancer. 2 2

Features of TNBC

Common Features Risk Factors Lacks ER, PR, and HER2 Younger age Family history of Subtypes include “basal-like” (>75% of TNBC), breast cancer immunomodulatory, mesenchymal, mesenchymal stem-like, and African American and High BMI luminal androgen receptor Hispanic women More aggressive clinical course in metastatic setting Underlying BRCA1 Low levels of physical Tends to be higher grade vs other types of breast cancer mutation activity More responsive to chemotherapy vs other types of breast cancer Higher parity Low socioeconomic (≥3 children) conditions Rapid progression from onset of metastasis to death Most deaths occur in first 5 years

ER = estrogen receptor; HER2 = human epidermal receptor 2; PR = progesterone receptor. Audeh MW. Pharmgenomics Pers Med. 2014;7:307-316; Brookes L. www.medscape.com/viewarticle/871606. Accessed Mar 23, 2020; Ismail-Khan R, Bui MM. Cancer Control. 2010;17:173-176; Mustacchi G, De Laurentiis M. Drug Des Devel Ther. 2015;9:4303-4318; Phipps AI, et al. Cancer Epidemiol Biomarkers Prev. 2011;20:454-463; Phipps AI, et al. J Natl Cancer Inst. 2011;103:470-477. 3 3

2020 PCE Spring Oncology Series 1 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Case Study: Carol, 56 Years Old

• Carol reported nodules in her right breast to her gynecologist ‒ No family history of breast or ovarian cancer ‒ Core biopsy: 2-cm high-grade infiltrating ductal carcinoma ‒ Immunohistochemistry: ER/PR/HER2-negative tumor • Carol is diagnosed with TNBC

4 4

BRCA Testing in Breast Cancer

• Testing recommendations include: ‒ Individuals from families with a known BRCA1/2 mutation ‒ Patients with a personal history of breast cancer plus one or more of the following: • Diagnosed ≤45 years of age • Diagnosed between 46 and 50 years with: ‒ An unknown or limited family history • Diagnosed ≤60 years of age with TNBC • Diagnosed at any age with: ‒ An additional primary breast cancer ‒ ≥1 close blood relative with breast cancer ‒ ≥1 close blood relative with high-grade prostate cancer ‒ Male relative with breast cancer ‒ Ashkenazi Jewish ancestry • In metastatic breast cancer: ‒ Assess germline BRCA1/2 mutations to identify candidates for PARP inhibitor monotherapy

NCCN.org. www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed Mar 23, 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020 5 5

Case Study (cont’d)

• Immunohistochemistry: ER/PR/HER2-negative tumor with BRCA1 mutation • Staging studies: right breast mass with possible lymph node involvement; no other areas of disease • After neoadjuvant dose dense AC-T chemotherapy, Carol underwent a lumpectomy and was found to have residual disease in her breast and one lymph node with malignant cells, RCB-II • She is treated with adjuvant capecitabine for 6 months • Two years later, Carol comes to see you complaining of intermittent right-upper quadrant pain, fatigue, and unexplained weight loss • A scan shows liver metastases; biopsy confirms mTNBC

AC-T = doxorubicin and cyclophosphamide followed by paclitaxel; mTNBC = metastatic triple-negative breast cancer; RCB = residual cancer burden. 6 6

2020 PCE Spring Oncology Series 2 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

PD-L1 Biomarker Testing in TNBC

• PD-L1 expression: status can currently help identify patients most likely to benefit from plus nab-paclitaxel ‒ PD-L1 expression occurs mainly on tumor-infiltrating immune cells • Can inhibit anticancer immune responses ‒ PD-L1 expression is defined as negative or positive

Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med. 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, et al. Appl Immunohistochem Mol Morphol. 2019;27:92-100. 7 7

PD-L1 Biomarker Testing: Available Assays

• SP142 assay: only validated test to predict benefit with atezolizumab plus nab-paclitaxel ⎻ PD-L1 expression: <1% or ≥1% • 22C3 assay: used to select patients for therapy with ⎻ PD-L1 expression: calculated using CPS • Other assays used for different cancers/immunotherapies

CPS = combined positive score. Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med. 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, et al. Appl Immunohistochem Mol Morphol. 2019;27:92-100. 8 8

Overview: Chemotherapy Options for mTNBC

• Stage I-III: HER2-Negative Neoadjuvant or Preferred regimens adjuvant Anthracyclines PARP inhibitors (for HER2-negative tumors Platinum (for triple-negative tumors • Doxorubicin, liposomal doxorubicin and germline BRCA1/2 mutation) and germline BRCA1/2 mutation) chemotherapy + Taxanes • Olaparib • Carboplatin surgery • Paclitaxel • Talazoparib • Cisplatin Antimetabolites Atezolizumab + albumin-bound • Stage IV: • Capecitabine, gemcitabine paclitaxel (for PD-L1-positive Microtubule inhibitors TNBC) chemotherapy • Vinorelbine, eribulin alone Other recommended regimens • Choice and order Cyclophosphamide Albumin-bound paclitaxel Epirubicin of chemotherapy Ixabepilone depends on Useful in certain circumstances Doxorubicin/cyclophosphamide Docetaxel/capecitabine Gemcitabine/carboplatin multiple factors Epirubicin/cyclophosphamide Gemcitabine/paclitaxel Paclitaxel/ Cyclophosphamide/methotrexate/ Carboplatin/albumin-bound fluorouracil paclitaxel Carboplatin/paclitaxel

Ehab M, Elbaz M. Breast Cancer (Dove Med Press). 2016;8:83-91; NCCN Guidelines. Breast cancer. www.nccn.org/ professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schwartz KL, et al. Cancer. 2018;124:2104-2114. 9 9

2020 PCE Spring Oncology Series 3 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Paclitaxel vs Nab-Paclitaxel: Taxane Derivatives

• Taxane therapy indicated in the adjuvant and metastatic setting • Paclitaxel is a poorly water soluble, potent microtubule inhibitor that is a taxane derivative • Nab-paclitaxel: nanoparticle, albumin-bound injectable version of paclitaxel ‒ Eliminates use of polyoxyethylated castor oil (Cremophor EL), a cause of toxicity in patients receiving taxane therapy ‒ Shorter infusion time ‒ Does not require premedication with corticosteroids for hypersensivity reactions ‒ Uses albumin transport mechanisms to form concentrations within the tumor

Abraxane [prescribing information]. Celgene Corporation; 2018; Al-Hajeili M, et al. Oncol Targets Ther. 2014;7:187-192; Taxol [prescribing information]. Bristol-Myers Squibb Company; 2011; Waks AG. www.lbbc.org/learn/treatments-and-research/chemotherapy/types-chemotherapy/nab- paclitaxel. Accessed Mar 23, 2020. 10 10

Immune Checkpoint Inhibitors: Mechanism of Action

• Compared with other subtypes, TNBC is associated with higher prevalence of tumor infiltrating lymphocytes and higher rates of PD-L1 positivity • Checkpoint pathways regulate the immune system and help prevent autoimmune responses ‒ Cancers may evade destruction by the immune system by co-opting the CTLA-4 and PD-1 immune checkpoint pathways • Immune checkpoint inhibitors: ‒ Target CTLA-4, PD-1, PD-L1 ‒ Block cancer cells from using the checkpoint pathway ‒ Allow re-establishment of the immune response

Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39:98-106; Dine J, et al. Asia Pac J Oncol Nurs. 2017;4:127-135; Katz H, Alsharedi M. Med Oncol. 2017;35:13; Shimelis H, et al. J Natl Cancer Inst. 2018;110:855-862. 11 11

IMpassion130: Atezolizumab + Nab-Paclitaxel in PD-L1 + mTNBC

100 Median OS, mo Population HR (95% CI) 90 A + nab-P P + nab-P 80 PD-L1 IC+ 25.0 18.0 0.71 (0.54, 0.94) 70 PD-L1 IC− 19.6 19.6 0.99 (0.80, 1.23) 60 50

OS (%) OS 40 30 A + nab-P (PD-L1+ n = 185) • Improved OS in 20 P + nab-P (PD-L1+ n = 184) A + nab-P (PD-L1− n = 266) PD-L1–positive P + nab-P (PD-L1− n = 267) 10 patients 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Time (months)

Clinical cutoff date: January 2, 2019. A = Atezolizumab; CI = confidence interval; IC = immune cell; HR = hazard ratio; ITT = intent to treat; nab-P = nab-paclitaxel; OS = overall survival; P = placebo. Schmid P, et al. Lancet Oncol. 2020;21:44-59. 12 12

2020 PCE Spring Oncology Series 4 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

IMpassion130: Progression-free Survival in PD-L1 + mTNBC

100 A + nab-P (PD-L1+ n = 185) Median OS, mo P + nab-P (PD-L1+ n = 184) Population HR (95% CI) 90 A + nab-P (PD-L1− n = 266) A + nab-P P + nab-P P + nab-P (PD-L1− n = 267) 80 PD-L1+ (41%) 7.5 mo 5.3 mo 0.63 (0.50, 0.80) PD-L1- (59%) 5.6 mo 5.6 mo 0.93 (0.77, 1.11) 70

60

50

F (%) PFS 40

30

20

10

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Months PFS = progression-free survival. Schmid P, et al. Lancet Oncol. 2020;21:44-59. 13 13

Patient Counseling: Nab-Paclitaxel AEs

Type of AE Advice to Patients Alopecia • Hair loss is common and may begin within a few days or weeks of treatment • Usually grows back once treatments are over and sometimes between treatments • Color and texture may change Hematologic effects • Low blood cell counts increase risk of severe and life-threatening infections • Wash hands often and avoid crowds and people who are sick • Report fever or evidence of infection to healthcare provider immediately Nervous system • Sensory neuropathy frequently occurs • Report numbness, tingling, pain, or weakness involving the extremities to healthcare provider • Should resolve slowly after end of treatment Pneumonitis • Indicated by sudden onset of dry persistent cough or shortness of breath • May overlap with atezolizumab-related pneumonitis when used in combination • Contact healthcare provider immediately

Abraxane [prescribing information]. Celgene Corporation; 2018; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20paclitaxel_ handout.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med. 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019. 14 14

Patient Counseling: Nab-Paclitaxel AEs (cont’d)

Type of AE Advice to Patients Hypersensitivity • Could be severe and sometimes fatal • Contact healthcare provider for any signs of an allergic reaction that occur soon after treatment Common adverse reactions • Fatigue/asthenia and myalgia/arthralgia occur frequently with nab-paclitaxel • Contact healthcare provider for persistent nausea and vomiting, diarrhea or constipation, or signs of dehydration Embryo-fetal toxicity • Women should use effective contraception during treatment and for at least 6 months after the last dose • Males with female partners should use effective contraception during treatment and for 3 months after the last dose

Abraxane [prescribing information]. Celgene Corporation; 2019; BC Cancer. www.bccancer.bc.ca/drug-database-site/Drug%20Index/nab%20 paclitaxel_handout.pdf. Accessed Mar 23, 2020. 15 15

2020 PCE Spring Oncology Series 5 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Select Ongoing Immunotherapy Trials in TNBC

Setting Trial Name Regimen Neoadjuvant/ Carboplatin + paclitaxel + (anthracycline) + cyclophosphamide ± KEYNOTE-522 Adjuvant pembrolizumab➔ pembrolizumab Doxorubicin + cyclophosphamide + paclitaxel + carboplatin ± atezolizumab NCT03281954 ➔ atezolizumab Doxorubicin + cyclophosphamide + nab-paclitaxel ± atezolizumab ➔ IMpassion031 atezolizumab NeoTRIPaPDL1 Atezolizumab + carboplatin + nab-paclitaxel Michelangelo Adjuvant Paclitaxel ➔ dose-dense doxorubicin/epirubicin + cyclophosphamide ± IMpassion030 atezolizumab

Locally advanced KEYNOTE-355 or mTNBC Abraxane or paclitaxel or carboplatin/gemcitabine ± pembrolizumab

IMpassion131 Paclitaxel ± atezolizumab

➔ = followed by. Marra A, et al. BMC Med. 2019;17:90; Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04. 16 16

KEYNOTE-522: Neoadjuvant Pembrolizumab Plus Chemotherapy in Early TNBC

Pembrolizumab + Chemo Placebo + Chemo

• Greater increase in pCR in patients with 100 Δ 6.3 (95% CI, Δ 20.6 (95% CI, lymph node-positive vs lymph node- -5.3 to 18.2) 8.9 to 31.9) 90 negative disease 80 64.9% 64.8% 58.6% • Improvement in pCR rates occurred 70 44.1% regardless of PD-L1 status 60

• In the preoperative TNBC setting with 50

pembrolizumab plus chemotherapy, 40

PD-L1 does not seem to be a predictive CI) %(95% pCR, 30

biomarker 20

10 124/191 58/99 136/210 45/102 0 Negative Positive Nodal Status pCR = pathological complete response. Schmid P, et al. N Engl J Med. 2020;382:810-821. 17 17

KEYNOTE-522: Event-free Survival

Pembrolizumab-chemotherapy 100 91.3% 90

80

70 85.3% Placebo-chemotherapy 60

50

40

30 Event or Death (%) Death or Event Patients Without an an Without Patients 20

10

0 0 3 6 9 12 15 18 21 24 27 Months No. at risk Pembrolizumab-chemotherapy 784 780 765 666 519 376 242 73 2 0 Placebo-chemotherapy 390 386 380 337 264 186 116 35 1 0

Schmid P, et al. N Engl J Med. 2020;382:810-821. 18 18

2020 PCE Spring Oncology Series 6 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

NeoTRIPaPDL1 Michelangelo Study

• Early, high-risk and locally advanced TNBC treated with: ‒ Atezolizumab plus carboplatin and nab-paclitaxel ‒ Compared with carboplatin and nab-paclitaxel • pCR rates did not improve in atezolizumab group • PD-L1 expression most significant factor for influencing pCR, regardless of treatment regimen • TRAEs similar for both regimens except: ‒ Significantly higher overall incidence of serious AEs and liver function test abnormalities with atezolizumab

TRAEs = treatment-related adverse events. Gianni L, et al. 2019 San Antonio Breast Cancer Symposium; Abstract GS3-04. 19 19

KEYNOTE-355: First-line Pembrolizumab in PD-L1+ Patients With mTNBC

• Phase 3 trial; chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) with or without pembrolizumab • Primary endpoint: PFS and OS in the overall population vs PD-L1-positive ‒ PD-L1 status defined by 22C3 assay with CPS • Interim analysis: in patients with PD-L1 CPS >10, first-line pembrolizumab + chemotherapy demonstrated statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone ‒ No new safety signals observed with pembrolizumab

Tucker N. www.targetedonc.com/news/keynote355-meets-a-coprimary-end-point-for-treatment-of-patients-with-mtnbc. Accessed Mar 23, 2020. 20 20

Case Study (cont’d)

• After her second treatment with atezolizumab plus nab-paclitaxel, Carol returns to your office with a rash on her chest and back ‒ She says she is very uncomfortable ‒ She has tried to treat the rash with high-potency topical corticosteroids with no relief • You diagnose inflammatory dermatitis

21 21

2020 PCE Spring Oncology Series 7 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Potential irAEs With Immune Checkpoint Inhibitors

System irAEs Ocular Uveitis, episcleritis Pulmonary Pneumonitis Hepatic Increased liver function enzymes Pancreatic Elevated lipase levels Infusion-related Infusion-related reaction or hypersensitivity Endocrine Hypothyroidism, hyperthyroidism, hypopituitarism, hypophysitis, adrenal insufficiency • Testing for TSH and FT4 every 4 to 6 weeks should be part of routine clinical monitoring on therapy Dermatologic Pruritus, rash, vitiligo, alopecia Gastrointestinal Diarrhea, colitis, nausea General Fatigue, headache, decreased appetite, arthralgia

irAEs = immune-related adverse events; FT4 = free thyroxine 4; TSH = thyroid stimulating hormone. Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- types/immunotherapy. Accessed Mar 23, 2020; Postow MA, et al. N Engl J Med. 2018;378:158-168. 22 22

Current Recommendations: Managing irAEs With Immune Checkpoint Inhibitors

Toxicity Grade Recommendation

Continue checkpoint inhibitors with close monitoring, with the exception of some neurologic, hematologic, Grade 1 and cardiac toxicities Hold for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values return to grade 1 or less Grade 2 Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be given • For pneumonitis, corticosteroids need to be tapered slowly over at least 4 weeks to prevent flare-up Hold checkpoint inhibitors; initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) • Taper corticosteroids over course of at least 4 to 6 weeks • If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for Grade 3 some toxicities • Consider resuming checkpoint inhibitors when symptoms and/or laboratory values return to grade 1, after discussion of risk/benefits with patients

Warrants permanent discontinuation of checkpoint inhibitors, with exception of endocrinopathies controlled by Grade 4 hormone replacement

Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Postow MA, et al. N Engl J Med. 2018;378:158-168. 23 23

Immune Checkpoint Inhibitors: Patient and Caregiver Education

• Immunotherapy may take longer to work than other cancer treatments ‒ Disease may progress before patients experience improvement • Most irAEs occur within 2 to 3 treatment cycles, but can occur any time—even after therapy is discontinued ‒ Typically mild, but can be severe, irreversible, or life-threatening ‒ Do not occur in all patients for unknown reasons • Need for management of side effects throughout the continuum of cancer care

Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- types/immunotherapy. Accessed Mar 23, 2020; Postow MA, et al. N Engl J Med. 2018;378:158-168. 24 24

2020 PCE Spring Oncology Series 8 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Case Study (cont’d)

• 14 months after treatment with atezolizumab and nab-paclitaxel, Carol develops shortness of breath • A scan shows multiple bilateral pulmonary nodules ‒ Biopsy of one of the nodules showed it to be consistent with the primary cancer

25 25

PARP Inhibition in TNBC

• PARP — enzymes that help maintain DNA integrity during replication • When cells lack BRCA1 or 2—proteins involved in homologous-directed repairs of DNA—PARP inhibitors disrupt DNA damage repair mechanisms of tumor cells ‒ May lead to cell death and potentially reduction or stoppage of tumor growth ‒ May play a role in treatment of TNBC: BRCA mutations often associated with TNBC

PARP BER Cell DNA Damage Pathway Survival

DNA Repair Inactivated NAD+ PARP

BER indicates base excision repair PARP Apoptosis Inhibition DNA Collapse

BER = base excision repair; NAD = nicotinamide adenine dinucleotide. Benafif S, Hall M. Onco Targets Ther. 2015;8:519-528; Livraghi L, Garber JE. BMC Med. 2015;13:188; Okuma HS, Yonemori K. Adv Exp Med Biol. 2017;1026:271-286. 26 26

OlympiAD: Olaparib Therapy Significantly Improved PFS

• Olaparib vs chemotherapy evaluated in BRCA-mutated, high-risk, HER2-negative primary breast cancer previously treated with two lines of chemotherapy

100

90

80 Olaparib Chemotherapy TPC 70 (n = 205) (n = 97) 60 Events (%) 163 (79.5) 71 (73.2) 50 Olaparib Median PFS, months 7.0 4.2

PFS (%)PFS 40

30 Standard therapy 20

10

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time From Randomization (months)

TPC = treatment of physician’s choice. Lynparza [prescribing information]. AstraZeneca Pharmaceuticals LP; 2019; Robson M, et al. N Engl J Med. 2017;377:523-533. 27 27

2020 PCE Spring Oncology Series 9 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

OlympiAD: Overall Survival Analysis

• No significant OS benefit at 64% data maturity: olaparib 19.3 vs TPC 17.1 months • Possible meaningful OS benefit among chemotherapy-naïve patients Overall population No prior chemotherapy

1.0 Olaparib TPC 1.0 Olaparib TPC 0.9 Deaths, n (%) 130 (63) 62 (64) 0.9 Deaths, n (%) 30 (50.8) 21 (75.0) Median OS, mo 19.3 17.1 Median OS, mo 22.6 14.7 0.8 0.8 0.7 0.7 Olaparib 0.6 0.6

0.5 Olaparib 0.5

0.4 0.4 0.3 TPC 0.3 TPC 0.2

0.2 OS of Probability Probability of OS of Probability 0.1 0.1

0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Time From Randomization (months) Time From Randomization (months) No. at risk No. at risk Olaparib 205 199 178 146 124 92 55 23 11 6 0 Olaparib 59 57 53 44 40 32 17 7 5 4 0 TPC 97 85 74 62 48 40 30 15 5 2 0 TPC 28 25 20 17 12 9 7 4 1 0 0

Robson ME, et al. Annals Oncol. 2019;30:558-566. 28 28

EMBRACA: Talazoparib Significantly Improved PFS

• Talazoparib vs standard chemotherapy for Talazoparib Standard Therapy locally advanced or metastatic breast cancer (n = 287) (n = 144) with a germline BRCA1/2 mutation Events (%) 186 (65) 83 (58) Median, months (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7)

100 90 80 70 60 50

PFS (%) PFS 40 30 Talazoparib 20 10 Standard therapy 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months

Litton JK, et al. N Engl J Med. 2018;379:753-763; Talzenna [prescribing information]. Pfizer Inc.; 2019. 29 29

Talazoparib and the EMBRACA Trial: No Significant Improvement in OS*

Talazoparib Standard Therapy (n = 287) (n = 144) 100

90 Events (%) 108 (38) 55 (38)

80 Median, months (95% CI) 22.3 (18.1-26.2) 19.5 (16.3-22.4)

70

60

50 OS (%) OS 40 Talazoparib 30

20 Standard therapy

10

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months

*These findings represent immature interim data. Litton JK, et al. N Engl J Med. 2018;379:753-763. 30 30

2020 PCE Spring Oncology Series 10 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Management of Toxicities Associated With PARP Inhibitors

• Majority of AEs typically occur during first cycles of treatment Toxicity Management Strategy Hematologic • Common class effect, particularly anemia • Monitor CBC with differential monthly in patients starting a PARP inhibitor or undergoing dose modification • Transfusions recommended for symptomatic anemia and for hemoglobin <7 g/dL Gastrointestinal • Common for all PARP inhibitors, especially nausea • Mostly based on expert opinion; similar to management of chemotherapy-induced GI toxicities Renal • Elevated serum creatinine might not reflect a true decline in GFR or kidney insufficiency • If GFR is appropriate, avoid dose reductions or interruptions Fatigue • Universal toxicity for all PARP inhibitors • Consider nonpharmacologic treatments: exercise, massage therapy, cognitive behavioral therapy • For more symptomatic patients, consider pharmacologic interventions with psychostimulants, such as methylphenidate and ginseng

CBC = complete blood count; GFR = glomerular filtration rate. LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 31 31

Management of Toxicities Associated With PARP Inhibitors (cont’d)

Toxicity Management Strategy Laboratory • Increased cholesterol and serum aminotransferase common abnormalities • Manage persistent hypercholesterolemia with appropriate statin therapy, with careful attention to elevated liver enzymes Less Common Toxicities Neurologic • Headache, insomnia • Offer symptomatic therapies Respiratory • Most involve dyspnea, cough, nasopharyngitis, and upper respiratory tract infection • With new or worsening respiratory symptoms, hold PARP inhibitor and rule out cause Cutaneous • Mostly mild and consist of photosensitivity reactions, pruritus, rash, and peripheral edema • Counsel patients to use sun protection measures and skin moisturizers

LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 32 32

Management of Nonhematologic AEs for PARP Inhibitors by Grade

Grade Management Strategies • Continue PARP inhibitor 1 • Symptomatic treatment if necessary • Continue PARP inhibitor 2 • Consider dose interruption, reduction, or both, if toxicity remains uncontrolled despite symptomatic or prophylactic therapies • Withhold until resolution of AE: for olaparib, ≤grade 1 • Might continue treatment if AE is nausea, vomiting, or diarrhea, and controlled on 3 or 4 medication • If treatment was interrupted, consider dose reduction upon resumption (particularly if after second time withholding) 3 or 4 lasting more than 28 • Discontinue PARP inhibitor days with the lowest dose of PARP inhibitor

LaFargue CJ, et al. Lancet Oncol. 2019;20:e15-e28. 33 33

2020 PCE Spring Oncology Series 11 Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Case Conclusion

• Carol’s pulmonary nodules show minor response for 6 months, then progress • She is started on eribulin

34 34

Later-line Therapy

• Options include carboplatin, gemcitabine, eribulin, vinorelbine • Best supportive care is also an option • Newly approved therapy: ‒ -hziy; first-in-class ADC in mTNBC: • In third line or later therapy: response rate 33.3%; clinical benefit rate (including stable disease for at least 6 months), 45.4% • Phase 3 trial in mTNBC refractory or relapsing after at least 2 prior (including a taxane) compared with TPC currently under way

ADC = antibody-drug conjugate. Bardia A, et al. N Engl J Med. 2019;380:741-751; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02574455?term=eribulin&cond= Triple+Negative+Breast+Cancer&phase=2&draw=2&rank=3. Accessed Mar 23, 2020. 35 35

PCE Action Plan

 Test all patients with metastatic breast cancer for BRCA1/2 mutations  Test all patients with mTNBC for PD-L1  Consider rechallenge with checkpoint inhibitor therapy with caution in patients whose irAE symptoms and/or laboratory values revert to grade 1 after higher grade toxicity and drug holding  Initiate a discussion with patients and caregivers on how checkpoint inhibitor therapy differs from chemotherapy  Closely monitor patients for AEs during the first cycles of treatment with PARP inhibitors

PCE Promotes Practice Change

36 36

2020 PCE Spring Oncology Series 12 Key Updates in the Treatment of HER2-Positive Breast Cancer

Key Updates in the Treatment of HER2-Positive Breast Cancer

1

Learning Objectives

• Apply current evidence and guideline recommendations to identify the appropriate use of and optimally sequence HER2-targeted agents in the treatment of HER2- positive metastatic breast cancer • Evaluate emerging research, the mechanisms of action, and the role of novel HER2-targeted therapies in clinical investigation for patients with HER2-positive metastatic breast cancer • Implement best practices for the management of HER2-positive breast cancer brain metastases • Develop strategies to effectively manage adverse events associated with treatments for HER2-positive breast cancer

HER2 = human epidermal 2. 2 2

Targeted Therapies for HER2+ Breast Cancer

HER2-Targeted mAbs HER2-Targeted ADCs

Pertuzumab T-DM1 HER2 T-DXd HER3 HER2 HER2 HER2

P P P hsp90 inhibitor P P MK-2206 BKM120 HER2-Targeted P13K Proteasome TKIs BEZ235 hsp90 T-DM1 AKT T-DXd Breakdown mTOR of HER2 P Endosome

T-DM1 T-DXd

ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. Gajria. Expert Rev Anticancer Ther. 2011;11:263. Pernas. Ther Adv Med Oncol. 2019;11:1758835919833519. 3 3

PCE 2020 Spring Oncology Series 1 Key Updates in the Treatment of HER2-Positive Breast Cancer

Guideline-Recommended Regimens for HER2-Positive Recurrent or Stage IV Breast Cancer

Preferred regimens* Other Recommended Regimens* • Taxane + trastuzumab + (THP)† • Ado- (T-DM1) • (T-DXd) • Trastuzumab + chemotherapy‡§ • Trastuzumab + lapatinib (without cytotoxic therapy) • Trastuzumab + other agents§ • Lapatinib + capecitabine • Neratinib + capecitabine • Trastuzumab + capecitabine + tucatinib

*An FDA-approved biosimilar is an acceptable substitute for trastuzumab. †Docetaxel or paclitaxel. ‡Paclitaxel ± carboplatin, docetaxel, vinorelbine, capecitabine. §Anthracyclines should be avoided due to significant cardiotoxicity. Wang. Signal Transduct Target Ther. 2019;4:34. Pernas. Ther Adv Med Oncol. 2019:11:1758835919833519. 4 4

CLEOPATRA: Standard First-line Treatment for HER2+ MBC With Docetaxel/Trastuzumab/Pertuzumab

End of Study OS in ITT Population* Median OS, 8 yrs 100 Mos THP 57.1 80 TH + Pbo 40.8

60 Landmark OS: 37% Events: 235 (58.5%) 40 OS(%)

20 Landmark OS: 23% HR: 0.69 (95% CI: 0.58-0.82) 0 Events: 280 (69.0%) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Mos Patients at Risk, n THP 402 371 318 269 228 188 165 150 137 120 71 20 0 0 TH + Pbo 406 350 289 230 181 149 115 96 88 75 44 11 1 0

*Crossover patients were analyzed in the placebo arm. H = trastuzumab; HR = hazard ratio; ITT = intention-to-treat; OS = overall survival; P = pertuzumab; Pbo = placebo; T = docetaxel. Swain. ASCO 2019. Abstr 1020. 5 5

MARIANNE: First-line T-DM1 ± Pertuzumab versus Docetaxel/Trastuzumab in HER2+ MBC

TH (n = 365) T-DM1 (n = 367) T-DM1 + P (n = 363) Median OS, mos 50.9 53.7 51.8 Events, n 169 175 168 100 Stratified HR vs HT (97.5% CI) -- 0.93 (0.73-1.20) 0.86 (0.67-1.11) Stratified HR vs T-DM1 (97.5% CI) -- -- 1.00 (0.78-1.28) 80

60

OS(%) 40 TH 20 T-DM1 T-DM1 + P 0 Day 1 12 Mos 24 Mos 36 Mos 48 Mos 60 Mos 72 Mos Patients at Risk, n TH 365 303 251 197 155 28 T-DM1 367 322 264 216 176 37 T-DM1 + P 363 309 257 217 172 41 T-DM1 = trastuzumab emtansine. Perez. Cancer. 2019;125:3974. 6 6

PCE 2020 Spring Oncology Series 2 Key Updates in the Treatment of HER2-Positive Breast Cancer

MARIANNE: Grade ≥ 3 AEs Trastuzumab + Taxane T-DM1 T-DM1 + Pertuzumab Grade ≥ 3 AE, % (n = 353) (n = 361) (n = 366) Any 55.8 47.1 48.6 Greater incidence Alopecia 60.1 7.2 9.0 with trastuzumab + Neutropenia 19.3 4.4 3.8 CT

Febrile neutropenia 6.5 0 0

Diarrhea 4.2 0.3 2.7

Hypertension 3.1 4.7 5.5 Greater incidence with T-DM1 Anemia 2.8 5.0 7.1

ALT increase 0.8 4.4 6.0

AST increase 0.3 6.9 3.3

GGT increase 0.3 3.3 2.5

Thrombocytopenia 0 6.6 9.0

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = chemotherapy; GGT = gamma-glutamyl transferase. Perez. Cancer. 2019;125:3974. 7 7

EMILIA and TH3RESA: Standard Second-line Therapy for HER2+ MBC With T-DM1 After Progression on HER2-Targeted Agents

EMILIA[1]: Randomized phase III study of T-DM1 vs lapatinib + TH3RESA[2]: Randomized phase III study of T-DM1 vs physician’s capecitabine for HER2+ MBC with progression on trastuzumab + choice for HER2+ MBC with progression on a taxane, lapatinib, and taxane (N = 991) ≥2 HER2-targeted regimens including trastuzumab (N = 602)

Median OS, mos 100 T-DM1 30.9 100 Median OS, mos 85.2% Lapatinib + Cape 25.1 T-DM1 22.7 80 80 Physician’s choice 15.8 78.4% 64.7% 60 60 51.8% OS (%) OS

OS (%) OS 40 40

20 HR: 0.68 (95% CI: 0.55-0.85; P < .001) 20 Efficacy stopping boundary: HR of 0.73 or P = .0037 HR: 0.68 (95% CI: 0.54-0.85; P = .0007) 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Mos Mos Patients at Risk, n Patients at Risk, n (censored) Lapatinib + cape 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 Physician’s 198 (0) 150 (28) 122 (31) 107 (33) 80 (34) 66 (36) 59 (37) 39 (45) 16 (68) 1 (80) 0 choice T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 T-DM1 404 (0) 368 (17) 321 (29) 280 (35) 226 (43) 192 (44) 167 (45) 132 (66) 54 (138) 12 (172) 0

Cape = capecitabine; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine. 1. Verma. NEJM. 2012;367:1783. 2. Krop. Lancet Oncol. 2017;18:743. 8 8

What’s New in HER2-Targeted Agents?

• HER2 TKIs ‒ Neratinib ‒ Tucatinib (FDA approved 4/2020) • HER2 ADCs ‒ Trastuzumab deruxtecan (T-DXd; approved 12/2019) ‒ Trastuzumab duocarmazine/trastuzumab-vc-seco-DUBA (SYD985)

ADC = antibody–drug conjugate; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor. 9 9

PCE 2020 Spring Oncology Series 3 Key Updates in the Treatment of HER2-Positive Breast Cancer

Case Study: Sonia

• 49-yr-old woman presents with back pain and left breast mass (4 cm) ‒ She has no significant family history or past medical history ‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 3+ ‒ PET/CT: 3 liver lesions (largest 2 cm); several vertebral lesions in the thoracic and lower spine • She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 3 mos on therapy ‒ 18 mos later, progression is noted in liver (new 3-cm lesion, other lesions stable) • Receives T-DM1 and achieves PR in liver, with stable bone lesions ‒ 10 mos later, she complains of headache ‒ MRI of the brain: 3 lesions (1 cm) in the left frontal lobe with minimal edema ‒ PET/CT: liver lesions remain unchanged, no new liver lesions; bone lesions stable

ER = estrogen receptor, PgR = progesterone receptor, PR = partial response; T-DM1 = trastuzumab emtansine. 10 10

Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC

• Multiple treatment options are available for patients with HER2-positive MBC • Clinicians should reassess risks and benefits of additional lines of therapy based on patient’s fitness, comorbidities, and preferences at progression • If additional treatment is indicated, select therapy based on disease features as well as patient’s fitness, comorbidities, and preferences

11 11

In HER2+ MBC, CNS Disease Remains Incurable Despite Current Treatment Options

• ≥ 50% of patients with HER2+ MBC will develop Risk of CNS Metastasis in HER2+ MBC by Subgroup[2] [1] brain metastases Ethnicity: Hispanic/Latino OR (95% CI) • Lapatinib + capecitabine approved in this No vs Yes 1.181 (0.718-1.943) setting but few patients respond Race Other vs black/African American 1.268 (0.580-2.769) ‒ In a pooled analysis, CNS ORR was 21.4%, White vs black/African American 1.619 (1.072-2.444) median PFS was 4.1 mos, median OS was Age at MBC diagnosis [1] 50-69 vs ≥ 70 years 2.042 (1.248-3.341) 11.2 mos < 50 vs ≥ 70 years 3.128 (1.852-5.284) • Neratinib + capecitabine approved in this ECOG PS 1 vs 0 1.192 (0.876-1.622) setting in Feb 2020 ≥ 2 vs 0 1.900 (1.125-3.201) • Trastuzumab + capecitabine + tucatinib MBC diagnosis type Recurrent vs de novo 1.650 (1.239-2.196) approved in this setting in April 2020 Hormone receptor status • T-DM1, trastuzumab, and pertuzumab do not Negative vs positive 1.841 (1.359-2.494) penetrate the CNS under normal conditions 0 1 2 3 4 5

Lower Risk of CNS Metastasis Higher Risk of CNS Metastasis

CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; MBC = metastatic breast cancer; OR = odds ratio; PS = performance status; T-DM1 = trastuzumab emtansine. 1. Petrelli. Eur J Cancer. 2017;84:141. 2. Hurvitz. Clin Cancer Res. 2019;25:2433. 12 12

PCE 2020 Spring Oncology Series 4 Key Updates in the Treatment of HER2-Positive Breast Cancer

SystHERs Registry Analysis: PFS and OS by CNS Metastasis in HER2+ MBC

CNS Mets CNS Mets CNS Mets CNS Mets No CNS Mets No CNS Mets at Dx After Dx at Dx After Dx PFS (n = 678) OS (n = 678) (n = 87) (n = 212) (n = 87) (n = 212) Median PFS, mos 19.1 9.2 9.9 Median OS, mos NE 30.2 38.3 2.49 2.52 2.86 1.94 HR (95% CI) HR(95% CI) -- (1.93-3.20) (2.13-2.99) -- (2.05-4.00) (1.52-2.49) vs no CNS mets vs no CNS mets P < .0001 P < .0001 P < .0001 P < .0001 1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2 Proportion With PFS With Proportion Proportion Surviving Proportion

0 0 0 4 8 12 16 20 24 2832 36 40 44 48 52 56 60 64 68 0 4 8 12 16 20 24 2832 36 40 44 48 52 56 60 64 68 Mos on Study Since MBC Diagnosis Mos on Study Since MBC Diagnosis

CNS = central nervous system; Dx = diagnosis; MBC = metastatic breast cancer; mets = metastases; NE = not estimable. Hurvitz. Clin Cancer Res. 2019;25:2433. 13 13

CEREBEL: CNS Metastasis at First Relapse in HER2+ MBC With Lapatinib/Cape vs Trastuzumab/Cape

21-day • Randomized phase III study L + Cape T + Cape P cycle Endpoint (n = 251) (n = 250) Value Stratified by prior trastuzumab, lines of prior tx for MBC (0 vs ≥ 1) CNS as first 8 (3) 12 (5) .360 site of progression, n (%) Lapatinib 1250 mg/day + Patients with HER2+ MBC, Capecitabine 2000 mg/m2/day Incidence of CNS 17 (7) 15 (6) .865 any line of tx, including on Days 1-14 progression at any time, n (%) prior anthracyclines or Median time to first 5.7 4.4 NR taxanes; no CNS CNS progression, mos (range) (2-17) (2-27) metastasis Trastuzumab* 6 mg/kg Q3W + (N = 540) Capecitabine 2500 mg/m2/day Median PFS, mos 6.6 8.1 .021 on Days 1-14 • Trastuzumab naive 6.3 10.9 NR Median OS, mos 22.7 27.3 .095 *Loading dose of 8 mg/kg. ORR, % 27 32 NR

• Primary endpoint: CNS as first site of relapse • Trial closed early for futility in lapatinib • Secondary endpoints: PFS, OS + capecitabine arm

Cape = capecitabine; CNS = central nervous system; L = lapatinib; MBC = metastatic breast cancer; NR = not reported; T = trastuzumab; tx = therapy. Pivot. JCO. 2015;33:1564. 14 14

Neratinib: Mechanism of Action

• Pan-HER TKI HER1 (EGFR) HER2 HER3 HER4 • Irreversible inhibition Pertuzumab • Different MoA than trastuzumab and pertuzumab T-DM1 Trastuzumab

Lapatinib Neratinib

MoA = mechanism of action; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor. Baselga. Crit Rev Oncol Hematol. 2017;119:113. 15 15

PCE 2020 Spring Oncology Series 5 Key Updates in the Treatment of HER2-Positive Breast Cancer

NEfERT-T and TBCRC 022: Neratinib in HER2+ MBC

NEfERT-T[1]: Randomized phase III study of TBCRC 022 Cohort 3[2]: Single-arm 2-stage phase II study of neratinib/paclitaxel vs trastuzumab/paclitaxel in previously neratinib/capecitabine in HER2+ MBC with CNS disease (n = 49) untreated, HER2+ locally recurrent or MBC (N = 479) Best CNS Volumetric Response With Neratinib + Cape 1.0 100 in Lapatinib-Naive Patients (n = 37*)

0.8 80 60 0.6 18 responses by volumetric criteria; Neratinib + paclitaxel 40 CNS ORR: 49% (95% CI: 32-66) 0.4 Trastuzumab + paclitaxel 20 No CNS CNS No 0 Progression (%) Progression 0.2 HR:0.449 (95% CI: 0.259-0.780; log-rank P = .0036) -20 0 -40 CNS ORR with prior 0 4 8 12 16 20 24 2832 36 40 44 48 52 56 lapatinib: 33% (95% Mos -60 CI: 10-65) † † Change From Baseline (%) FromBaseline Change † Events Median Time to CNS Progression -80 † *n = 6 who did not reach first reimaging assigned 0. ††† N + P (n = 242) 20 NE -100 † †CNS response by RANO-BM criteria. † T + P (n = 237) 41 NE

Cape = capecitabine; CNS = central nervous system; MBC = metastatic breast cancer; N = neratinib; NE = not estimable; P = paclitaxel; RANO-BM = Response Assessment in Neuro-Oncology Brain Metastases criteria; T = trastuzumab. 1. Awada. JAMA Oncol. 2016;2:1557. 2. Freedman. JCO. 2019;13:1081. 16 16

NALA: Neratinib/Cape vs Lapatinib/Cape in HER2+ MBC With ≥ 2 Prior Lines of HER2-Targeted Agents

• International, open-label, randomized phase III trial 21-day cycle Stratified by no. prior HER2-targeted therapies, disease location, hormone receptor status, geographic location Neratinib 240 mg/day PO continuously + Capecitabine* 1500 mg/m2 PO on Days 1-14† Patients with centrally confirmed (n = 307) Until PD HER2+ MBC; previously treated with ≥ 2 lines of HER2-targeted Lapatinib 1250 mg/day PO continuously + Survival agents for MBC; asymptomatic, follow-up Capecitabine* 2000 mg/m2 PO on Days 1-14 stable brain metastases allowed (n = 314) (N = 621) *BID in 2 evenly divided doses. †Loperamide administered at 4 mg with first neratinib dose followed by 2 mg Q4H for first 3 days, followed by 2 mg every 6-8 hrs through end of cycle 1; as needed thereafter. • Secondary endpoints: PFS (locally determined), ORR, • Coprimary endpoints: OS, PFS (centrally confirmed) DoR, CBR, intervention for CNS metastases, safety, ̶ Study positive if either endpoint statistically PRO significant (OS, P < .04; PFS, P < .01) • No endocrine therapy permitted

Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; PD = progressive disease; PRO = patient-reported outcomes. Saura. ASCO 2019. Abstr 1002. NCT01808573. 17 17

NALA: Baseline Characteristics

Neratinib + Capecitabine Lapatinib + Capecitabine Characteristic, n (%) (n = 307) (n = 314) Age < 65 yrs 244(79) 248(79) Geographic region • Europe 121 (39) 123 (39) • North America 59 (19) 65 (21) • Rest of world 127 (41) 126 (40) Hormone receptor+ (ER+ and/or PgR+) 181 (59) 186 (59) Visceral disease at enrollment 247 (80) 253 (81) De novo metastatic disease 139 (45) 136 (43) No. prior HER2-targeted therapies for MBC • 2 215 (70) 215 (68) • ≥ 3 92 (30) 99 (32) Prior HER2-targeted therapies for MBC • Trastuzumab only 124 (40) 113 (36) • Trastuzumab + pertuzumab 24 (8) 23 (7) • Trastuzumab + T-DM1 58 (19) 64 (20) • Trastuzumab + pertuzumab + T-DM1 101 (33) 114 (36)

MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine. Saura. ASCO 2019. Abstr 1002. 18 18

PCE 2020 Spring Oncology Series 6 Key Updates in the Treatment of HER2-Positive Breast Cancer

NALA: Survival

PFS (Prespecified Means Analysis) OS (Coprimary Endpoint)

Mean PFS, Mos Mean OS, Mos Log-Rank Neratinib + capecitabine 8.8 1.0 1.0 Neratinib + capecitabine 24.0 HR (95% CI) P Value Lapatinib + capecitabine 6.6 Lapatinib + capecitabine 22.2 0.88 (0.72-1.07) .2086 0.8 0.8

0.6 0.6 Restriction: Restriction: 24 mos 0.4 0.4 48 mos Restricted mean analysis P = .0003 0.2 0.2 OS of Probability 1.7 mos

Probability of PFS of Probability 2.2 mos 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 3033 36 39 42 45 48 51 54 57 Patients Mos Since Randomization Patients Mos Since Randomization at Risk, n at Risk, n N + Cape 307 183 113 69 54 35 20 13 9 7 3 2 2 N + Cape 307 294 275 244 220 182 142 112 82 64 47 34 28 18 15 13 6 4 2 1 L + Cape 314 183 82 39 24 9 8 3 2 2 2 2 1 L + Cape 314 303 273 240 208 170 132 107 84 67 47 36 27 22 17 12 8 4 3 1

Cape = capecitabine; L = lapatinib; N = neratinib. Saura. ASCO 2019. Abstr 1002. 19 19

NALA: Time to Intervention for CNS Metastases

100 Neratinib + Capecitabine Lapatinib + Capecitabine Intervention, % (n = 55/307) (n = 75/314) Radiation therapy 11 15 80 Surgery/procedure 2 3 Anticancer medication 1 1

60 Neratinib + capecitabine Overall cumulative incidence (Gray’s test): 22.8% vs 29.2%; P = .043 Lapatinib + capecitabine 40

20 Cumulative incidence(%)

0 0 6 12 18 24 30 36 42 48 54 60 Mos Since Randomization

CNS = central nervous system. Saura. ASCO 2019. Abstr 1002. 20 20

NALA: Safety Neratinib + Capecitabine (n = 303) Lapatinib + Capecitabine (n = 311) Treatment-Emergent AE, % All Grade Grade 3/4 All Grade Grade 3/4 Overall 100 61 99 60 • Diarrhea 83 24* 66 13* • Hand–foot syndrome 46 10 56 11 • Hypokalemia 12 5 14 6 • Nausea 53 4 42 3 • Vomiting 46 4 31 2 • Fatigue 34 3 31 3 • Neutropenia 7 3 5 2 • Asthenia 12 3 12 2 • Decreased appetite 35 3 22 2 • Dehydration 6 2 6 2

• Median duration of treatment numerically longer with • Discontinuation due to treatment-emergent AEs: neratinib vs lapatinib (5.7 vs 4.4 mos) neratinib arm, 10.9%; lapatinib arm, 14.5% *No grade 4 diarrhea observed. AE = adverse event. Saura. ASCO 2019. Abstr 1002. 21 21

PCE 2020 Spring Oncology Series 7 Key Updates in the Treatment of HER2-Positive Breast Cancer

Phase II CONTROL Trial: Antidiarrheal Prophylaxis for Neratinib- Associated Diarrhea in Early HER2+ BC • Open-label phase II trial enrolled adults with stage I-IIIC HER2+ BC who completed trastuzumab- based adjuvant therapy* within 1 yr or who d/c due to AE (N = 501)

All prophylaxis cohorts Neratinib 240 mg/day (13 cycles) Neratinib dose-escalation cohorts Neratinib 120 mg/day D1-7  160 mg/day D8-14 Loperamide (LPM) LPM 4 mg TID D1-14, then BID D15-56  240 mg/day (13 cycles)

Budesonide 9 mg QD for 1 cycle LPM + Budesonide LPM as needed (16 mg/day max) LPM 4 mg TID D1-14, then BID D15-56

Colestipol 2 g BID for 1 cycle LPM + Colestipol Neratinib 160 mg/day D1-14  200 mg/day D15-28 LPM 4 mg TID D1-14, then BID D15-28  240 mg/day (13 cycles)

Colestipol 2 g BID for 1 cycle; Colestipol + LPM prn LPM as needed (16 mg/day max) LPM as needed (16 mg/day max)

0 1 2 3 4 5 6 7 8 910111213 0 1 2 3 4 5 6 7 8 9 10111213

*28-day cycles. Treatment-emergent diarrhea also managed with neratinib interruption/reduction, BSC. Data cutoff: August 26, 2019.; *Includes trastuzumab, trastuzumab + pertuzumab, and T-DM1. BC = breast cancer; AE = adverse event; d/c = discontinued; LPM = loperamide; tx = treatment. Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01. 22 22

ExteNET vs CONTROL: Antidiarrheal Prophylaxis Reduces Incidence, Severity of Diarrhea With Neratinib

ExteNET*: Adj Neratinib in CONTROL* Trastuzumab-Treated HER2+ EBC (N = 1408) Loperamide LPM + Budesonide LPM + Colestipol Neratinib Dose Escalation + LPM prn (n = 60) 5% (n = 137) (n = 64) (n = 136) 3% 14% 15% 20% 21% 17% 23% 31% 28% 40% 40% 25% 24% 28% 35% 42% 32% 25% 33%

Discontinuation rate due to diarrhea: 20.4% 10.9% 3.7% 3.3%

None Grade 1 Grade 2 Grade 3

• All preventive strategies in CONTROL reduced incidence of grade ≥ 3 diarrhea compared with phase III ExteNET trial as historical control (40%)

*n = 1 grade 4 diarrhea on ExteNET, none on CONTROL. Adj = adjuvant; EBC = early breast cancer. Chan. SABCS 2019. Abstr P5-14-03. Chan. Lancet Oncol. 2016;17:367. Hurvitz. SABCS 2017. P3-14-01. 23 23

Tucatinib: HER2-Selective TKI O N NH • Less EGFR-associated toxicity than other H N N N HER2-targeted TKIs N N O N • CNS penetration Phase Ib: Tucatinib + T-DM1 in HER2+ MBC • Well tolerated and active in combinations (eg, Overall Response in Patients with Measurable Disease with T-DM1, capecitabine, or trastuzumab) 60 40 1 prior HER2 agent 20 ≥ 2 prior HER2 agents

Cellular Selectivity, IC50 (nM) 0 Agent HER2 EGFR -20 Tucatinib 8 4000 -40 Neratinib 7 8 -60 Lapatinib 49 31 change sum Maxinof -80 -100lesions oftargetdiameter(%)

CNS = central nervous system; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; TKI = tyrosine kinase inhibitor. Borges. ASCO 2016. Abstr 513. Borges. JAMA Oncol. 2018;4:1214-1220. 24 24

PCE 2020 Spring Oncology Series 8 Key Updates in the Treatment of HER2-Positive Breast Cancer

Phase Ib Study: Tucatinib + Capecitabine/Trastuzumab in HER2+ MBC

Tucatinib + Capecitabine/Trastuzumab (n = 23) Tucatinib at RP2D in Evaluable Patients With Measurable CNS Disease (n = 12) 40 P P No brain mets (n = 14) Brain mets (n = 9) 40 20 P Prior pertuzumab (n = 18) 20 P P 0 0 P -20 P -20 P P P P -40 P -40 P P -60 Tucatinib + cape -60 P Tucatinib + Tz P -80 Tucatinib + cape + Tz Screening Post Cycle 6 -80 ORR: 61% (14/23) P -100 mDoR: 10 mos (95% CI: 2.8-19.3) (Images selected to demonstrate -100 CNS ORR: 42% (5/12) longest axis of lesions) P P Max Change in Sum of Tumor Diameters (%) Diameters Tumor of Sum in Change Max Max Change in Sum of Tumor Diameters (%) Diameters Tumor of in Sum Change Max

Bars represent change in measurable lesions, but some patients n = 29 of 52 patients had brain mets at baseline, also have nonmeasurable lesions. n = 4 patients with 17 with nonmeasuarable lesions only nonmeasurable lesions only not included here. n = 1 patient did not have follow-up scan

Cape = capecitabine; CNS = central nervous system; mDoR = median duration of response; MBC = metastatic breast cancer; mets = metastases; RP2D = recommended phase II dose; Tz = trastuzumab. Hamilton. SABCS 2016. Abstr P24-21-01. Murthy. Lancet Oncol. 2018;19:880. 25 25

HER2CLIMB: Phase II Study Design

• Randomized, double-blind, placebo-controlled, active comparator phase II trial at 155 sites in 15 countries (February 2016 to May 2019); data cutoff: September 4, 2019; median f/u: 14.0 mos Stratified by brain mets (yes vs no), ECOG PS 21-day cycles (0 vs 1), and region (US or Canada vs rest of world) Tucatinib 300 mg PO BID + Patients with HER2+ MBC; Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + prior trastuzumab, pertuzumab, Capecitabine 1000 mg/m2 PO BID on Days 1-14 and T-DM1; ECOG PS 0/1; (n = 410) brain mets allowed* (N = 612) Placebo PO BID + Trastuzumab 6 mg/kg Q3W (loading dose: 8 mg/kg C1D1) + *Including previously treated stable mets, untreated Capecitabine 1000 mg/m2 PO BID on Days 1-14 mets not needing immediate local therapy, and previously treated progressing mets not needing (n = 202) immediate local tx. • Primary endpoint: PFS (RECIST v 1.1 by BICR) among • Secondary endpoints (total population): OS, PFS in first 480 randomized patients patients with brain mets, ORR in patients with measurable disease, safety in patients who received ≥ ̶ 90% power with 288 events at α = 5%, HR: 0.67 1 dose of study tx

BICR = blinded independent central review; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; MBC = metastatic breast cancer; mets = metastases; RECIST = Response Evaluation Criteria in Solid Tumors; PS = performance status; T-DM1 = trastuzumab emtansine; tx = treatment. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 26 26

HER2CLIMB: Baseline Characteristics (Total Population)

Tucatinib + Trastuzumab/Capecitabine Placebo + Trastuzumab/Capecitabine Characteristic (n = 410) (n = 202) Female, n (%) 407 (99) 200 (99) Median age, yrs (range) 55.0 (22-80) 54.0 (25-82) ECOG PS 0/1, n (%) 204 (50)/206 (50) 94 (47)/108 (54) Stage IV at initial diagnosis, n (%) 143 (35) 77 (39) Hormone receptor status, n (%) . ER and/or PgR positive 243 (60) 127 (63) . ER and PgR negative 161 (40) 75 (37) Median prior lines of therapy, n (range) . Overall 4.0 (2-14) 4.0 (2-17) . Metastatic setting 3.0 (1-14) 3.0 (1-13) Presence or history of brain metastases, n (%) 198 (48) 93 (46) . Treated, stable 118 (59.6) 55 (59.1) . Untreated 44 (22.2) 22 (23.7) . Treated, progressing 36 (18.2) 16 (17.2) • Baseline characteristics balanced between endpoint populations and treatment arms

ECOG = Eastern Cooperative Oncology Group; PS = performance status. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 27 27

PCE 2020 Spring Oncology Series 9 Key Updates in the Treatment of HER2-Positive Breast Cancer

HER2CLIMB: PFS (Primary Endpoint Population)

100 Events, Median PFS, 1-Yr PFS, n/N Mos (95% CI) % (95% CI)

80 Tucatinib + Trastuzumab/Cape 178/320 7.8 (7.5-9.6) 33 (27-40) Placebo + Trastuzumab/Cape 97/160 5.6 (4.2-7.1) 12 (8-21) 62.9 60 HR: 0.54 (95% CI: 0.42-0.71; P < .00001) 46% reduction in risk of disease progression 40 46.3 33.1

20 DiseaseProgression(%)

PatientsAliveFree andFrom 12.3 0 0 3 6 9 1215 18 21 24 27 3033 36 Patients Mos Since Randomization at Risk, n Tucatinib arm 320 235 152 98 40 29 15 10 8 4 2 1 0 Placebo arm 160 94 45 27 6 4 2 1 1 0 0 0 0 Cape = capecitabine. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 28 28

HER2CLIMB: PFS in Patients With Brain Metastases (Total Population)

100 Events, Median PFS, 1-Yr PFS, n/N Mos (95% CI) % (95% CI) 80 Tucatinib + Trastuzumab/Cape 106/198 7.6 (6.2-9.5) 25 (17-34) Placebo + Trastuzumab/Cape 51/93 5.4 (4.1-5.7) 0

60 60.4 HR: 0.48 (95% CI: 0.34-0.69; P < .00001) 52% reduction in risk of disease progression 40

33.9 24.9 20 DiseaseProgression(%) PatientsAliveFree andFrom 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Patients Mos Since Randomization at Risk, n Tucatinib arm 198 144 78 45 14 8 2 1 1 1 1 1 0 Placebo arm 93 49 12 4 0 0 0 0 0 0 0 0 0 Cape = capecitabine. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 29 29

HER2CLIMB: OS (Total Population)

100 Events, Median OS, 2-Yr OS, n/N Mos (95% CI) % (95% CI) 80 75.5 Tucatinib + trastuzumab/cape 130/410 21.9 (18.3-31.0) 45 (37-53) Placebo + trastuzumab/cape 85/202 17.4 (13.6-19.9) 27 (16-39)

60 62.4 HR: 0.66 (95% CI: 0.50-0.88); P = .0048) 44.9 34% reduction in risk of death 40 PatientsAlive(%) 20 26.6

0 0 3 6 9 1215 18 21 24 27 30 33 36 Patients Mos Since Randomization at Risk, n Tucatinib Arm 410 388 322 245 178 123 80 51 34 20 10 4 0 Placebo Arm 202 191 160 119 77 48 32 19 7 5 2 1 0 Cape = capecitabine. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 30 30

PCE 2020 Spring Oncology Series 10 Key Updates in the Treatment of HER2-Positive Breast Cancer

HER2CLIMB: OS Subgroup Analysis

OS in Total Population Subgroup Event/N HR for Death (95% CI) Total 215/612 0.66 (0.50-0.88) Age ≥ 65 yrs 53/116 0.58 (0.32-1.06) < 65 yrs 162/496 0.69 (0.50-0.95) Race White 160/444 0.69 (0.50-0.96) Nonwhite 55/168 0.51 (0.28-0.93) Hormone receptor status Positive for ER, PgR, or both 128/370 0.85 (0.59-1.23) Negative for ER and PgR 87/242 0.50 (0.31-0.80) Baseline brain metastasis Yes 114/291 0.58 (0.40-0.85) No 101/319 0.72 (0.48-1.08) ECOG PS 0 81/298 0.51 (0.33-0.80) 1 134/314 0.84 (0.59-1.20) Geographic region United States and Canada 148/369 0.68 (0.48-0.95) Rest of world 67/243 0.63 (0.39-1.03) 0.1 1.0 10.0 Favors Tucatinib Arm Favors Placebo Arm ECOG = Eastern Cooperative Oncology Group; PS = performance status. Murthy. SABCS 2019. Abstr GS1-01. Murthy. NEJM. 2019;382:597. 31 31

HER2CLIMB: Most Common Adverse Events (≥ 20% in Tucatinib Arm)

100 Grade Grade Grade 1 2 ≥ 3 80 Tucatinib + trastuzumab/cape 60 Placebo + trastuzumab/cape

40

Frequency (%) 20

0

ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cape = capecitabine; PPE = palmar–plantar erythrodysesthesia. Murthy. SABCS 2019. Abstr GS1-01. 32 32

Optimal Use of HER2-Targeted TKI for Patients With HER2- Positive MBC and Brain Metastases

• HER2 TKIs known to have CNS penetration, data from clinical trials show systemic benefit as well as CNS benefit • Standard of care for patients with single or limited brain metastases continues to be radiotherapy of CNS lesions followed by continuation of current systemic therapy • For patients with progressive brain metastases despite initial radiotherapy, consider switching to systemic therapy with HER2 TKI • HER2 TKIs may also be an option for patients without brain lesions due to overall systemic benefit observed in clinical trials • On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting

CNS = central nervous system; MBC = metastatic breast cancer; TKI = tyrosine kinase inhibitor. 33 33

PCE 2020 Spring Oncology Series 11 Key Updates in the Treatment of HER2-Positive Breast Cancer

Tucatinib Approval

• On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab/capecitabine for treatment of advanced, unresectable or metastatic HER2+ BC, including patients with brain metastases, who have received ≥ 1 previous HER2-targeted therapy in the metastatic setting ‒ Administration: 300 mg taken orally twice daily with or without food • Reduce dose to 200 mg orally twice daily for patients with severe hepatic impairment ‒ Tucatinib can cause severe diarrhea; administer antidiarrheal treatment as clinically indicated ‒ Tucatinib can cause severe hepatotoxicity; monitor ALT, AST, and bilirubin prior to starting tucatinib, every 3 weeks during treatment, and as clinically indicated ‒ Management of AEs may require temporary interruption, dose reduction, or discontinuation • Approval based on efficacy data from randomized phase II HER2CLIMB trial

AEs = adverse events; ALT = alanine aminotransferase; AST = Aspartate transaminase; BC = breast cancer. Tucatinib PI. 34 34

Case Study: May

• 60-yr-old woman presents with back pain and right breast mass (2 cm) ‒ She has no significant family history or past medical history ‒ Core biopsy of breast mass: invasive ductal carcinoma; ER: 0%, PgR: 0%, HER2: 2+; FISH ratio: 3.4 with copy number of 7 ‒ PET/CT: 3 liver lesions (largest 3 cm); several vertebral lesions in the thoracic and lumbar spine • She receives docetaxel/trastuzumab/pertuzumab (THP) and achieves PR in liver after 4 mos • 16 mos later, she experiences progression in liver (new 2.5-cm lesion, other lesions stable) • She receives T-DM1 and achieves PR in liver, with stable bone lesions • 12 mos later PET/CT shows increase in liver lesions to 3 cm, no new liver lesions, and bone lesions remain stable ‒ No brain lesions on MRI

RCB = residual cancer burden; T-DM1 = trastuzumab emtansine. 35 35

Optimal Sequence of HER2-Targeted Agents for Patients With HER2-Positive MBC

• For patients who have received multiple lines of therapy including trastuzumab, pertuzumab, and T-DM1, consider treatment with next- generation ADC T-DXd ‒ T-DXd was granted accelerated FDA approval in Dec 2019 for treatment of unresectable or metastatic HER2-positive breast cancer after ≥ 2 previous lines of anti–HER2-based regimens for metastatic disease

ADC = antibody–drug conjugate; MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. 36 36

PCE 2020 Spring Oncology Series 12 Key Updates in the Treatment of HER2-Positive Breast Cancer

Structure of Antibody–Drug Conjugates

Tumor antigen

• Tumor antigen: abundant in tumors, Antigen- mAb that targets minimal in normal tissues; internalized binding Site tumor-specific or upon ADC binding tumor-associated antigens • Antibody: high affinity, avidity for antigen; optimal PK; internalized • Linker: stable in plasma; efficient release of cytotoxic agent inside tumor cells • Payload: drug cytotoxic to targeted Stable linker tumor cells; not hydrophobic; must be releases Potent cytotoxic potent since limited number of payload only in target cell payload molecules can be attached to antibody

ADC = antibody–drug conjugate; mAb = monoclonal antibody; PK = pharmacokinetics. Thomas. Lancet Oncol. 2016;17:e254. 37 37

Mechanism of Action of HER2-Directed ADCs

ADC = antibody–drug conjugate. Image from Rinnerthaler. Int J Mol Sci. 2019;20:1115. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Licensed under Creative Commons Attribution 3.0 Unported License (CC BY 3.0). 38 38

Early- vs New-Generation Antibody–Drug Conjugates

• Early generation • New generation ‒ Mouse antibodies; immunogenic — Chimeric or humanized antibodies; ‒ Unstable in circulation reduced immunogenicity ‒ Unable to release cytotoxic drug within — Stable in circulation tumor cell — Efficient linker technology able to ‒ Cytotoxic payload: chemotherapy drugs release cytotoxic drug within tumor cell such as doxorubicin, vinca alkaloids (eg, disulfide, dipeptide, or hydrazone (eg, vinblastine), or methotrexate linkage) — Cytotoxic payload: highly potent agents with subnanomolar IC50 such as calicheamicin, maytansine derivative (eg, DM1, DM4), or auristatin (eg, MMAE, MMAF)

Thomas. Lancet Oncol. 2016;17:e254. 39 39

PCE 2020 Spring Oncology Series 13 Key Updates in the Treatment of HER2-Positive Breast Cancer

Structure of ado-Trastuzumab-Emtansine (T-DM1), a HER2-Targeted ADC

• Tumor antigen: HER2 Thioether linker Trastuzumab • Antibody: monoclonal antibody (HER2-targeted mAb) trastuzumab • Linker: systemically stable thioether, not cleavable • Cytotoxic drug payload: Emtansine (DM1), a highly potent tubulin destabilizer Cytotoxic agent: DM1

ADC = antibody–drug conjugate. Lewis Phillips et al. Cancer Res. 2008;68:9280. 40 40

HER2-Targeted ADC: Trastuzumab Deruxtecan (DS-8201)

Humanized anti-HER2 IgG1 mAb with same amino acid sequence as trastuzumab • High drug:antibody Tetrapeptide-based cleavable linker O O ratio: ~ 8 OH • Stable linker-payload O N O • Tumor-selectable O O O N H H H N N N cleavable linker Cys N N N N O H H O H O O O F • High potency, membrane-permeable O HO payload with short Cysteine residue NH systemic half-life Drug/linker O N F N • Bystander killing effect O

OH Topoisomerase I inhibitor (DXd) payload O (exatecan derivative)

ADC = antibody–drug conjugate; mAb = monoclonal antibody. Nakada. Chem Pharm Bull (Tokyo). 2019;67:173. Trail. Pharmacol Ther. 2018;181:126. Ogitani. Cancer Sci. 2016;107:1039. 41 41

DESTINY-Breast01: Trastuzumab Deruxtecan (T-DXd) in Advanced HER2+ Breast Cancer

• Open-label, multicenter, 2-part phase II study Part 1 Part 2

Pharmacokinetics (n = 65) Dose Finding* (n = 54) Continuation (n = 134) T-DXd 5.4 mg/kg T-DXd 5.4 mg/kg Adult patients with Newly T-DM1 (n = 22) (n = 28) T-DXd 5.4 mg/kg HER2+ unresectable enrolled R/R T-DXd 6.4 mg/kg T-DXd 6.4 mg/kg (n = 130) patients and/or metastatic (n = 249) (n = 22) (n = 26) BC; prior T-DM1; T-DXd 7.4 mg/kg ECOG PS 0/1; (n = 23) stable, treated brain T-DM1 *5.4 mg/kg confirmed as RP2D. metastases allowed; Intolerant T-DXd 5.4 mg/kg (n = 4) history of significant (n = 4) ILD excluded Total enrolled at 5.4 mg/kg: n = 184

• Primary endpoint: ORR by ICR (RECIST v1.1) • Data cutoff: August 1, 2019 • Secondary endpoints: investigator-assessed ORR, ‒ 79 (42%) continuing treatment DCR, DoR, CBR, PFS, OS, PK, safety ‒ 105 (57.1%) d/c (mostly for PD, 28.8%) CBR = clinical benefit rate; d/c = discontinuation; DCR = disease control rate; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; ICR = independent central review; ILD = interstitial lung disease; PD = progressive disease; PK = pharmacokinetics; PS = performance status; RP2D = recommended phase II dose; RECIST = Response Evaluation Criteria in Solid Tumors; R/R = resistant/refractory. Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610-621. 42 42

PCE 2020 Spring Oncology Series 14 Key Updates in the Treatment of HER2-Positive Breast Cancer

DESTINY-Breast01: Baseline Characteristics

T-DXd 5.4 mg/kg T-DXd 5.4 mg/kg Characteristic Characteristic (N = 184) (N = 184) Median age, yrs (range) 55 (28-96) Median prior lines of treatment, n (range) 6 (2-27) Female, % 100 . Trastuzumab, % 100 . T-DM1, % 100 Region, % . Pertuzumab, % 65.8 . Asia 34.2 . Other anti-HER2 therapy, % 54.3 . North America 28.8 . Hormone therapy, % 48.9 . Europe 37.0 . Other systemic therapy, % 99.5 ECOG PS, % Visceral disease, % 91.8 . 0/1 55.4/44.0 . 2 0.5 History of brain metastases, % 13.0 Hormone receptor status, % HER2 expression, % . Positive 52.7 . IHC 3+ 83.7 . Negative 45.1 . IHC 2+, ISH+ 15.2 . Unknown 2.2 . IHC 1+, ISH+ 1.1

ECOG = Eastern Cooperative Oncology Group; PS = performance status; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 43 43

DESTINY-Breast01: Response

T-DXd 5.4 mg/kg Response (ITT) (N = 184) 100 Best Change in Tumor Size ORR* (by ICR; n = 112), % 60.9 (53.4-68.0) 80 (95% CI) (by ICR; n = 168) • CR (n = 11) 6.0 60 • PR (n = 101) 54.9 40 • SD (n = 67) 36.4 20

• PD (n = 3) 1.6 0 • Not evaluable (n = 2) 1.1 -20

DCR, % (95% CI) 97.3 (93.8-99.1) -40 6-mo CBR, % (95% CI) 76.1 (69.3-82.1) -60

Median DoR, of Sum Diameters in Baseline

14.8 (13.8-16.9) From Change PercentageBest -80 mos (95% CI) Line at 20% indicates PD; line at −30% indicates PR. -100 Median time to response, 1.6 (1.4-2.6) mos (95% CI) Patients (N = 168) *Patients who received T-DXd 5.4 mg/kg.

CBR = clinical benefit rate; DCR = disease control rate; DoR = duration of response; ICR = independent central review; ITT = intention-to-treat; PD = progressive disease; SD = stable disease; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 44 44

DESTINY-Breast01: ORR by Subgroup Subgroup Events/ Total Patients, n/N Objective Response, % (95% CI)

All patients 112/184 61 (53-68) Previous pertuzumab use Yes 78/121 64 (55-73) No 34/63 54 (41-67) Hormone receptor Positive 56/97 58 (47-68) Negative 55/83 66 (55-76) No. of regimens excluding HT ≥ 3 99/167 59 (51-67) < 3 13/17 76 (50-93) Brain metastasis Yes 14/24 58 (37-78) No 98/160 61 (53-69) Presence of visceral disease Yes 102/169 60 (53-68) No 10/15 67 (38-88) Geographic region Asia 37/63 59 (46-71) North America 33/53 62 (48-75) Europe 42/68 62 (49-73) ECOG PS 0 67/102 66 (56-75) 1 45/81 56 (44-67) T-DXd tx immediately after T-DM1 Yes 36/56 64 (50-77) No 76/128 59 (50-68) HER2-positive tumor IHC 3+ 97/154 63 (55-71) IHC 1+ or 2+, ISH positive 13/28 46 (28-66) ECOG = Eastern Cooperative Oncology group; HT = hormone therapy; 01020 30 40 50 60 70 80 90 100 PS = performance status; tx = therapy. Modi. NEJM. 2020;382:610. 45 45

PCE 2020 Spring Oncology Series 15 Key Updates in the Treatment of HER2-Positive Breast Cancer

DESTINY-Breast01: Survival

PFS OS mPFS: 16.4 mos (95% CI: 12.7-NR) mOS: NR 1.0 mPFS in 24 patients with brain mets: 1.0 18.1 mos (95% CI: 6.7-18.1) 0.8 0.8

0.6 0.6

0.4 0.4

0.2 Censored: 68.5% 0.2 Censored: 86.4% ProbabilityPFS of Events: 31.5% ProbabilityOS of Events: 13.6% 0 0 0 1 2 3 4 5 6 7 8 9 1011121314151617181920 0 1 2 3 4 5 6 7 8 910 11121314151617181920 Mos Mos Patients Patients at Risk, 184 182 174 155 153 135 121 107 103 94 69 54 38 17 11 10 9 4 at Risk, 184 183 182 179 174 171 167 161 155 147 133 101 66 36 21 16 12 9 8 n 3 1 0 n 4 0 • Median follow-up: 11.1 mos (range: 0.7-19.9)

Mets = metastases; mPFS = median PFS; NR = not reached; T-DXd = trastuzumab deruxtecan. Modi. NEJM. 2020;382:610. 46 46

DESTINY-Breast01: AEs in Overall Population

Nausea Fatigue Grade 1/2 Alopecia Grade ≥ 3 Vomiting Constipation Neutropenia Decreased appetite Anemia Diarrhea Decreased WBC count Thrombocytopenia Headache Cough 0 10 2030 40 50 60 7080 90 100

AE = adverse events; WBC = white blood cell count. Krop. SABCS 2019. Abstr GS1-03. Modi. NEJM. 2020;382:610. 47 47

Case Study: May

• After progressing on THP and T-DM1, she begins therapy with trastuzumab deruxtecan (T-DXd) 5.4 mg IV Q3W ‒ Treatment is generally tolerated well with minimal diarrhea and alopecia • At 3 months, PET/CT shows PR in liver, stable bone lesions • At 6 months, PET/CT shows continued PR but hazy infiltrates in upper lobes of both lungs ‒ She has no apparent symptoms and reports no shortness of breath or dyspnea on exertion

T-DM1 = trastuzumab emtansine; THP = docetaxel/trastuzumab/pertuzumab, Q3W = every 3 weeks. 48 48

PCE 2020 Spring Oncology Series 16 Key Updates in the Treatment of HER2-Positive Breast Cancer

DESTINY-Breast01: Interstitial Lung Disease

T-DXd 5.4 mg/kg (N = 184) AE, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Any Grade ILD 5 (2.7) 15 (8.2) 1 (0.5) 0 4 (2.2) 25 (13.6)

• Among the 25 ILD events: ‒ Median time to investigator-reported onset: 193 days (range: 42-535) ‒ 17/20 patients with grade ≥ 2 ILD received glucocorticoids ‒ 7 patients recovered, 2 were recovering, 12 were unknown/not followed to ILD resolution, 4 had died • For 4 fatal cases, onset was from 63-148 days and death 9-60 days after ILD diagnosis (3 received steroids) • Recommendation: monitor for symptoms; hold T-DXd and re-image for grade 1 ILD; discontinue T- DXd and start steroids immediately upon suspecting grade 2 or greater ILD

AE = adverse events; ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. 49 49

Strategies to Manage ILD Associated with T-DXd Therapy in HER2-Positive MBC

• Monitor for ILD and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms ‒ Evaluate with imaging and consider pulmonology consult • For patients with asymptomatic ILD, hold T-DXd and re-image in 4 wks ‒ Consider corticosteroid treatment, if necessary ‒ If resolved, restart T-DXd with dose reduction • For patients with symptomatic ILD, discontinue T-DXd and initiate steroids ‒ Consider pulmonary consult

ILD = interstitial lung disease; MBC = metastatic breast cancer; T-DXd = trastuzumab deruxtecan. 50 50

Guidelines for the Management of Trastuzumab Deruxtecan–Induced Interstitial Lung Disease

Grade 1 Grade 2 Grade 3/4 • Monitor with close follow-up in 2-7 days for • Immediately begin systemic steroids (≥ 1 • Hospitalization required onset of clinical symptoms, pulse oximetry mg/kg/day prednisone or equivalent) until • Immediately begin empiric high-dose • Consider follow-up imaging in 1-2 wks (or as clinical improvement, followed by gradual methylprednisolone IV (500-1000 mg/day for 3 days), followed by ≥ 1 mg/kg/day of clinically indicated) taper over at least 4 wks prednisone (or equivalent) until clinical • Consider initiating systemic steroids (≥ 0.5 • Monitor symptoms closely improvement, followed by gradual taper over mg/kg/day prednisone or equivalent) until • Re-image as clinically indicated at least 4 wks improvement, followed by gradual taper over • For worsening symptoms or no improvement • Re-image as clinically indicated at least 4 wks within 5 days: • For no improvement within 3-5 days: • If ILD worsens despite initiation of ⎻ Consider increasing dose of steroids to ⎻ Reconsider additional workup for corticosteroids, follow grade 2 guidelines 2 mg/kg/day prednisone or equivalent alternative etiologies as described above and/or switch to IV administration with • Restart T-DXd if ILD resolves within 28 days Consider other immunosuppressants methylprednisolone ⎻ after onset and/or treat per local practice ⎻ Reconsider additional workup for • Restart T-DXd at reduced dose if ILD resolves alternative etiologies as described above > 28 days after onset ⎻ Escalate care as clinically indicated • Permanently discontinue T-DXd if grade 1 ILD occurs beyond cycle Day 22 and has not • Permanently discontinue T-DXd resolved within 49 days from last infusion • Permanently discontinue T-DXd

ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan. Krop. SABCS 2019. Abstr GS1-03. 51 51

PCE 2020 Spring Oncology Series 17 Key Updates in the Treatment of HER2-Positive Breast Cancer

Trastuzumab Deruxtecan Approval

• On December 20, 2019, the FDA approved fam-trastuzumab deruxtecan-nxki for treatment of patients with unresectable or metastatic HER2+ BC who have received ≥ 2 previous HER2-targeted therapies in the metastatic setting ‒ Administration/dose: IV 5.4 mg/kg QW3 ‒ Monitor CBC prior to each administration; assess LVEF prior to initiation and at regular intervals during treatment as clinically indicated; monitor for ILD and pneumonitis during treatment ‒ Management of AEs may require temporary interruption, dose reduction, or discontinuation • Based on ORR and DoR data from randomized phase II DESTINY-Breast01 trial

AE = adverse event; BC = breast cancer; CBC = complete blood count; DoR = duration of response; ILD = interstitial lung disease; LVEF = left ventricle ejection fraction. Trastuzumab deruxtecan PI. 52 52

Future Directions in HER2+ MBC

53

HER2CLIMB-02: Tucatinib or Placebo + T-DM1 in Unresectable HER2-Positive Breast Cancer

• Randomized, double-blind, phase III trial

Patients with HER2+ unresectable LA Tucatinib 300 mg PO BID + or metastatic BC; previous treatment T-DM1 3.6 mg/kg IV Q3W with trastuzumab and a taxane; previous pertuzumab permitted but not required; untreated brain mets not requiring immediate therapy or PlaceboPlacebo300 mg300 PO mg BID PO +BID + previously treated and stable brain T-DM1 T-DM13.6 mg/kg 3.6 mg/kg IV Q3W IV Q3W mets permitted (planned N = 460)

• Primary endpoint: PFS (RECIST v 1.1 by investigator assessment) • Secondary endpoints: OS, PFS (BICR), ORR, DoR, CBR, rate of AEs

AE = adverse event; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; DoR = duration of response; LA = locally advanced; mets = metastases; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. NCT03975647. 54 54

PCE 2020 Spring Oncology Series 18 Key Updates in the Treatment of HER2-Positive Breast Cancer

DESTINY-Breast02: T-DXd vs Trastuzumab/Cape or Lapatinib/Cape in HER2+ MBC With Prior T-DM1

• Randomized, open-label, active-controlled phase III trial Stratified by hormone receptor status, prior pertuzumab, history of visceral disease

Patients with HER2+, unresectable Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W and/or metastatic BC; at least third (planned n = 400) line; progression on prior HER2- targeted agents including T-DM1; no prior capecitabine; Investigator’s Choice of Trastuzumab/Cape no CNS metastases or Lapatinib/Cape (planned N = 600) (planned n = 200)

• Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, PFS by investigator assessment, ORR, DoR, CBR

BC = breast cancer; BICR = blinded independent central review; Cape = capecitabine; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. NCT03523585. 55 55

DESTINY-Breast03: Second-line T-DXd vs T-DM1 in HER2+ MBC After Progression on Trastuzumab/Taxane

• Randomized, open-label phase III trial at ~160 sites in North America and Europe Stratified by hormone receptor status, prior pertuzumab, history of visceral disease

Patients with HER2+, Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W unresectable and/or metastatic (Planned n = 250) BC; previous treatment with trastuzumab and a taxane; no prior HER2-targeted ADC; CNS T-DM1 3.6 mg/kg IV Q3W metastases allowed (planned N = 500) (Planned n = 250)

• Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, ORR, DoR, CBR, PFS (investigator assessment)

ADC = antibody–drug conjugate; BC = breast cancer; BICR = blinded independent central review; CBR = clinical benefit rate; CNS = central nervous system; DoR = duration of response; MBC = metastatic breast cancer; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. NCT03529110. 56 56

Efficacy of Trastuzumab Deruxtecan in HER2-Low MBC

100 % Change in Tumor Size by Best % Change in Tumor Size by 80 HER2 IHC Status 80 HER2 IHC Status 60 60 n = 48 IHC 2+ 40 40 IHC 1+ 20 20 * 0 x 0 ** * * ** * -20 * -20 -40 IHC 2+ Change in Tumorin Change Size From BL (%) BL From Size * -40 -60 * in Change % Best Tumor Size From BL From Size Tumor -60 IHC 1+ -80 -80 -100 -100 *Hormone receptor negative 10 20 30 40 50 60 70 80 90100 110 120 Line at 20% indicates PD; line at -30% indicates PR. Time (weeks) Efficacy in HER2-Low MBC Confirmed ORR, % Median DoR, Mos Median PFS, Mos All (N = 54) 37.0 10.4 11.1 IHC 2+ (n = 26) 38.5 -- -- IHC 1+ (n = 28) 35.7 -- -- HR+ (n = 47) 40.4 -- -- Prior CDK4/6 inhibitor (n = 16) 43.8 -- -- BL = baseline; DoR = duration of response; ILD = interstitial lung disease; MBC = metastatic breast cancer; NR = not reported; PD = progressive disease. Modi. JCO. 2020: JCO1902318. 57 57

PCE 2020 Spring Oncology Series 19 Key Updates in the Treatment of HER2-Positive Breast Cancer

DESTINY-Breast04: T-DXd vs Chemotherapy in Unresectable HER2- Low Breast Cancer

• Randomized, open-label, active-controlled phase III trial

Stratified by HER2 IHC status, no. of prior lines of CT, HR status (HR+ without previous CDK4/6i vs HR+ with previous CDKi vs HR-)

Patients with HER2-low (IHC1+ or Trastuzumab Deruxtecan 5.4 mg/kg IV Q3W IHC2+/ISH-), unresectable and/or (planned n = 360) metastatic BC; previous treatment with trastuzumab and a taxane; progression on endocrine therapy; Physician’s Choice of CT: no prior HER2 positivity Capecitabine, Eribulin, Gemcitabine, Paclitaxel or nab-Paclitaxel (planned N = 540) (planned n = 180)

• Primary endpoint: PFS (RECIST v 1.1 by BICR) • Secondary endpoints: OS, PFS (investigator assessment), ORR, DoR

BC = breast cancer; BICR = blinded independent central review; CT = chemotherapy; DoR = duration of response; HR = hormone receptor; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan. NCT03734029. 58 58

HER2-Targeted ADC: Trastuzumab Duocarmazine (SYD985)

• HER2 antibody with same amino Trastuzumab-vc-seco-duocarmycin-hydroxybenzamide-azaindole acid sequence as trastuzumab Antibody Linker Prodrug • Proteolytic cleavage of linker in Trastuzumab Maleimide Protease- Self- Seco-duocarmycin linker cleavable elimination progrug tumor microenvironment leads to linker spacers activation of prodrug payload Valine PABC Cyclization • Active toxin (DUBA) alkylates Citrulline spacer

DNA, kills dividing and O NH2 HN CI nondividing cells O O H H • Bystander killing effect N N S N O O N O N H OH H O N N N O O O N O O N SYD985 O O O OH ~2.8

ADC = antibody–drug conjugate. Dokter. Mol Cancer Ther. 2014;13:2618. Elgersma. Mol Pharm. 2015;12:1813. 59 59

Phase I Study: Trastuzumab Duocarmazine in Locally Advanced or Metastatic HER2+ Breast Cancer

Dose-Expansion Cohorts (n = 146) 100 Drug-Related AE, n (%) Best % Change in Tumor Size in HER2+ Cohort Grade 1/2 Grade 3 80 60 Fatigue 43 (29) 5 (3) 40 ORR: 33% (95% CI: 20.4-48.4) Conjunctivitis 41 (28) 4 (3) 20 Dry eye 44 (30) 1 (1) 0 * * ** * Increased lacrimation 29 (20) 0 -20 Dry skin 26 (18) 0 -40 Best Change in in Change Best -60 Decreased appetite 27 (18) 2 (1)

Tumor Size From BL (%) BL From Size Tumor -80 Alopecia 26 (18) 0 -100 Nausea 27 (18) 0 *Dose-expansion phase. n = 5 patients with 0% best percentage change. Stomatitis 24 (16) 0 • Most drug-related TEAEs mild to moderate Neutropenia 14 (10) 9 (6) ⎻ Ocular toxicity reported in 2/3 of patients; most Vomiting 17 (12) 0 common reason for treatment discontinuation Anemia 13 (9) 2 (1) ⎻ Ocular toxicity, neutropenia most common reason Pyrexia 9 (6) 0 for dose modifications

AE = adverse event; BL = baseline; TEAE = treatment-emergent adverse event. Banerji. Lancet Oncol. 2019;20:1124. 60 60

PCE 2020 Spring Oncology Series 20 Key Updates in the Treatment of HER2-Positive Breast Cancer

TULIP: Trastuzumab Duocarmazine vs Physician’s Choice of Tx in Locally Advanced or Metastatic Breast Cancer

• Randomized, active-controlled phase III trial

Patients with HER2+, Trastuzumab Duocarmazine Q3W Until PD, unresectable, locally (planned n = 230) advanced and/or metastatic toxicity, or BC; progression on or after ≥ withdrawal 2 HER2-targeted regimens or Survival f/u after T-DM1; Physician’s Choice: Lapatinib/Capecitabine, ECOG PS 0-2 Trastuzumab/Capecitabine, Trastuzumab/Vinorelbine, Q3M (planned N = 345) Trastuzumab/Eribulin (planned n = 115)

Tumor evaluation Q6W

• Primary endpoint: PFS (RECIST v 1.1) • Secondary endpoints: OS, PFS (investigator assessment), ORR, PROs/QoL

BC = breast cancer; ECOG = Eastern Cooperative Oncology Group; f/u = follow-up; PD = progressive disease; PRO = patient-reported outcomes; PS = performance status; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; T-DM1 = trastuzumab emtansine. NCT03262935. 61 61

Margetuximab: Novel HER2-Targeted Monoclonal Antibody

Increased CD16A Affinity: Enhance Innate Immunity/More Potent ADCC Stimulation • has the same specificity, NK affinity to HER2 as trastuzumab with similar Cell Perforins Cancer Cell ability to disrupt signaling Destruction HER2 • However, via Fc engineering with intent to CD16A HER2+ Cancer Cell activate immune responses, margetuximab Granzymes has altered Fc receptor affinity ‒ Trastuzumab: WT IgG1 effector domains; Decreased CD32B Affinity: binds and activates immune cells Enhance Adaptive Immunity/Increase Immune Activation HER2-specific ‒ Margetuximab: Increased affinity for Lymphocyte activating Fcγ RIIIA (CD16A) and Proliferation decreased affinity for inhibitory Fcγ RIIB CD32B T-cell (CD32B) APC TAA ADCC = Antibody-dependent cellular cytotoxicity; APC, antigen presenting cell; WT = wildtype. Nordstrom. Breast Cancer Res. 2011;13:R123. Stavenhagen. Cancer Res. 2007;67:8882. Nordstrom. ASCO 2019. Abstr 1030. Clynes. Nat Med. 2000;6:443. 62 62

SOPHIA: Margetuximab vs Trastuzumab in HER2+ Advanced Breast Cancer After ≥ 2 HER2 Therapies

• Randomized, open-label phase III trial (data cutoff: September 30, 2019) Stratified by CT, no. of prior lines of tx (> 2 vs ≤ 2), no. of metastatic sites (> 2 vs ≤ 2)

Margetuximab 15 mg/kg Q3W + CT* Patients with HER2+ advanced BC with in 3 wk cycles ≥ 2 previous anti-HER2 therapies, (n = 266) including pertuzumab; 1-3 prior lines of tx for metastatic disease; prior brain metastasis allowed if Trastuzumab 8 mg/kg loading  6 mg/kg Q3W + treated/stable CT* in 3-wk cycles (N = 536) (n = 270)

*Investigators choice of CT: capecitabine, eribulin, gemcitabine, or vinorelbine. • Sequential primary endpoint: PFS, OS • Secondary endpoints: ORR by central blinded analysis, investigator-assessed PFS • Tertiary and exploratory endpoints: investigator-assessed CBR, DoR, safety, and effect of CD16A, CD32A, and CD32B alleles on margetuximab efficacy

BC = breast cancer; CBR = clinical benefit rate; CT = chemotherapy; DoR = duration of response; tx = treatment. Rugo. SABCS 2019. Abstr GS1-02. 63 63

PCE 2020 Spring Oncology Series 21 Key Updates in the Treatment of HER2-Positive Breast Cancer

SOPHIA: Investigator-Assessed PFS

Investigator-Assessed PFS (Oct 2018 Cutoff) Investigator-Assessed PFS (Sep 2019 Cutoff)

100 + Events, Median PFS, 100 + Events, Median PFS, ++ + n Mos (95% CI) + n Mos (95% CI) + ++ 5.7 (5.22-6.97) +++ Margetuximab + CT (n = 266) 160 5.6 (5.06-6.67) + + Margetuximab + CT (n = 266) 208 80 + + 80 + Trastuzumab + CT (n = 270) 222 4.4 (4.14-5.45) ++ ++ Trastuzumab + CT (n = 270) 177 4.2 (3.98-5.39) + ++++ + + + + ++ + HR: 0.70 (95% CI: 0.56-0.87; P = .001) HR: 0.71 (95% CI: 0.58-0.86; P = .0006) 60 ++++ 60 ++ +++ 30% reduction in risk of disease progression + 29% reduction in risk of disease progression + + + ++ + ++ + + + 40 + +++ 40 + + (%) PFS PFS (%) PFS + +++ + ++ + + 20 + + + + 20 ++ ++ ++ ++ + ++ + + ++ ++ + + ++ + +++ ++ + + ++ + ++ + + + 0 + + 0 + 0 510 15 20 25 0 10 20 30 Mos From Randomization Mos From Randomization Margetuximab + CT 266 206 155 112 72 61 33 32 16 13 8 7 3 2 2 0 0 0 Margetuximab + CT 266 210 137 100 62 36 25 14 11 6 5 3 2 2 0 Trastuzumab + CT 270 184 130 87 59 45 25 21 10 5 4 3 1 1 1 1 1 0 Trastuzumab + CT 270 192 108 72 42 20 8 4 3 2 2 1 0

CT = chemotherapy. Rugo. SABCS 2019. Abstr GS1-02. 64 64

SOPHIA: Interim OS Analyses (ITT)

First Interim OS Analysis (Oct 2018 Cutoff) Second Interim OS Analysis (Sep 2019 Cutoff) Events, Median OS, n Mos (95% CI) Events, Median OS, n Mos (95% CI) Margetuximab + CT (n = 266) 78 18.9 (16.16-25.07) 100 +++++++++++++ 80 17.2 (15.80-33.31) 100 ++ Margetuximab + CT (n = 266) 131 21.6 (18.86-24.05) +++++++++ Trastuzumab + CT (n = 270) + + ++++++++++ Trastuzumab + CT (n = 270) 139 19.8 (17.54-22.28) ++++ HR: 0.95 (95% CI: 0.69-1.31; P = .758) +++++++ + 80 +++++++ 80 HR: 0.89 (95% CI: 0.69-1.13; P = .326) +++++ +++++++++ +++++++++ + +++ ++++ 60 ++++++++++ 60 ++++ +++++ + +++++++++++++++++ + ++++ + ++++++ 40 ++++ +++++ +++++++++ + + 40 ++

OS (%) OS + OS (%) OS ++++++++++++ + Median difference: 1.8 mos ++++ ++++++++ ++ + + ++++ + Median difference: 1.7 mos +++ + ++ 20 20 + + Median follow-up: 9.2 mos Median follow-up: 15.6 mos 0 0 0 10 20 30 0 10 20 30 40 Mos From Randomization Mos From Randomization

Margetuximab + CT 266 241 209 174 125 85 57 42 29 17 8 3 2 0 0 Margetuximab + CT 266 259 249 239 230 214 186 159 131 107 80 64 47 35 31 22 14 9 3 2 2 0 Trastuzumab + CT 270 237 194 163 122 92 63 37 24 14 6 3 2 1 0 Trastuzumab + CT 270 260 246 235 218 205 183 160 126 102 74 57 43 30 22 16 10 6 2 2 2 1 0

CT = chemotherapy; ITT = intention-to-treat. Rugo. SABCS 2019. Abstr GS1-02. 65 65

SOPHIA: Prespecified Exploratory OS in CD16A-158F Carriers

100 +++ + ++ + Events, Median OS, ++ n Mos (95% CI) + 80 ++ Margetuximab + CT (n = 221) 103 23.7 (18.89-28.32) ++ ++ 114 19.4 (16.85-22.28) + Trastuzumab + CT (n = 216) ++++++ 60 ++ +++ ++ +++ HR: 0.79 (95% CI: 0.61-1.04; P = .087) +++ +++++++ +++ ++ ++ ++ Median follow-up: 15.6 mos 40 + ++++++++++ OS(%) + ++ + + +++++ +++ +++ +++ + +++ + 20 + Median difference: 4.3 mos + +

0 0 10 20 30 40 Mos From Randomization Margetuximab + CT 221 219 212 204196181 157 135111 91 68 55 42 31 27 19 13 8 2 1 1 0 Trastuzumab + CT 216 210 201 192176165 145 123 98 81 57 43 30 21 16 11 9 6 2 2 2 1 0 • CD16A-158F carriers (FF or FV): 437/506 (86%) of genotyped patients

CT = chemotherapy. Data Cutoff: September 2019. Rugo. SABCS 2019. Abstr GS1-02. 66 66

PCE 2020 Spring Oncology Series 22 Key Updates in the Treatment of HER2-Positive Breast Cancer

SOPHIA: Safety

Margetuximab + CT Trastuzumab + CT AEs, n (%) (n = 264) (n = 265) Any grade 260 (98.5) 261 (98.1) Any margetuximab- or trastuzumab-related AE 160 (60.6) 132 (49.6) Grade ≥ 3 AE 142 (53.8) 140 (52.6) Grade ≥ 3 margetuximab- or trastuzumab-related AE 34 (12.9) 22 (8.3) Any serious AE 43 (16.3) 49 (18.4) Any margetuximab- or trastuzumab-related serious AE 5 (1.9) 4 (1.5) AE leading to treatment discontinuation 8 (3.0) 7 (2.6) AE resulting in death* 3 (1.1) 2 (0.8) AEs of special interest All Grade Grade ≥ 3 All Grade Grade ≥ 3 • IRR 35 (13.3) 4 (1.5) 9 (3.4) 0 • Discontinuation due to IRR 2 (0.6) 0 0 0 4 (1.5) 0 6 (2.3) 0 • LV dysfunction resulting in delayed dosing or discontinuation

*Deaths due to pneumonia (n = 2), pneumonia aspiration (n = 1) in margetuximab arm; pneumonia (n = 1), acute kidney injury (n =1) in trastuzumab arm. None related to study treatments. Data cutoff: April 2019. AE = adverse event; CT = chemotherapy; IRR = infusion-related reaction; LV = left ventricle. Rugo. SABCS 2019. Abstr GS1-02. 67 67

Implications for Practice

• HER2-targeted TKIs are a reasonable therapy for HER2+ MBC in the third-line setting and beyond ‒ Tucatinib data are particularly strong and may be a good option for patients with progressive brain metastases • Trastuzumab deruxtecan is a major new therapy approved for HER2+ MBC in the third-line setting, likely to move to earlier settings ‒ Post neoadjuvant therapy ‒ Second-line T-DXd vs T-DM1 (DESTINY-Breast03) ‒ Also being looked at for HER2-low disease (DESTINY-Breast04) • Margetuximab is of unclear benefit (perhaps in CD16A-F allele carriers?)

MBC = metastatic breast cancer; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor. 68 68

PCE Action Plan

 Clinicians should reassess risks and benefits of additional lines of therapy based on patient’s fitness, comorbidities, and preferences at progression  If additional treatment is indicated, select therapy based on disease features as well as patient’s fitness, comorbidities, and preferences  For patients with brain metastases, consider treatment with HER2 TKI-based therapy  After ≥ 2 previous lines of anti–HER2-based therapy, consider T-DXd for eligible patients  For patients receiving T-DXd, monitor for signs of interstitial lung disease and manage ILD using recommended guidelines

PCE Promotes Practice Change

ILD = interstitial lung disease; T-DXd = trastuzumab deruxtecan; TKI = tyrosine kinase inhibitor. 69 69

PCE 2020 Spring Oncology Series 23 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

1

Learning Objectives

• Formulate treatment strategies for advanced renal cell carcinoma (RCC) based on current evidence and patient/disease factors • Identify potential immune-related adverse events (AEs) and their onset during and after therapy • Implement strategies to recognize and appropriately manage side effects associated with tyrosine kinase inhibitors (TKIs) for advanced RCC

2 2

Overview of RCC

• More than 50% of patients with RCC have no symptoms ‒ Diagnosis is through incidental imaging of the abdomen or chest ordered for unrelated symptoms • Hematuria serves as a warning sign: necessitates further evaluation and imaging leading to a diagnosis and treatment plan • Solid tumors are managed by size ‒ 20% of tumors >3 cm discovered incidentally will be benign ‒ Tumors ≥4 cm have metastatic potential • Treatment options include active surveillance, ablation, nephron-sparing tumor excision, nephrectomy, and systemic treatment • Predictors of a poor prognosis include poor functional status and metastasis

Gray RE, Harris GT. Am Fam Physician. 2019;99:179-184. 3 3

2020 PCE Spring Oncology Series 1 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

RCC Statistics

• 8th most common cancer – more common in men than women – representing 4.2% of all new cancers in the US • In 2019, there were ~73,820 new cases of kidney and renal pelvis cancer and ~14,770 deaths from this disease

Percent of Cases by Stage 5-Year Relative Survival 3% 100% 92.5% 16% Localized (Confined 80% to Primary Site) 69.6%

Regional (Spread to 60% Regional Lymph Nodes) 41.9% 40% Distant (Cancer Has 17% Metastasized) Percent Surviving Percent 20% 12.0% Unknown (Unstaged) 65% 0% Stage

Localized Regional Distant Unknown

National Cancer Institute Surveillance, Epidemiology, and End Results Program. seer.cancer.gov/statfacts/html/kidrp.html; Accessed Mar 26, 2020. 4 4

Risk Factors for RCC

• Hereditary factors include familial syndromes, including: ‒ von Hippel-Lindau syndrome ‒ Hereditary type 1 papillary renal carcinoma ‒ Familial renal oncocytoma ‒ Birt-Hogg-Dube syndrome • Few risk factors for RCC have been established ‒ Nonhereditary risk factors that possibly contribute to RCC include: • Cigarette smoking (increases in a dose-dependent fashion) • Obesity, particularly in women (as weight increases, risk of RCC increases) • Older age (median age at diagnosis: 64 years)

Chow WH, et al. Nat Rev Urol. 2010;7:245-257; Sachdeva K, et al. emedicine.medscape.com/article/281340-overview#showall. Accessed Mar 26, 2020. 5 5

Histology of RCC

• Clear-cell RCC is the most common variety: 70% to 90% • Non−clear-cell RCC includes: ‒ Papillary: 10% to 15% ‒ Chromophobe: 3% to 5% ‒ Collecting duct: 1% to 2% ‒ Unclassified: 4% to 6% • In one study of 254 patients with advanced RCC, 16.1% harbored pathogenic germline mutations ‒ More than 20% of patients with non−clear-cell RCC had germline mutations • Sarcomatoid or rhabdoid features can be associated with any histology ‒ Harbinger of a poor prognosis in the VEGF TKI era

VEGF = vascular endothelial growth factor. Carlo MI, et al. JAMA Oncol. 2018;4:1228-1235; Muglia VF, Prando A. Radiol Bras. 2015;48:166-174; Warren AY, Harrison D. World J Urol. 2018;36:1913-1926. 6 6

2020 PCE Spring Oncology Series 2 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Patient Factors to Consider When Selecting Therapy

• Comorbidities, especially conditions that affect a patient’s immune status • Symptoms of disease • Sites of disease • ECOG PS • Histology • Risk stratification • Medication history, including use of steroids

ECOG PS = Eastern Cooperative Oncology Group performance status. Heng DY, et al. J Clin Oncol. 2009;27:5794-5799; Heng DY, et al. Lancet Oncol. 2013;14:141-148; van der Zanden LF, et al. Urol Oncol. 2017;35:e9-e16. 7 7

Risk Stratification: Laboratory and Clinical

IMDC Criteria Risk Factors Yes (1)/ Risk Group by Number of Risk Factors No (0) KPS <80% 1/0 Favorable 0 Time from diagnosis <12 months 1/0 Hemoglobin ULN 1/0 Poor 3-6 Platelet count >ULN 1/0 Corrected serum calcium >ULN 1/0

• Current FDA indications restrict certain treatments based on these risk categories

KPS = Karnofsky Performance Status; LLN = lower limit of normal; ULN = upper limit of normal. IMDC, International Metastatic RCC Database Consortium. Heng DY, et al. J Clin Oncol. 2009;27:5794-5799; Heng DY, et al. Lancet Oncol. 2013;14:141-148. 8 8

Goals of Treatment

• Goal of therapy is different for each patient ‒ May be curative vs improvement in length and/or quality of life, depending on staging • For active sites of disease ‒ Medical treatments aim to shrink and destroy the cancer ‒ Surgical treatment aims to remove the cancer ‒ Ablative treatments (eg, radiation or thermal) aim to destroy local disease • For patients with multiple sites of disease, the mainstay treatment has been medical/systemic therapy

Choueiri TK, et al. J Urol. 2011;185:60-66; NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020. 9 9

2020 PCE Spring Oncology Series 3 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Changing Treatment Landscape for Metastatic RCC

• In the last 15 years, the landscape of treatment for clear-cell mRCC has changed immensely

Sorafenib Temsirolimus +

Targeted Therapy Era Immunotherapy Combination Era

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Pembrolizumab Bevacizumab + IFN-⍺ Nivolumab +Axitinib Everolimus Everolimus + Levatinib + Axitinib mRCC = metastatic renal cell carcinoma. Klaassen Z. www.urotoday.com/conference-highlights/asco-2019-annual-meeting/asco-2019-kidney-cancer/113076-asco-2019-evolving-front-line- therapy-in-metastatic-renal-cell-carcinoma.html. Accessed Mar 26, 2020. 10 10

Immunotherapy Mechanism of Action

• T-cell activation is required for effective antitumor response • PD-1 and CTLA-4 expressed on Activated T cell T cell T cells act as “off” switches to down- CTLA-4

regulate the immune response PD-1 • Tumor cells can masquerade as Anti-PD-1 CD28 TCR PD-L1 Anti- normal cells by expressing PD-L1 Tumor cell TCR death MHC CTLA-4 • Blockade of PD-1 and PD-L1 MHC B7 and CTLA-4 ultimately allow up-regulation of immune responses Antigen-presenting Renal cancer cell targeting the tumor cell

CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed cell death protein; PD-L1 = programmed death-ligand 1. Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39:98-106; Institute for Clinical Immuno-Oncology. www.accc-cancer.org/docs/immuno- oncology/iclio-webinar-new-mechanisms-of-action-v3-final. Accessed Mar 26, 2020; Tarhini A, et al. Cancer Biother Radiopharm. 2010;25:601-613. 11 11

Targeted Therapy Plus Immunotherapy in Advanced RCC

• Boosts the RCC armamentarium Anticancer Immunity • VEGF inhibitors infiltrate T cells into

tumors and enhance antitumor CD3 CD4 immunity

• Adding PD-1 inhibitors may augment Anti-VEGF Myeloid VEGF TKI CD3 these effects DCs

• Standard of care has shifted to VEGF/R Anti-PD-1

immunotherapy-based combination Treg CD3 APC regimens in the 1st-line setting PD-1

MDSCs Anti-PD-L1

Macrophage Tumor (M2 phenotype) PD-L1

Garje R, et al. Cancers (Basel). 2020;12:143. 12 12

2020 PCE Spring Oncology Series 4 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Case Study 1: Oliver

• 63-year-old African American man presented for evaluation of hematuria and urinary obstruction • Medical history notable for hypertension and ongoing smoking • CT scan showed a left renal mass: 13.3 x 12.3 x 10 cm • Imaging revealed multiple lung nodules measuring up to 1.5 cm, consistent with metastatic disease • Oliver underwent biopsy of a lung nodule ‒ Pathology revealed metastatic clear-cell RCC with no sarcomatoid features • Oliver has a good PS and no additional IMDC risk factors other than needing systemic therapy within a year of diagnosis

PS = performance status. 13 13

Guidelines for Recurrent or Advanced Clear-Cell RCC: First-line Therapy

Risk Status First-line Therapy • Axitinib + pembrolizumab Favorable risk • Pazopanib • Sunitinib Preferred regimens Poor/intermediate • Axitinib + pembrolizumab risk • Ipilimumab + nivolumab • Cabozantinib • Ipilimumab + nivolumab Favorable risk • Cabozantinib Other recommended regimens • Axitinib + avelumab

Poor/intermediate • Pazopanib risk • Sunitinib • Axitinib + avelumab

NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020. 14 14

KEYNOTE-426: Pembrolizumab + Axitinib in Treatment-naïve Advanced RCC

• Pembrolizumab is an anti–PD-1 antibody that OS in ITT Population has shown antitumor activity 100 • Axitinib is a highly potent VEGFR-TKI 90 Pembrolizumab + axitinib approved in the 2nd-line setting and has 80

shown antitumor activity in the 1st-line setting 70 • Combination pembrolizumab + axitinib Sunitinib 60 demonstrated high PFS, ORR, and OS vs sunitinib 50 ‒ OS in the ITT population at 12 months: 40 89.9% vs 78.3% 30

• Benefit observed in all IMDC subgroups 20 and PD-L1 expression categories (%) Were AliveWho Patients Hazard ratio for death, 0.53 (95% CI, 0.38-0.74) 10 ‒ PFS: 15.1 vs 11.1 months P <0.0001 0 ‒ ORR: 59.3% vs 35.7% (CR: 5.8% vs 1.9%) 0 4 8 12 16 18 24 CR = complete response; ITT = intent to treat; ORR = overall response rate; Months OS = overall survival; PFS = progression-free survival; VEGFR = vascular endothelial growth factor receptor. Rini BI, et al. N Engl J Med. 2019;380:1116-1127. 15 15

2020 PCE Spring Oncology Series 5 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

JAVELIN Renal 101: Avelumab + Axitinib vs Sunitinib as First-line Treatment

• PD-L1 inhibitor avelumab was studied in 100 PFS in Patients With PD-L1-Positive Tumors combination with axitinib (VEGFR-TKI) vs 90 sunitinib 80 • Patients stratified by ECOG PS and geographic region 70 • Improvements seen in patients with PD-L1– 60 Avelumab + axitinib positive tumors 50

‒ Median PFS: 13.8 vs 7.2 months (%) PFS 40 ‒ ORR: 55.2% vs 25.5% 30 Sunitinib ‒ Median OS: 11.6 vs 10.7 months (NS); longer follow-up needed 20 • PFS benefit maintained in overall population 10 as well, regardless of PD-L1 status 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months

Motzer RJ, et al. N Engl J Med. 2019;380:1103-1115. 16 16

CheckMate 214: Nivolumab + Ipilimumab vs Sunitinib as First-line Treatment

• Combination of checkpoint inhibitors 1.0 OS in Intermediate-/Poor-Risk Disease

nivolumab + ipilimumab was studied in 0.9 patients with intermediate- or poor-risk 74% advanced RCC 0.8 0.7 Nivolumab + ipilimumab • Extended follow-up (minimum 42 v 60% months) showed superiority of nivolumab 0.6 52% + ipilimumab vs sunitinib: 0.5 60% 47% ‒ OS: 47.0 vs 26.6 months 0.4 39% OS (probability) OS ‒ ORR: 42% vs 29% (CR: 12% vs 1%) 0.3 Sunitinib • In ITT patients, nivolumab + ipilimumab 0.2 showed improved efficacy compared with 0.1

sunitinib 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 No. at risk Months

Tannir NM, et al. 2020 ASCO GU; Abstract 609. 17 17

Case Study (cont’d): Oliver

• Oliver agrees to begin axitinib and pembrolizumab for his advanced RCC • Both Oliver and his family are educated on the treatment plan, mechanisms of action of the drugs, and potential adverse effects of therapy • He is instructed to take daily BP assessments at home and to call the office if he develops hypertension, defined for this patient as 150/90 mm Hg • He is to call the oncology provider if he develops any new symptoms

18 18

2020 PCE Spring Oncology Series 6 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

irAEs and Their Toxicity Spectrum

irAEs Can Affect Any Organ System • Checkpoint inhibitors stimulate the immune Encephalitis Aseptic meningitis Uveitis environment and can cause irAEs Hypophysitis Thyroiditis Dry mouth • irAEs differ from AEs with chemotherapy and Hypothyroidism Mucositis targeted therapy Hyperthyroidism ‒ Many occur within 2 to 3 treatment cycles, Pneumonitis Myocarditis but can occur any time—even after therapy is discontinued Hepatitis

Autoimmune ‒ Typically mild, but can be severe, irreversible, Colitis Diabetes Enteritis or life-threatening Pancreatitis Thrombocytopenia Rash • irAEs do not occur in all patients Anemia Vitiligo Vasculitis ‒ Reasons are unknown Neuropathy Arthralgia

19 Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Cancer Council Victoria. www.cancervic.org.au/cancer-information/treatments/treatments- types/immunotherapy. Accessed March 30, 2020; Postow MA, et al. N Engl J Med. 2018;378:158-168. 19 19

Most Common AEs (≥20%) Associated With Pembrolizumab + Axitinib Combination Treatment (n = 429)

AE, % Any Grade (n = 429) Grade 3, 4, or 5 (n = 425) AEs of any cause 98.4 75.8 Diarrhea 54.3 9.1 Hypertension 44.5 22.1 Fatigue 38.5 2.8 Hypothyroidism 35.4 0.2 Decreased appetite 29.6 2.8 Hand-foot-skin reaction 28.0 5.1 Nausea 27.7 0.9 ALT increased 26.8 13.3 AST increased 26.1 7.0 Dysphonia 25.4 0.2 Cough 21.2 0.2 Constipation 20.7 0

ALT = alanine aminotransferase; AST = aspartate transaminase. Rini BI, et al. N Engl J Med. 2019;380:1116-1127. 20 20

Combination Therapy Patient Education

• Before starting treatment: ⎻ Educate patients about mechanisms of action and reasons for using combination treatment ⎻ Record all medications, including supplements and OTC medications ⎻ Provide patients with a wallet card outlining the type of treatments they are receiving, potential AEs, and their care team contact numbers ⎻ Educate patients/caregivers about potential toxicity profiles, presenting symptoms, and timing of their treatments ⎻ Inform patients of educational resources • Tell patients to notify the oncology healthcare team: ⎻ If any new signs or symptoms develop • Monitor symptoms for at least 2 years after treatment has concluded ‒ When admitted to the hospital ‒ If any new medications are prescribed or prior to receiving any immunizations/vaccines

NCCN Guidelines. Management of immunotherapy-related toxicities. www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed Mar 26, 2020. 21 21

2020 PCE Spring Oncology Series 7 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Case Study (cont’d): Oliver

• Front-line treatment with pembrolizumab 200 mg IV every 3 weeks and axitinib 5 mg twice a day was initiated, and a follow-up call 2 days later revealed no adverse effects • 8 days after initiation of cycle 3 of axitinib and pembrolizumab, Oliver called with complaints of increasing fatigue, loss of appetite, difficulty with fluid intake, and 5 loose stools in the past 24 hours (grade 2) despite maximum dosing of loperamide

22 22

Managing Diarrhea Associated With Axitinib + Pembrolizumab

• Diarrhea is one of the most common side effects of axitinib ‒ For most cases, supportive care and use of antidiarrheals can control this toxicity ‒ For grade 3 or 4 diarrhea, reduce the axitinib dose or interrupt therapy until diarrhea improves to grade 1 • When diarrhea occurs when axitinib is given in combination with pembrolizumab and can be attributed to either drug, stop axitinib for a few days as an initial step ‒ Axitinib-induced toxicity should improve significantly with cessation of therapy due to its short half-life ‒ Pembrolizumab-induced toxicity would not improve after stopping axitinib • If diarrhea does not resolve with axitinib cessation and an irAE is suspected, follow the appropriate guidelines

Greene HR. www.practiceupdate.com/content/management-of-diarrhea-associated-with-targeted-rcc-therapy/27360. Accessed Mar 26, 2020; Wood LS, Ornstein MC. JCO Oncology Practice. 2020;16(2 suppl):15s-19s. 23 23

Guidelines for Managing irAEs

Toxicity Grade Recommendation Continue checkpoint inhibitors with close monitoring, with exception of some neurologic, hematologic, and cardiac Grade 1 toxicities Hold for most grade 2 toxicities and consider resuming when symptoms and/or laboratory values return to Grade 2 grade 1 or less Corticosteroids (initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent) may be given Hold checkpoint inhibitors for grade 3 AEs and initiate high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1 to 2 mg/kg/d) Grade 3 • Taper corticosteroids over course of at least 4 to 6 weeks • If symptoms do not improve with 48 to 72 hours of high-dose corticosteroid, infliximab may be offered for some toxicities Warrants permanent discontinuation of checkpoint inhibitors, with exception of endocrinopathies controlled by Grade 4 hormone replacement

• When symptoms and/or lab values revert to grade 1 or less, rechallenging with checkpoint inhibitors may be offered. Use caution when administering to patients with early-onset irAEs, and dose adjustments are not recommended.

Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Postow MA, et al. N Engl J Med. 2018;378:158-168. 24 24

2020 PCE Spring Oncology Series 8 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Monitoring Patients on Drugs With Different Mechanisms of Action

• Dealing with two different mechanisms of action with two sets of AE profiles is challenging • Classical AEs of VEGF TKIs are fatigue, hypertension, diarrhea, oral pain, and hand-foot-skin reaction • Classical AEs of immunotherapy involve organ inflammation • Notable crossover AEs: fatigue, diarrhea, hypothyroidism, LFT elevations

LFT = liver function test. Rini BI, et al. N Engl J Med. 2019;380:1116-1127. 25 25

Case Conclusion: Oliver

• Oliver’s TSH increased from 3.4 at baseline to 13.0, and he was put on levothyroxine • Otherwise, he tolerated the combination of axitinib and pembrolizumab with no other AEs except occasional diarrhea • Imaging 3 months after start of treatment demonstrated regression of all lung nodules and shrinkage of the primary renal mass • The plan is to continue treatment for up to 2 years and take a break

TSH = thyroid stimulating hormone. 26 26

Case Study 2: Margaret

• 72-year-old woman diagnosed with advanced clear-cell RCC and lung and liver metastases • She was treated 1st-line with axitinib + pembrolizumab • After 3 months on treatment, her first follow-up scan showed marked progression in her lung and local recurrence • Her KPS was 70 and her risk score was 2 (intermediate)

27 27

2020 PCE Spring Oncology Series 9 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Tyrosine Kinase Inhibitors

Mechanism of Action of Multi-TKIs • The novel multitargeted TKIs cabozantinib Growth factor Growth factor and (combined with everolimus) signals to make signals for the have shown favorable data in advanced RCC blood vessels cell to divide

‒ Cabozantinib is an inhibitor of multiple Receptor Receptor receptor tyrosine kinases, including Multi TKI VEGFR, MET, the TAM kinases, KIT, FLT3, blocks TRKB, and TIE2 the signal TKI going ‒ Lenvatinib is an inhibitor of VEGFR1–3, into cell FGFR1–4, PDGFRa, KIT, and RET • Inhibiting these signaling molecules contributes to the antitumor immunomodulatory effect of these drugs

Bergerot P, et al. Mol Cancer Ther. 2019;18:2185-2193; De Lisi D, et al. Expert Opin Drug Metab Toxicol. 2018;14:461-467. 28 28

Guidelines for Recurrent or Advanced Clear-Cell RCC: Subsequent Lines

Subsequent Therapy • Cabozantinib (category 1) Preferred regimens • Nivolumab (category 1) • Ipilimumab + nivolumab • Axitinib (category 1) • Lenvatinib + everolimus (category 1) Other recommended • Axitinib + pembrolizumab regimens • Everolimus • Pazopanib • Sunitinib • Axitinib + avelumab (category 3)

NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020. 29 29

Lenvatinib + Everolimus

• Multitargeted TKI lenvatinib was 100 PFS by Treatment Group approved in 2016 as combination

therapy with the mTOR inhibitor 80 everolimus for 2nd-line treatment of Levatinib + everolimus Single-agent lenvatinib advanced RCC Single-agent everolimus 60 • Small randomized phase 2 study with ~50 patients in each of 3 arms 40 • Median PFS vs everolimus monotherapy: 14.6 vs 5.5 months 20

• Median OS vs everolimus: 25.5 vs Survival(%) Progression-free 15.4 months 0 0 3 6 9 12 15 18 21 24 Time (months)

mTOR = mammalian target of rapamycin. Lenvima [prescribing information]. Eisai Inc; 2020; Motzer RJ, et al. Lancet Oncol. 2015;16:1473-1482. 30 30

2020 PCE Spring Oncology Series 10 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Cabozantinib

• Multitargeted TKI approved in 2017 for front-line use in previously untreated RCC in patients with intermediate/poor risk ‒ Approval based on results from the phase 2 CABOSUN trial ‒ Compared with sunitinib, cabozantinib reduced risk of progression or death by 52% ‒ Median PFS: 8.6 months vs 5.3 months with sunitinib • Now approved for both 1st- and 2nd-line treatment of advanced RCC • Toxicity profile of cabozantinib similar to other VEGFR TKIs for the treatment of advanced RCC ‒ Most common grade 3 or 4 side effects were hypertension, diarrhea, and fatigue

Cabometyx [prescribing information]. Exelixis, Inc; 2020; Choueiri TK, et al. 2017 ESMO Congress. LBA38; Choueiri TK, et al. J Clin Oncol. 2017;35:591-597; Martinez Chanza N, et al. Lancet Oncol. 2019;20:581-590; US Food and Drug Administration. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm589842.htm. Accessed Mar 26, 2020 31 31

Case Study (cont’d): Margaret

• After 2 months of treatment with combination lenvatinib and everolimus, Margaret begins to experience extreme fatigue

32 32

Toxicity Profile of Lenvatinib + Everolimus

Lenvanitib + • Most common grade 1-2 TEAEs AE, % Lenvanitib Everolimus Everolimus reported in lenvatinib + everolimus group Diarrhea 65 60 32 ‒ Diarrhea, decreased appetite, Decreased appetite 45 54 18 fatigue Fatigue 45 42 36 • Most common TEAEs of grade ≥3 in the lenvatinib + everolimus group ‒ Constipation, diarrhea, fatigue • For toxicities thought to be related to everolimus alone, such as stomatitis and noninfectious pneumonitis, the drug should be discontinued, interrupted, or used on alternate days, according to the label • For toxicities considered to be related to both lenvatinib and everolimus, the lenvatinib dose should be reduced first

TEAEs = treatment-emergent adverse events. Afinitor [prescribing information]. Novartis Pharmaceuticals Corporation; 2020; Motzer RJ, et al. Lancet Oncol. 2015;16:1473-1482; Stenger M. ascopost.com/issues/june-10-2016/lenvatinib-in-combination-with-everolimus-in-advanced-renal-cell-carcinoma/. Accessed Mar 26, 2020. 33 33

2020 PCE Spring Oncology Series 11 Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma

Case Conclusion

• Eight months later, Margaret complained of fatigue, abdominal discomfort, and weight loss; she subsequently developed back pain • CT scan of abdomen and chest showed new liver lesions and progression of previously identified lesions • MRI of the spine showed multiple metastatic lesions of the thoracic and lumbar vertebrae, with no evidence of cord compression • She was switched to cabozantinib 60 mg and her symptoms subsided within 4 weeks • She was maintained on cabozantinib for approximately 13 months until the disease progressed • Margaret is being considered for enrollment into a clinical trial

MRI = magnetic resonance imaging. 34 34

PCE Action Plan

 Be aware of patient factors that help determine the most appropriate therapy options  Provide patients with resource materials, reminders, and other tools (eg, wallet cards) to reinforce details about toxicities related to combination therapy  Consider rechallenge with checkpoint inhibitor therapy with caution in patients whose irAE symptoms and/or laboratory values revert to grade ≤1  It is important to discern causative therapy, since management of AEs is dependent on differentiation

PCE Promotes Practice Change

35 35

2020 PCE Spring Oncology Series 12 Evolving Options in Metastatic Prostate Cancer

Evolving Options in Metastatic Prostate Cancer

1

Learning Objectives

• Implement guideline-recommended treatment strategies for patients with nonmetastatic castrate-resistant prostate cancer (CRPC) • Formulate personalized management strategies for patients with metastatic CRPC based on patient preferences and efficacy and safety of novel agents • Apply strategies to identify and manage AEs associated with novel therapies for CRPC

AE = adverse event. 2 2

Prostate Cancer in 2020

• Estimated for 2020 ‒ 191,930 new cases ‒ 33,330 deaths ‒ Incidence and mortality rates have declined ‒ 10-year overall survival (OS): 98% • Risk factors ‒ Advancing age ‒ African ancestry Image: Histology slide showing prostate cancer. Courtesy of the National Cancer Institute. ‒ Family history Photographer: Otis Brawley, ‒ Genetic mutations

American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020. 3 3

2020 PCE Spring Oncology Series 1 Evolving Options in Metastatic Prostate Cancer

Advances in Treatment Approvals

Apalutamide (next- Enzalutamide (next- generation ARSI) Darolutamide Docetaxel Cabazitaxel for nmCRPC generation ARSI) Radium-223 (next-generation ARSI) (taxane) (novel taxane) postdocetaxel (radiopharmaceutical) for nmCRPC

2004 2010 2011 2012 2013 2014 2018 2019

Sipuleucel-T Abiraterone (next- Abiraterone Enzalutamide Enzalutamide (immunotherapy) generation ARSI) predocetaxel predocetaxel Enzalutamide for mHSPC postdocetaxel for nmCRPC

mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = nonmetastatic castrate-resistant prostate cancer. Komura K, et al. Int J Urol. 2018;25:220-231; US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm596768.htm. Accessed Mar 24, 2020; US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=210951. Accessed Mar 24, 2020. US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. Accessed Mar 24, 2020; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide- metastatic-castration-sensitive-prostate-cancer. Accessed Mar 24, 2020. 4 4

CHAARTED: ADT + Docetaxel in mHSPC

All Patients 100 OS Benefit by Volume of Disease • High volume: 17 months • Low volume: no benefit 80

60 ADT + docetaxel:

OS(%) 40 (median OS, 57.6 months)

Death with ADT + docetaxel (n = 397): ADT alone (n = 393): 20 HR, 0.61 (95% CI, 0.47-0.80) (median OS, 44.0 months) P <.001 0 0 12 24 36 48 60 72 84 Number at Risk ADT + docetaxel 397 333 189 89 46 5 2 0 ADT alone 393 318 168 71 27 3 1 0

Median follow-up: 28.9 months

ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen. Sweeney CJ, et al. N Engl J Med. 2015;373:737-746. 5 5

STAMPEDE, Arm C: ADT and Docetaxel in HSPC

Median OS (Months) 70% 5-Year Survival (%)

60% 45 Months 63% 50% 60 Months Metastatic MedianOS 40% 50% 55%

30% 71 Months 39% 20% 81 Months Median OS Median 10%

0 10 20 30 40 50 60 70 80 90 0% ADT Alone ADT + Docetaxel 5-Year Survival (Metastatic) 5-Year Survival ADT Alone ADT + Docetaxel ADT alone: n = 1184 ADT + docetaxel: n = 592 Median follow-up: 43 months

James ND, et al. Lancet. 2016;387:1163-1177. 6 6

2020 PCE Spring Oncology Series 2 Evolving Options in Metastatic Prostate Cancer

Phase 3 Trials of ADT + Abiraterone in mHSPC

LATITUDE STAMPEDE, Arm G N = 1199: ADT + abiraterone + prednisone vs ADT + placebo N = 960: ADT + abiraterone + prednisolone vs ADT alone

100

100 80 ADT + abiraterone 80 60 60 Abiraterone

40 40

PFS (%) PFS ADT PS(%) rPFS Placebo 20 HR, 0.47 (95% CI, 0.39-0.55) P <.001 20 HR, 0.29 (95% CI, 0.25-0.34) 0 P <.001 0 8 16 24 32 40 0 Months 0 6 12 18 24 30 36 42 48 54 Months

PFS = progression-free survival; rPFS = radiographic progression-free survival. Fizazi K, et al. N Engl J Med. 2017;377:352-360; James ND, et al. N Engl J Med. 2017;377:338-351. 7 7

Some Agents Used in Advanced Settings Are Now Being Used in Earlier Disease

rPFS: significant TITAN Phase 3 ADT + apalutamide vs improvement in both low- Study ADT + placebo in and high-volume disease (N >1050) mHSPC (P <.001) with apalutamide

PFS: significant ARCHES Phase 3 ADT + enzalutamide vs improvement in both low- Study ADT + placebo in and high-volume disease (N = 1150) mHSPC (P <.001) with enzalutamide

Armstrong AJ, et al. J Clin Oncol. 2019;37(7 suppl):Abstract 687; Chi KN et al. J Clin Oncol. 2019;37(15 suppl):Abstract 5003; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate- cancer. Accessed Mar 24, 2020. 8 8

2019 NCCN Guidelines for mHSPC

• Based on results of clinical trials, for patients with mHSPC, consider adding to ADT: ‒ Docetaxel 75 mg/m2 every 3 weeks for 6 cycles • Patients with high-volume disease derive greater benefit ‒ Abiraterone acetate + steroid ‒ Apalutamide ‒ Enzalutamide

NCCN = National Comprehensive Cancer Network. NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 9 9

2020 PCE Spring Oncology Series 3 Evolving Options in Metastatic Prostate Cancer

Castrate-Resistant Prostate Cancer

• Disease progression despite castrate levels of (<50 ng/mL) • Heterogeneous—can be symptomatic or asymptomatic, with or without metastases • Affects 10% to 20% of men with prostate cancer within 5 years of diagnosis ‒ Before recent therapeutic advances, ≥50% of these patients would have died within 3 years • Natural history can involve progressive decline in health-related QoL • Metastasis-free survival (MFS) is a new, reasonable endpoint for both clinical trials and clinical discussions with patients

QoL = quality of life. Anantharaman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633; Beaver JA, et al. N Engl J Med. 2018;378:2458-2460; Nussbaum N, et al. Prostate Cancer Prostatic Dis. 2016;19:111-121. 10 10

Typical Progression of CRPC

Rising PSA mHSPC despite castrate Criterion 1: levels of Rising Identification of testosterone PSA metastases Both criteria Localized/locally met Definitive Biochemical Start advanced mCRPC therapy recurrence ADT prostate cancer Criterion 2: Rising PSA Identification of despite castrate metastases levels of testosterone nmCRPC

Adapted with permission from Anantharaman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633. 11 11

Nonmetastatic CRPC

• CRPC with no clinical or radiologic evidence of metastases • Newer imaging techniques have greater sensitivity (eg, 18F-fluorocholine or PSMA-targeted PET) ‒ May reveal metastases earlier • PSA testing every 4 to 6 months is advised • Treatment is recommended for men with PSADT ≤10 months • Until recently, no approved drugs were available for nmCRPC

Image from Singh A, et al. PET Clin. 2017;12:193-203. PET = positron emission tomography; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen. Anantaraman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633; Virgo KS, et al. J Clin Oncol. 2017;35:1952-1964; Zimmerman ME, et al. Clin Adv Hematol Oncol. 2019;17:455-463. 12 12

2020 PCE Spring Oncology Series 4 Evolving Options in Metastatic Prostate Cancer

Case Study 1: Earl, 69 Years Old

• Earl has mild COPD and occasional arrhythmias ‒ No family history of cancer • He underwent radiotherapy for localized prostate cancer 4 years ago • Earl experienced biochemical recurrence as evidenced by increasing PSA • Because of previous radiotherapy, he was not considered a candidate for surgery • He was started on ADT 1 year ago

13 13

Case Study (cont’d): Earl’s Test Results

• PSA increased from 6 ng/mL to 14 ng/mL, with PSADT of 8 months ‒ Testosterone level: 23 ng/dL ‒ No evidence of metastases on CT or bone scan, no bone pain ‒ No lymph node masses detected • Now diagnosed with nmCRPC

14 14

Factors to Consider When Selecting Therapies

Patient Disease Treatment • Preferences • Metastatic? • Toxicity profile • Medical history, – To bone? • Possible drug-drug comorbidities, medications – Visceral? interactions • Treatment and response • Disease volume • Effects on pain, QoL history – Low or high? • Practitioner experience • Symptoms • Risk level/aggressiveness and preference • Overall condition and performance status

Basch E, et al. J Clin Oncol. 2014;32:3436-3448; Crawford ED, et al. J Urol. 2015;194:1537-1547; Nussbaum N, et al. Prostate Cancer Prostatic Dis. 2016;19:111-121; Zarrabi K, et al. J Hematol Oncol. 2019;12:89. 15 15

2020 PCE Spring Oncology Series 5 Evolving Options in Metastatic Prostate Cancer

Shared Decision-Making

• Especially important for complex diseases such as CRPC • Endorsed by all major guidelines • Patients and clinicians collaborate on treatment selection • May enhance adherence to therapies • May improve outcomes: Greater adherence → better treatment responses

Fennimore LA, Ginex PK. Nurs Clin North Am. 2017;52:115-131; Makarov DV, et al. www.auanet.org/guidelines/shared-decision-making. Accessed Mar 24, 2020. 16 16

SPARTAN and PROSPER: Grade ≥3 AEs Occurring in >1% of Patients

SPARTAN PROSPER AE Apalutamide + ADT Placebo + ADT Enzalutamide + ADT Placebo + ADT Any grade ≥3 AE 362 (45.1%) 136 (34.2%) 292 (31%) 109 (23%) Hypertension 115 (14.3%) 47 (11.8%) 43 (5%) 10 (2%) Rash 42 (5.2%) 1 (0.3%) NR NR Fracture 22 (2.7%) 3 (0.8%) NR NR Falls 14 (1.7%) 3 (0.8%) 12 (1%) 3 (1%) Fatigue 7 (0.9%) 1 (0.3%) 27 (3%) 3 (1%) Hematuria NR NR 16 (2%) 13 (3%)

NR = not reported. Hussain M, et al. N Engl J Med. 2018;378:2465-2474; Smith MR, et al. N Engl J Med. 2018;378:1408-1418. 17 17

ARAMIS: Darolutamide in nmCRPC

Phase 3, placebo-controlled trial; N = 1509 (PSADT ≤10 months)

1.0 AEs (≥5% or grade ≥3) were similar HR, 0.41 (95% CI, 0.34-0.50) P <.001 between groups and included: 0.8 Darolutamide: 40.4 months (median) • Fatigue 0.6 • Back pain 0.4 • Arthralgia Placebo: 18.4 months (median) Without Metastasis Without • Diarrhea Survivalof Probability 0.2

0.0 • Hypertension 0 4 8 12 16 20 24 28 32 36 40 44 48 • Constipation Months Median follow-up time at primary analysis: 17.9 months Risk of metastasis or death from any cause was reduced by 59%

Fizazi K, et al. N Engl J Med. 2019;380:1235-1246. 18 18

2020 PCE Spring Oncology Series 6 Evolving Options in Metastatic Prostate Cancer

2019 NCCN Guidelines for nmCRPC

• In addition to continuing ADT to maintain castrate serum levels of testosterone (<50 ng/dL): ‒ For men whose PSADT is ≤10 months: apalutamide, darolutamide, enzalutamide, or other secondary hormone therapy ‒ For men whose PSADT is >10 months: observation or other secondary hormone therapy

NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 19 19

Case Conclusion

• Earl is taking apalutamide 240 mg/day and continuing ADT • Bone health is being monitored closely • Disease progression has plateaued ‒ PSA = 3.5 ng/mL • Will continue serial PSA monitoring • Will undergo imaging only if new symptoms develop or PSA level increases

20 20

Metastatic Prostate Cancer

• 72% increase from 2004 to 2013, even as incidence of low-risk prostate cancer declined ‒ Trend started before USPSTF recommendation for reduced routine early screening so is not associated solely with that reduction • 5-year survival rate: ~30% vs nearly 100% for nonmetastatic disease • Approximately 90% of men with mCRPC have bone metastases • Treatment evolving rapidly ‒ Novel therapies improve outcomes but increase treatment complexity

USPSTF = United States Preventive Services Task Force. American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Weiner AB, et al. Prostate Cancer Prostatic Dis. 2016;19:395-397; Vogelzang NJ et al. Clin Genitourin Cancer. 2017;15:42-52. 21 21

2020 PCE Spring Oncology Series 7 Evolving Options in Metastatic Prostate Cancer

Case Study 2: Eli, 72 Years Old

• Eli has prehypertension and well-controlled diabetes ‒ Family history: mother had breast cancer • Diagnosed 6 years ago with de novo metastatic prostate cancer, with a PSA level of 45 ng/mL • Has high-volume disease: metastasis to multiple bone sites and to lymph nodes

22 22

Case Study (cont’d): Eli’s Initial Treatment

• Started on ADT and received 6 cycles of docetaxel ‒ His PSA level became undetectable but began to increase 2 years after he started treatment • Presents with asymptomatic mCRPC ‒ Reports no pain ‒ Imaging unchanged since completion of chemotherapy

23 23

Treatment Options: Immunotherapy

Sipuleucel-T Day 1 Days 2-3 Days 3-4 Leukapheresis Sipuleucel-T is manufactured Patient receives infusion • First FDA-approved immunotherapy for prostate cancer • Shows OS benefit, even without PSA response Apheresis Center Central Processing Clinician’s Office • Most beneficial in less advanced disease → thus, early use recommended COMPLETE COURSE OF THERAPY Weeks 0, 2, 4

Gupta S et al. Onco Targets Ther. 2011;4:79-96; Hu R et al. Ther Adv Urol. 2016;8:272-278; Kantoff PW et al. N Engl J Med. 2010;363:411-422. 24 24

2020 PCE Spring Oncology Series 8 Evolving Options in Metastatic Prostate Cancer

Sipuleucel-T: Randomized Phase 3 IMPACT Trial

• AEs more frequent (≥20%) than Sipuleucel-T: Survival Benefit in Phase 3 Trial with placebo: chills, fatigue, pyrexia, nausea 100 P = .032 (Cox model) HR, 0.78 (95% CI, 0.61 – 0.98) Median survival benefit = 4.1 months • Explain to patients that 75 benefits may not manifest as typical signs of improvement 50 Sipuleucel-T (n = 341) (eg, changes in PSA) Median survival: 25.8 months 25 Placebo (n = 171)

Probability of Survival (%) Survival of Probability Median survival: 21.7 months 0 0 6 12 18 24 30 36 42 48 54 60 66 Months Since Randomization

Kantoff PW et al. N Engl J Med. 2010;363:411-422; Pieczonka CM et al. Rev Urol. 2015;17:203-210. 25 25

Case Study (cont’d)

• Eli undergoes 3 sessions of sipuleucel-T infusion over 4 weeks • At interim assessment a few months later, his cancer has progressed, with additional bone lesions revealed on scanning, but lymph node disease is stable • He reports back pain that is not debilitating, but he now requires intermittent opioids

26 26

Treatment Options for mCRPC: Newer ARSIs

• Both drugs are approved for use with or without prior docetaxel

Abiraterone Enzalutamide • Inhibits CYP17, enzyme needed • Androgen receptor (AR) for androgen synthesis antagonist; binds competitively to • Administered with steroids ligand-binding domain of AR • Concomitant steroids not required

CYP = cytochrome. Beer TM, et al. N Engl J Med. 2014;371:424-433; de Bono JS, et al. N Engl J Med. 2011;364:1995-2005; Gomez L, et al. Steroids. 2015;95:80-86; Ryan CJ, et al. N Engl J Med. 2013;368:138-148; Scher HI, et al. N Engl J Med; 2012;367:1187-1197. 27 27

2020 PCE Spring Oncology Series 9 Evolving Options in Metastatic Prostate Cancer

COU-AA-301: Phase 3 Trial of Second-line Abiraterone in mCRPC

• Abiraterone vs placebo: 100 HR, 0.65 (95% CI, 0.54-0.77) P <.001 1195 patients with mCRPC

progressing after docetaxel 80 Abiraterone Acetate Median survival: 14.8 months • 2 prior chemo OS: 14.0 months (95% Cl, 14.1-15.4) abiraterone vs 10.3 months placebo 60 • 1 prior chemo OS: 15.4 months abiraterone vs 11.5 months placebo 40 Placebo Median survival: 10.9 months Survival (%) Survival • Most common AEs, grade ≥3: (95% Cl, 10.2-12.0) 20 ‒ Fatigue (<9% vs 10%)

‒ Anemia (7% vs 8%) 0 ‒ Back pain (<7% vs <10%) 0 3 6 9 12 15 18 21 Months

de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 28 28

AFFIRM: Phase 3 Trial of Second-line Enzalutamide in mCRPC

Enzalutamide vs placebo for 1199 men with mCRPC after chemotherapy

100 100 HR, 0.40 (95% CI, 0.35-0.47) 80 80 P <.001

60 Enzalutamide 60

40 40 OS (%) OS Placebo Enzalutamide PS(%) rPFS 20 HR, 0.63 (95% CI, 0.53-0.75) 20 P <.001 Placebo 0 0 0 6 12 18 24 0 6 12 18 24 Months Months

Most common grade ≥3 AEs: fatigue (6% vs 7%), diarrhea (1% vs <1%), cardiac disorder (1% vs 2%)

Scher HI, et al. N Engl J Med. 2012;367:1187-1197. 29 29

Phase 3 Trials in Chemotherapy-naïve mCRPC

COU-302: Abiraterone + Prednisone PREVAIL: Enzalutamide 100 100 Enzalutamide 80 80 Abiraterone + prednisone 60 60 Placebo Placebo + prednisone 40 40 OS (%) OS (%) OS

Men with mild or no HR, 0.71 (95% CI, 0.60-0.84) 20 HR, 0.81 (95% CI, 0.70-0.93) 20 P <.001 P = .0033 symptoms 0 0 0 6 12 13 24 30 36 42 43 54 60 Primary endpoints: 0 3 6 9 1215 18 21 24 27 30 33 OS (Months) OS, rPFS OS (Months)

100 HR, 0.53 (95% CI, 0.45-0.93) 100 HR, 0.19 (95% CI, 0.15-0.23) P = .0033 No prior P <.001 80 80 ketoconazole Enzalutamide Abiraterone + prednisone 60 60

40 Men with liver 40

PFS (%) PFS metastases eligible in (%) PFS Placebo + prednisone Placebo 20 PREVAIL 20 0 0 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 PFS (Months) PFS (Months)

Beer TM, et al. N Engl J Med. 2014;371:424-433; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med. 2013;368:138-148. 30 30

2020 PCE Spring Oncology Series 10 Evolving Options in Metastatic Prostate Cancer

Abiraterone and Enzalutamide: Drug Characteristics and Toxicities

Abiraterone Enzalutamide Dosage 1000 mg/day orally 160 mg/day orally Empty stomach required Yes No Prednisone required Yes No Drug interactions (CYP) Yes Yes Hypokalemia Yes No Lowers seizure threshold No Yes Potential liver toxicity Yes Less likely Hypertension Yes* Yes Fatigue Yes More likely Cardiac toxicity More likely Yes

*Risk of hypertension is increased by required coadministration of prednisone. Beer TM, et al. N Engl J Med. 2014;371:424-433; Mayo Clinic. www.mayoclinic.org/steroids/art-20045692. Accessed Mar 24, 2020; Moreira RB, et al. Oncotarget. 2017;8:84572-84578; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med. 2013;368:138-148; Tonyali S, et al. Curr Urol. 2017;10:169-173; Zytiga [prescribing information]. Janssen Biotech; 2018. 31 31

Treatment Options: Radiopharmaceuticals ─Radium-223

• Unlike beta-emitting radioisotopes (eg, samarium-153), radium-223, an alpha-emitting isotope, delivers less radiation to bone marrow, resulting in fewer effects of marrow suppression

ALSYMPCA: randomized, placebo-controlled study of symptomatic mCRPC with bone metastases

Overall Survival Time to First Symptomatic Skeletal Event 100 100 HR, 0.70 (95% Cl, 0.58-0.83) HR, 0.66 (95% Cl, 0.52-0.83) P <.001 P <.001 80 80 Radium-223 (median time to first symptomatic Radium-223 60 60 skeletal event, 15.6 months) (median OS, 14.9 months)

40 40 Placebo

Survival (%) (median time to first symptomatic Placebo skeletal event, 9.8 months) 20 (median OS, 11.3 months) Skeletal Event (%) 20

0 PatientsWithout Symptomatic 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 Months Since Randomization Months Since Randomization

Most common AEs: bone pain, nausea, anemia; no clinically meaningful between-group differences

Anderson M, Vogelzang N. pcri.org/insights-blog/2017/3/17/targeted-radiation-administered-by-injection. Accessed Mar 24, 2020; Parker C, et al. N Engl J Med. 2013;369:213-223; Parker C, et al. Prostate Cancer Prostatic Dis. 2018;21:37-47. 32 32

Case Study (cont’d)

• Eli is treated with enzalutamide, which was chosen because of the extent of his disease and to avoid steroids, which are necessary with abiraterone but are contraindicated for patients with diabetes • Subsequently treated with radium-223 • After an initial decrease in PSA, his mCRPC progresses, with a PSA increase to 38 ng/mL, and his use of opioids for pain has become more regular

33 33

2020 PCE Spring Oncology Series 11 Evolving Options in Metastatic Prostate Cancer

Role of Genetic Testing

• Germline mutations have raised the issue of inheritable cancer risk • No validated biomarkers available; several are being investigated • Every patient with prostate cancer should be considered for genetic testing and possible genetic counseling • Patients should be counseled before genetic testing

Connors LM. Clin J Oncol Nurs. 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020. 34 34

Biomarkers: Examples of Potential Utility

• PTEN loss may indicate increased risk of disease progression Imaging • AR-V7 leads to loss of binding in the AR ‒ May indicate resistance to ARSIs but Serum not to taxanes

• DNA repair gene mutations Tissue (biopsy) ‒ Seen in approximately ¼ of patients with mCRPC Urine ‒ Promising: BRCA1/BRCA2

AR-V7 = androgen receptor variant 7; PTEN = phosphatase and tensin homolog. Connors LM. Clin J Oncol Nurs. 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020. 35 35

Treatment Options: Chemotherapy

• Docetaxel (first-generation taxane) ‒ Until 2010, only approved drug to improve OS for mCRPC Cabazitaxel ‒ Appropriate for castrate-sensitive disease in select Docetaxel 2010 patients 2004 Mitoxantrone • Cabazitaxel (next-generation taxane) 1996 ‒ Improves OS among docetaxel-pretreated patients Cyclophosphamide with mCRPC 1993 ‒ Improves QoL; reduces pain through 5-FU 10 treatment cycles 1991 ‒ Approved at lower dosage (20 mg/m2) in 2017 for patients with mCRPC previously treated with docetaxel ‒ Likely to move up in sequencing

Bahl A, et al. BJU Int. 2015;116:880-887; de Wit R, et al. N Engl J Med. 2019;381:2506-2518; Eisenberger M, et al. J Clin Oncol. 2017;35:3198- 3206; Parimi S, et al. Int J Urol. 2016;23:726-733. 36 36

2020 PCE Spring Oncology Series 12 Evolving Options in Metastatic Prostate Cancer

CARD Trial: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in mCRPC

N = 255 men with mCRPC that progressed ≤12 months on prior alternative ARSI (before or after docetaxel)

rPFS OS rPFS, months (95% CI) Median OS, months (95% CI) 100 Cabazitaxel: 8.0 (5.7-9.2) 100 Cabazitaxel: 13.6 (11.5-17.5) 90 ARSI: 3.7 (2.8-5.1) 90 ARSI: 11.0 (9.2-12.9) 80 80 HR for progression or death, 0.54 HR for death, 0.64 (95% CI, 0.46-0.89) 70 70 (95% CI, 0.40-0.73) P = .001 P = .008 60 60 50 50 40 40 30 Cabazitaxel Cabazitaxel 30 Patients With PFS (%) PFS With Patients ARSI 20 ARSI 20 10 Patients Who Were Alive (%) Were AliveWho Patients 10 0 0 0 3 6 9 12 18 24 30 0 3 6 9 12 18 24 30 Months Months

de Wit R, et al. N Engl J Med. 2019;381:2506-2518. 37 37

Example of Therapy Sequencing for mCRPC

• Optimal sequencing not First Line* Second Line* Third Line* established (sample Asymptomatic Sipuleucel-T Abiraterone Docetaxel shown) (chemonaïve) or or Enzalutamide Cabazitaxel • Treatment pathway is unique for each patient Symptomatic Abiraterone Docetaxel Cabazitaxel • Cross-resistance between or or or abiraterone and Enzalutamide Radium-223 Radium-223 or (bone (bone enzalutamide Docetaxel metastases) metastases) • Need to identify molecular Treatment Exhaustion subtypes for more rational mCRPC Patient sequencing Clinical Trials (eg, PARP inhibitors, immunotherapy)

*All treatment options should include ADT (surgical/medical orchiectomy). PARP = poly (ADP-ribose) polymerase. Li Y, et al. Am J Hematol Oncol. 2017;13:26-31; Lorente D, et al. Lancet Oncol. 2015;16:e279-92; Parente P, et al. Asia Pac J Clin Oncol. 2014;10:205-215; Sartor O. Clin Adv Hematol Oncol. 2015;13:570-572; Sartor O, et al. N Engl J Med. 2018;378:645-657; Terada N, et al. Int J Urol. 2017;24:441-448. 38 38

Several Novel Agents Are Under Study

PARP INHIBITORS IMMUNE CHECKPOINT INHIBITORS

Olaparib: Phase 3 study in mCRPC with homologous recombination repair (HRR) mutation Pembrolizumab: Tissue-agnostic granted FDA priority review approval (for MSI-H) Has shown promise in prostate Niraparib: Phase 2 study for BRCA1/BRCA2 gene-mutated mCRPC  cancer studies breakthrough therapy designation

Talazoparib: Promising interim results from phase 2 Ipilimumab: Being studied in phase 1, 2, TALAPRO-1 study and 3 trials in prostate cancer

Rucaparib: Priority review for supplemental NDA granted from FDA based on phase 3 TRITON3 trial

MSI-H = microsatellite instability-high. ASCO Post Staff. ascopost.com/news/february-2020/talazoparib-for-pretreated-patients-with-metastatic-castration-resistant-prostate-cancer/. Accessed March 24, 2020; Boettcher AN et al. Front Oncol. 2019;9:884; Clarke N, et al. Lancet. 2018;19:975-986; Hansen AR, et al. Ann Oncol. 2018;29:1807- 1813; Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR; Smith MR, et al. Ann Oncol. 2019;30(suppl 5):v884-v885; Zhu J. www.urotoday.com/conference-highlights/asco-2018/asco-2018-prostate-cancer/104947-asco-2018-keynote-199-pembrolizumab-for-docetaxel- refractory-metastatic-castration-resistant-prostate-cancer-mcrpc.html. Accessed Mar 24, 2020. Clinicaltrials.gov. NCT02975934. Accessed April 9, 2020. 39 39

2020 PCE Spring Oncology Series 13 Evolving Options in Metastatic Prostate Cancer

PROfound Trial: Phase 3 Study of Olaparib vs Enzalutamide or Abiraterone for mCRPC With HRR Gene Alterations

Olaparib 300 mg bid Cohort A: n = 162 Endpoints Key Eligibility BRCA1, BRCA2, or Criteria ATM N = 245 Physician’s Choice Primary: n = 83 mCRPC with disease - rPFS in Cohort A progression on prior NHA, eg, abiraterone 2:1 Randomization Upon BICR progression, physician’s choice Secondary: or enzalutamide Open Label patients were allowed to cross over to olaparib - rPFS in Cohorts A & B Alterations in ≥1 of Olaparib 300 mg bid - ORR in Cohort A any qualifying gene Cohort B: n = 94 - TTPP in with a direct or Cohort A Other alterations indirect role in HRR - OS in Cohort A N = 142 Physician’s Choice n = 48

ATM = ataxia-telangiectasia mutated gene product; BICR = blinded independent central radiology; NHA = new hormonal agent; ORR = objective response rate; TTPP = time to PSA progression. Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR. 40 40

PROfound Trial: Results

• Patients with mCRPC + HRR Cohort A: rPFS by BICR Among Patients With Alterations in alterations who progressed on BRCA1, BRCA2, or ATM prior abiraterone + prednisone and/or enzalutamide had 1.0 6-month rate significantly improved rPFS and 59.76% 0.8 22.63 12-month rate Physician’s ORR vs physician’s choice of Olaparib 28.11% choice either enzalutamide or 0.6 9.40% abiraterone + prednisone Events (%) 106 (65.4) 68 (81.9) 0.4 Median PFS (months) 7.39 3.55 • Favorable trend for OS was HR (95% Cl) 0.34 (0.25-0.47) observed despite crossover by a 0.2 P <.0001 large proportion of patients rPFS of Probability initially treated with physician’s 0.0 choice hormonal therapy 0 1 3 5 7 9 11 13 15 17 19 21 Time From Randomization (months) Prespecified sensitivity analysis based on investigator assessment: HR, 0.24% (95% Cl, 0.17-0.34); P <.0001

Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR. 41 41

Phase 2 GALAHAD Study: Breakthrough Therapy Designation for Niraparib for Treatment of mCRPC

Oral PARP inhibitor for BRCA 1/2 gene-mutated mCRPC (prior taxane chemo and AR-targeted therapy)

BRCA1/2 (n = 46) Non-BRCA (n = 35) Response n (%) (95% CI) n (%) (95% CI)

ORR 12/29 (41) (23.5-61.1) 2/22 (9) (1.1-29.2)

≥50% Decline in PSA 23/46 (50) (34.9-65.1) 1/35 (3) (0.1-14.9)

Circulating Tumor Cells Conversion 18/38 (47) (31.0-64.2) 5/24 (21) (7.1-42.2)

Composite Response Rate 29/46 (63) (47.6-76.8) 6/35 (17) (6.6-33.7)

Months (95% CI) Months (95% CI)

Median rPFS, months (95% CI) 8.2 (5.2-11.1) 5.3 (1.9-5.7)

Median OS, months (95% CI) 12.6 (9.2-15.7) 14.0 (5.3-20.1)

Smith M, et al. oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/Pre-specified-interim-analysis-of-GALAHAD-A-phase-2-study-of- niraparib-in-patients-pts-with-metastatic-castration-resistant-prostate-cancer-mCRPC-and-biallelic-DNA-repair-gene-defects-DRD. Accessed Mar 24, 2020. 42 42

2020 PCE Spring Oncology Series 14 Evolving Options in Metastatic Prostate Cancer

Case Conclusion

• Eli receives 20 mg/m2 of cabazitaxel every 3 weeks • His blood pressure and neutrophil count are monitored regularly • At the end of first treatment cycle: ‒ PSA has decreased to 7 ng/mL ‒ He reports decreased pain ‒ Bone scans show stable lesions and no new lesions ‒ Blood pressure has not increased

43 43

Overcoming Barriers to Effective Treatment

• Patient and clinician perceptions of AEs may differ: Communication is key • Monitor and manage AEs to optimize adherence and treatment benefit • High costs of some treatments may make them unattainable for some patients and/or affect adherence ‒ Investigate financial assistance programs

Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer. 2017;8:2663-2668; Pollard ME, et al. Asian J Urol. 2017;4:37-43; Sartor O, et al. N Engl J Med. 2018;378:645-657. 44 44

Evidence-based Strategies to Reduce AEs of ADT and Other Treatments

• Skeletal: resistance exercise; bone-protective agents • Metabolic: exercise (aerobic and resistance); diet; treatment for dyslipidemia, hypertension; monitoring/treatment for diabetes • Fatigue: exercise (aerobic and resistance) • Hot flushes: medroxyprogesterone, venlafaxine, gabapentin • Gynecomastia: prophylactic radiation, tamoxifen

Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer. 2017;8:2663-2668; Pollard ME, et al. Asian J Urol. 2017;4:37-43; Sartor O, et al. N Engl J Med. 2018;378:645-657. 45 45

2020 PCE Spring Oncology Series 15 Evolving Options in Metastatic Prostate Cancer

PCE Action Plan

 For patients with mHSPC, consider adding docetaxel (± prednisone), abiraterone + steroid, apalutamide, or enzalutamide to ADT  Implement shared decision-making to optimize treatment outcomes  Consider early use of approved agents for nmCRPC to improve MFS  Consider genetic testing and possible genetic counseling for all patients with prostate cancer

PCE Promotes Practice Change

46 46

2020 PCE Spring Oncology Series 16 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Advances in CLL: Key Elements for Today’s Clinics

1

Learning Objectives

• Analyze the efficacy and safety of treatment options as well as molecular features of CLL and patient characteristics/preferences to aid in the successful delivery of individualized therapy to patients with newly diagnosed and relapsed/refractory CLL • Consider the optimal treatment for patients with newly diagnosed and relapsed/refractory CLL based on available clinical data, guidelines, and expert recommendations • Develop team-based strategies to address challenges to optimal treatment, including the identification and management of AEs, to ensure treatment compliance as well as improved clinical outcomes and quality of life

AE = adverse event; CLL = chronic lymphocytic leukemia. 2 2

CLL/SLL: Background

• More than 21,000 estimated new cases in 2020 in the United States alone[1] ‒ Most common type of leukemia in adults (37%) • Median age at diagnosis: 70 years[2] • SLL and CLL considered the same B-cell malignancy[3] ‒ CLL: > 5000 clonal B cells in peripheral blood ‒ SLL: presence of lymphadenopathy and/or splenomegaly and < 5000 clonal B cells in peripheral blood • Historical 5-year survival: 66% (range: few mos to normal life span)[4] ‒ Current (2009-2015) 5-year survival: 85%[2]

SLL = small lymphocytic lymphoma. 3 1. Siegel. CA Cancer J Clin. 2020;70:7. 2. SEER Cancer Stat Facts. Chronic lymphocytic leukemia. 3. American Cancer Society. Chronic lymphocytic leukemia. 4. Nabhan. JAMA. 2014;312:2265. 3 3

2020 PCE Spring Oncology Series 1 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

CLL: Prognostic Value of FISH

Probability of OS From Diagnosis, by Genetic Aberration FISH Abnormalities Present in 268/325 Patients (82%) 100 17p deletion Lesion % Median OS, Mos 11q deletion 12q trisomy del(13q) 55 133 80 Normal del(11q) 18 79 13q deletion as sole abnormality Trisomy 12 16 114 del(17p) 7 32 60 del(6q) 6 N/A Normal 18 111 40 FISH Patients With Abnormality (%) Lesion Dohner et al Oscier et al Jarosova et Dewald et Sindelarava (%) Surviving Patients 1997 1999 al 2001 al 2003 et al 2005 20 del(13q) 45 36 18 47 54

Trisomy 12 15 15 13 25 16 0 del(17p) 10 8 11 8 16 del(11q) 20 17 11 15 12 Months

Dohner. NEJM. 2000;343:1910. Dohner. Leukemia. 1997;11(suppl 2):S19. Oscier. Haematologica. 1999;84(suppl EHA-4):88. Jarosova. Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet. 2005;160:27. 4 4

CLL: Impact of TP53 Mutations and TP53 Deletion on OS (N = 1148)

• OS effect of TP53 wild type: ‒ vs TP53 mut only: P = .013 ‒ vs TP53 del only: P = .006 ‒ vs TP53 mut + del: P < .001

9 100 100 TP53 mut only TP53 wt 8 TP53 del only TP53 wt 7 TP53 mut + del 80 80 6 Alterations in Alterations 60 60 5 TP53 mut only (%) TP53 4 40 40 OS (%) OS TP53 alteration (%) OS TP53 del only 3

2 20 20 TP53 mut + del 1

Frequency ofFrequency P < .001

Relationto TotalCohort Eachof Size 0 0 0 CLL 0123456789 10 0123456789 10 Years Years • Analysis based on cases referred to the Munich Leukemia Laboratory between August 2005 and May 2013 Stengel. Leukemia. 2017;31:705. 5 5

Survival in CLL According to IGHV Mutational Status

All Patients (n = 84) Binet Stage A Patients (n = 62) 100 100

80 80 Mutated 60 Mutated 60

40 40 Surviving(%) Surviving(%) Unmutated 20 Unmutated 20 P = .001 P = .0008 0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Months Months

Hamblin. Blood. 1999;94:1848. 6 6

2020 PCE Spring Oncology Series 2 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Previously Untreated CLL

7

Case Study 1: An Elderly Patient With del(17p) and a TP53 Mutation

• 75-year-old female patient who presented in 2013 with WBC 13K, ALC 9, Hgb 13, PLTs 160K • Flow: typical CLL pattern • FISH: no mutations • She was observed for 5 years • In 2018, progressive weight loss, splenomegaly, bulky lymphadenopathy, WBC 310K, Hgb 9 ‒ IGHV unmutated, TP53 mutation ‒ FISH: del(17p)

8 8

Phase III RESONATE-2: vs Chlorambucil in Patients 65 Years of Age or Older With Untreated CLL/SLL

• An international, randomized phase III trial

Ibrutinib 420 mg/day until PD or unacceptable toxicity Patients 65 years of age (n = 136) Crossover or older with treatment- upon PD (n = 43) naive CLL/SLL; no Chlorambucil del(17p); no warfarin use 0.5 mg/kg (up to maximum of 0.8 mg/kg) (N = 269) on Days 1, 15 of 28-day cycle for up to 12 cycles (n = 133) • Primary endpoint: PFS • Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety

9 Burger. NEJM. 2015;373:2425. 9 9

2020 PCE Spring Oncology Series 3 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

RESONATE-2: 5-Year Follow-up Results

100 100 Ibrutinib 80 80 Ibrutinib

Ibrutinib Chlorambucil 60 Chlorambucil 60 (n = 136) (n = 133) mPFS, mos NE 15

HR (95% CI) 0.146 (0.098-0.218) (%) OS 40 Ibrutinib Chlorambucil PFS (%) PFS 40 5-year PFS rate, % 70 12 mOS, mos NE NE HR (95% CI) 0.450 (0.266-0.761) 20 Chlorambucil 20 5-year OS rate, % 83 68

0 0 0 3 6 9 12 15 18 21 24 27 30 3336 39 42 45 48 51 54 57 6063 66 69 0 36 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 Months Months

• Ibrutinib was generally well tolerated with no new safety signals reported with long-term follow-up (many AEs decreased over time) • More than one half (58%) of patients remained on ibrutinib at the 5-year follow-up

Burger. Leukemia. 2020;34:787. 10 10

Phase III E1912 Trial of Ibrutinib + vs FCR in Patients ≤ 70 Years of Age With Previously Untreated CLL

• Primary analysis of randomized, open-label phase III trial (data cutoff: October 24, 2018)

Stratified by age (< vs ≥ 60 yrs), ECOG PS (0/1 vs 2), stage (III-IV vs I-II), del(11q22.3) vs other

Ibrutinib 420 mg PO daily for cycles 1-7 + Patients with previously untreated CLL Rituximab 50 mg/m2 IV on Day 1, cycle 2, then 325 mg/mg2 on Ibrutinib maintenance requiring treatment per IWCLL 2008, ≤ Day 2, cycle 2, then 500 mg/m2 on Day 1, cycles 3-7 until PD 70 years of age, ECOG PS 0-2, CrCl > (n = 354) 40 mL/min, ability to tolerate FCR, no del(17p) by FISH Fludarabine 25 mg/m2 IV on Days 1-3 for cycles 1-6 + (N = 529) Cyclophosphamide 250 mg/m2 IV on Days 1-3 for cycles 1-6 + Rituximab 50 mg/m2 IV on Day 1, cycle 1, then 325 mg/mg2 on Day 2, cycle 1, then 500 mg/m2 on Day 1, cycles 2-6 (n = 175) 28-day cycles • Primary endpoint: PFS ⎻ Study has 80% power to detect PFS HR for IR vs FCR of 0.67 using stratified log-rank test, with prespecified boundary of 2.87 for first PFS interim analysis corresponding to 1-sided P = .0025 • Secondary endpoints: OS, safety

11 Shanafelt. NEJM. 2019;381:432. Shanafelt. ASH 2019. Abstr 33. 11 11

E1912: PFS (Primary Endpoint)

Median follow-up: 48 months

1.0

Ibrutinib + rituximab (58 events/354 cases) 0.8 FCR (52 events/175 cases)

0.6

0.4 Probability

0.2 HR: 0.39 (95% CI: 0.26-0.57) P < .0001 3-year rates: 89%, 71% 0 0 1 2 3 4 5 Years Number at risk FCR 175 145 123 82 31 0 Ibrutinib + R 354 338 321 280 121 8

Shanafelt. ASH 2019. Abstr 33. 12 12

2020 PCE Spring Oncology Series 4 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

E1912: PFS by IGHV Status

Median follow-up: 48 months IGHV Unmutated IGHV Mutated 1.0 1.0 Ibrutinib + rituximab (10 events/70 cases) 0.8 Ibrutinib + rituximab 0.8 FCR (8 events/44 cases) (36 events/210 cases) FCR (29 events/71 cases) 0.6 0.6

0.4 0.4 Probability Probability

0.2 HR: 0.28 (95% CI: 0.17-0.48) 0.2 HR: 0.42 (95% CI: 0.16-1.16) P < .0001 P = .086 3-year rates: 89%, 65% 3-year rates: 88%, 82% 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Number at risk Number at risk FCR 71 63 50 31 8 0 FCR 44 38 34 25 11 0 Ibrutinib + R 210 202 193 165 72 7 Ibrut + R 70 67 64 54 20 1

Shanafelt. ASH 2019. Abstr 33. 13 13

E1912: OS

Median follow-up: 48 months

1.0 Ibrutinib + rituximab (11 events/354 cases)

0.8 FCR (12 events/175 cases)

0.6

0.4 Probability

0.2 HR: 0.34 (95% CI: 0.15-0.79) P = .009 3-year rates: 99%, 93% 0 0 1 2 3 4 5 Years Number at risk FCR 175 155 143 131 69 9 Ibrutinib + R 354 347 343 355 193 37

Shanafelt. ASH 2019. Abstr 33. 14 14

First-line Ibrutinib vs Ibrutinib + Rituximab vs Bendamustine + Rituximab in CLL/SLL (A041202): Study Design

• Multicenter, randomized, double-blind phase III study (data cutoff: October 4, 2018) Stratified by Rai stage (high vs intermediate risk), del(11q22.3) or del(17p13.1) (presence vs absence), ZAP-70 methylation (< vs ≥ 20%)

Ibrutinib 420 mg daily Until PD Untreated patients with CLL meeting (n = 182) IWCLL 2008 criteria for tx initiation; ≥ 65 years of age; ECOG Ibrutinib 420 mg daily + PS 0-2; ANC ≥ 1000 unless due to Rituximab 375 mg/m2 weekly x 4 weeks starting cycle 2 Day 1; cycles 3-6 Day 1* Ibrutinib until PD BM involvement; PLT ≥ 30; (n = 182) CrClCG ≥ 40; AST/ALT ≤ 2.5 x ULN; Crossover to no heparin or warfarin Bendamustine 90 mg/m2 on Days 1, 2 + (N = 547) ibrutinib within Rituximab 375 mg/m2 on cycle 1 Day 1; 500 mg/m2 on cycles 2-6 Day 1* 1 year of PD (n = 183) allowed *28-day cycles. • Primary endpoint: PFS ‒ 2 primary comparisons of ibrutinib vs BR and ibrutinib + R vs BR with 90% power to detect HR of 0.586 (estimated 2-yr PFS rates: ibrutinib, 75%; BR, 61%) and overall 1-sided α = 0.025 for each comparison ‒ If both primary comparisons significant, third planned comparison of ibrutinib + R vs ibrutinib

Woyach. NEJM. 2018;379:2517. 15 15

2020 PCE Spring Oncology Series 5 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

A041202: PFS of Eligible Patients* (Primary Endpoint)

• PFS significantly improved with 100 ibrutinib vs BR and ibrutinib + R 80 vs BR (both 1-sided P < .001) ‒ HR for ibrutinib vs BR: 60 Events, Median PFS, 2-Yr PFS, 0.39 (95% CI: 0.26-0.58) 40 PFS(%) n/N Mos (95% CI) % (95% CI) ‒ HR for ibrutinib + R vs BR: 0.38 Ibrutinib 34/178 NR 87 (81-92) 20 Ibrutinib + R 32/170 NR 88 (81-92) (95% CI: 0.25-0.59) BR 68/176 43 (38-NR) 74 (66-80) 0 • No significant difference for ibrutinib + 0 6 12 18 24 30 36 42 48 R vs ibrutinib only (1-sided P = .49) Number at risk Months ‒ HR: 1.00 (95% CI: 0.62-1.62) Ibrutinib 178 165 154 147 136 120 78 45 22 0 Ibrutinib + R 170 159 145 138 132 115 74 40 20 0 BR 176 140 129 122 103 88 57 26 11 0

*524 of 547 randomized patients.

Woyach. NEJM. 2018;379:2517. 16 16

A041202: PFS by del(17p) and del(11q) Status

del(17p) del(11q) Neither del(17p) or del(11q) 1.0 1.0 1.0

0.8 0.8 0.8

0.6 0.6 0.6

0.4 0.4 0.4 PFS Probability PFS 0.2 0.2 0.2

0 0 0 0 6 12 18 24 30 36 42 48 52 0 6 12 18 24 30 36 42 48 52 0 6 12 18 24 30 36 42 48 52 Months Months Months Events, Median PFS, Events, Median PFS, Events, Median PFS, n/N Mos (95% CI) n/N Mos (95% CI) n/N Mos (95% CI) Ibrutinib 2/9 NE Ibrutinib 4/35 NE Ibrutinib 27/137 NE Ibrutinib + R 3/11 NE Ibrutinib + R 7/37 NE Ibrutinib + R 25/132 NE BR 10/14 7 (4-23) BR 15/33 41 (36-NE) BR 45/134 51 (43-NE)

• PFS benefit with ibrutinib-containing regimens vs BR observed in all cytogenetic factor–related subgroups, with del(17p13.1) being most pronounced

Woyach. NEJM. 2018;379:2517. 17 17

A041202: PFS by IGHV Mutation Status

Mutated IGHV Unmutated IGHV 1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4 Events, Median PFS, Events, Median PFS,

PFSProbability n/N Mos (95% CI) n/N Mos (95% CI) PFSProbability 0.2 Ibrutinib 7/45 NE 0.2 Ibrutinib 16/77 NE Ibrutinib + R 6/45 NE Ibrutinib + R 20/70 NE (48-NE) BR 12/52 51 (51-NE) BR 31/71 39 (32-NE) 0 0 0 6 12 18 24 30 36 42 48 52 0 6 12 18 24 30 36 42 48 52 Months Months

• No significant interaction between IGHV mutation status and PFS benefit by regimen ‒ Increased PFS among patients with mutated vs unmutated IGHV disease (HR: 0.51; 95% CI: 0.32-0.81)

Woyach. NEJM. 2018;379:2517. 18 18

2020 PCE Spring Oncology Series 6 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

A041202: Safety

Ibrutinib Ibrutinib + R BR Grade 3-5 AEs During Treatment or Follow-up,* n (%) P Value (n = 180) (n = 181) (n = 176) Any hematologic 74 (41) 70 (38) 107 (61) < .001 • Anemia 21 (12) 11 (6) 22 (13) .09 • Neutropenia 27 (15) 39 (22) 71 (40) < .001 • Thrombocytopenia 12 (7) 9 (5) 26 (15) .008 Any nonhematologic 133 (74) 134 (74) 111 (63) .04 • Bleeding 3 (2) 5 (3) 0 .46 • Infections 37 (21) 37 (20) 26 (15) .62 • Febrile neutropenia 3 (2) 1 (1) 13 (7) < .001 • Atrial fibrillation 17 (9) 10 (6) 5 (3) .05 • Hypertension 53 (29) 61 (34) 25 (14) < .001 Death • Unexplained/unwitnessed 7 (4) 4 (2) 2 (1) .24 • During active treatment + 30 days 13 (7) 13 (7) 2 (1) -- • During active treatment + 30 days, up to 6 cycles 3 (2) 6 (3) 2 (1) --

*Excludes crossover.

Woyach. ASH 2018. Abstr 6. Woyach. NEJM. 2018;379:2517. 19 19

Phase III ELEVATE TN (ACE-CL-007): Study Design

Stratified by del(17p) status, ECOG PS 0/1 vs 2, geographic region

Acalabrutinib 100 mg PO BID + * Patients with treatment- (n = 179) naive CLL who are ≥ 65 years or 100 mg PO BID < 65 years with CIRS (n = 179) Crossover allowed to score > 6 or CrCl acalabrutinib after IRC- < 70 mL/min confirmed progression (N = 535) Obinutuzumab† + Chlorambucil 0.5 mg/kg PO D1, 15 (n = 177)

*1000 mg IV on D1, 2, 8, 15 of 28-day cycle 2; Day 1 of subsequent cycles for total of 6 cycles. †1000 mg IV on D1, 2, 8, 15 of 28-day cycle 1; Day 1 of cycles 2-6.

• Primary endpoint: PFS by IRC with acalabrutinib + obinutuzumab vs obinutuzumab + chlorambucil • Key secondary endpoints: PFS of acalabrutinib vs obinutuzumab + chlorambucil, ORR by IRC and investigators, time to next treatment, OS, safety

Sharman. ASH 2019. Abstr 31. 20 20

ELEVATE TN: Progression-Free Survival (IRC Assessed)

100 93%

HR (95% CI) 80 87% Acala-O 0.10 (0.06-0.17) vs Chl-O P < .0001 60 Acalabrutinib 0.20 (0.13-0.30) 47% vs Chl-O P < .0001 40 Acala-O 0.49 (0.26-0.95) PFS(%) vs Acalabrutinib

Acalabrutinib + Obinutuzumab 20 Acalabrutinib Chlorambucil + Obinutuzumab (Median PFS: 22.6 months; 95% CI: 20.2-27.6) 0 0 6 12 18 24 30 36 42 Number at risk Months Acalabrutinib 179 176 170 168 163 160 159 155 109 104 46 41 4 2 Acalabrutinib + O 179 166 161 157 153 150 148 147 103 94 43 40 4 3 Chlorambucil-O 177 162 157 151 136 113 102 86 46 41 13 13 3 2 Sharman. ASH 2019. Abstr 31. 21 21

2020 PCE Spring Oncology Series 7 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

ELEVATE TN: Progression-Free Survival Across Patient Subgroups No. of Events/No. of Patients Bulky disease Acala-O Acala Chl-O HR (95% CI) < 10 cm Acala-O 14/173 81/167 0.11 (0.04-0.19) Acala 21/160 81/167 0.18 (0.11-0.30) ≥ 10 cm Acala-O 0/4 11/14 NE (NE-NE) Acala 4/15 11/14 0.22 (0.07-0.71) del(17)(p13.1) and/or TP53 mutation Yes Acala-O 3/25 16/25 0.10 (0.03-0.34) Acala 6/23 16/25 0.23 (0.09-0.61) No Acala-O 11/154 77/152 0.10 (0.05-0.18) Acala 20/156 77/152 0.19 (0.11-0.31) del(11)(q22.3) Yes Acala-O 4/31 26/33 0.09 (0.03-0.26) Acala 3/31 26/33 0.07 (0.02-0.22) No Acala-O 10/146 66/143 0.10 (0.05-0.20) Acala 23/148 66/143 0.26 (0.16-0.41) IGHV mutation status Unmutated Acala-O 11/103 78/116 0.08 (0.04-0.16) Acala 16/119 78/116 0.11 (0.07-0.19) Mutated Acala-O 3/74 14/59 0.15 (0.04-0.52) Acala 10/58 14/59 0.69 (0.31-1.56) Complex karyotype Yes Acala-O 3/29 20/32 0.09 (0.03-0.29) Acala 3/31 20/32 0.10 (0.03-0.33) No Acala-O 9/126 59/121 0.11 (0.05-0.21) Acala 20/117 59/121 0.27 (0.15-0.46)

0.01 0.1 1 22 Sharman. ASH 2019. Abstr 31. Favor Acala-O or acalabrutinib Favor Chl-O 22

ELEVATE TN: Safety (Most Common AEs)

Acalabrutinib + Acalabrutinib Obinutuzumab + AEs in ≥ 15% of Patients Obinutuzumab (n = 178) (n = 179) Chlorambucil (n = 169) in Any Treatment Arm, % Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any 96.1 70.2 95.0 49.7 98.8 69.8 Headache 39.9 1.1 36.9 1.1 11.8 0 Diarrhea 38.8 4.5 34.6 0.6 21.3 1.8 Neutropenia 31.5 29.8 10.6 9.5 45.0 41.4 Fatigue 28.1 1.7 18.4 1.1 17.2 0.6 Contusion 23.6 0 15.1 0 4.1 4.1 Arthralgia 21.9 1.1 15.6 0.6 4.7 1.2 Cough 21.9 0 18.4 0.6 8.9 0 URTI 21.3 2.2 18.4 0 8.3 0.6 Nausea 20.2 0 22.3 0 31.4 0 Dizziness 18.0 0 11.7 0 5.9 0 Infusion-related reaction 13.5 2.2 0 0 39.6 5.3 Pyrexia 12.9 0 6.7 0.6 20.7 0.6

Sharman. ASH 2019. Abstr 31. 23 23

ELEVATE TN: AEs of Clinical Interest for Acalabrutinib

Acalabrutinib + Acalabrutinib Obinutuzumab + AE, n (%) Obinutuzumab (n = 178) (n = 179) Chlorambucil (n = 169) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Atrial fibrillation 6 (3.4) 1 (0.6) 7 (3.9) 0 1 (0.6) 0 Hypertension 13 (7.3) 5 (2.8) 8 (4.5) 4 (2.2) 6 (3.6) 5 (3.0) Bleeding 76 (42.7) 3 (1.7) 70 (39.1) 3 (1.7) 20 (11.8) 0 • Major bleeding 5 (2.8) 3 (1.7) 3 (1.7) 3 (1.7) 2 (1.2) 0 Infection 123 (69.1) 37 (20.8) 117 (65.4) 25 (14.0) 74 (43.8) 14 (8.3) Second primary malignancy* 10 (5.6) 6 (3.4) 5 (2.8) 2 (1.1) 3 (1.8) 2 (1.2)

*Excluding non skin cancer.

Sharman. ASH 2019. Abstr 31. 24 24

2020 PCE Spring Oncology Series 8 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

First-line Venetoclax + Obinutuzumab vs Chlorambucil + Obinutuzumab in CLL (CLL14): Study Design

• Open-label, multicenter, randomized phase III trial

Venetoclax PO 5-wk ramp up from 20 to 400 mg/day starting on Day 22 of cycle 1, then 400 mg/day until end of cycle 12 Patients with previously + Obinutuzumab IV 1000 mg Days 1, 8, 15 of cycle 1, Total 28-day cycles untreated CLL and then 1000 mg Day 1 of cycles 2-6 • Venetoclax: 12 (n = 216) coexisting medical • Chlorambucil: 12 conditions (CIRS > 6 • Obinutuzumab: 6 and/or CrCl < 70 mL/min) Chlorambucil PO 0.5 mg/kg Days 1, 15 of cycles 1-12 (N = 432) + Obinutuzumab IV 1000 mg Days 1-2, 8, 15 of cycle 1, then 1000 mg Day 1 in cycles 2-6 (n = 216)

• Primary endpoint: investigator-assessed PFS • Secondary endpoints: IRC-assessed PFS, ORR, MRD negativity, OS, safety

Fischer. NEJM. 2019;380:2225. NCT02242942. 25 25

CLL14: Investigator-Assessed PFS (Primary Endpoint)

100

80 88% Venetoclax + obinutuzumab (n = 216) 60 Chlorambucil + obinutuzumab 64% (n = 216)

PFS (%) PFS 40

20 HR: 0.35 (95% CI: 0.23-0.53; P < .001) 0 0 6 12 18 24 30 36 Months 26 Fischer. NEJM. 2019;380:2225. 26 26

CLL14: PFS by IGHV Mutation and TP53 Status

PFS by IGHV Mutation PFS by TP53 Status 100 100

80 80

60 60

PFS(%) 40 PFS(%) 40

Venetoclax + obinutuzumab and IGHV mutated 20 20 Venetoclax + obinutuzumab and TP53 deletion and/or mutation Venetoclax + obinutuzumab and IGHV unmutated Venetoclax + obinutuzumab and wild-type TP53 Chlorambucil + obinutuzumab and IGHV mutated Chlorambucil + obinutuzumab and TP53 deletion and/or mutation Chlorambucil + obinutuzumab and IGHV unmutated Chlorambucil + obinutuzumab and wild-type TP53 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months 27 Fischer. NEJM. 2019;380:2225. 27 27

2020 PCE Spring Oncology Series 9 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

CLL14: Response and OS

100 P < .001 100 Chlorambucil + obinutuzumab PR CR 80 80 Venetoclax + obinutuzumab 35.2 60 60 48.1

40 (%)OS 40

49.5 20 20 HR: 1.24 (95% CI: 0.64-2.40; P = .52) PatientsWithResponse(%) 23.1 0 0 Venetoclax + Chlorambucil + 0 6 12 18 24 30 36 Obinutuzumab Obinutuzumab Months (n = 216) (n = 216)

Fischer. NEJM. 2019;380:2225. 28 28

CLL14: MRD Negativity

Venetoclax + Chlorambucil + MRD Status, % Obinutuzumab Obinutuzumab P Value (n = 216) (n = 216) Peripheral blood • Negative (< 10-4)* 76 35 < .001 • Negative (< 10-6)† 42 7 Bone marrow • Negative (< 10-4)* 57 17 < .001

*MRD status assessed by ASO-PCR 3 months after completion of treatment. †MRD status assessed by NGS 3 months after completion of treatment.

• MRD negativity (< 10-4) with venetoclax + obinutuzumab occurred early and was durable

Fischer. NEJM. 2019;380:2225. 29 29

CLL14: Safety

Venetoclax + Chlorambucil + Venetoclax + Chlorambucil + Grade 3/4 AE, % Obinutuzumab Obinutuzumab Grade 5 AE, % Obinutuzumab Obinutuzumab (n = 212) (n = 214) (n = 212) (n = 214) Hematologic AEs 60 55 Total events 8 4

• Neutropenia 53 48 Events during therapy 2 2 • Thrombocytopenia 14 15 • Infections and 2 1 •Anemia 8 7 infestations • Febrile neutropenia 5 4 • Neoplasms < 1 < 1 Injury, poisoning, procedural Events after therapy 12 14 5 2 complications completion • Infusion-related reaction 9 10 • Cardiac disorders 1 < 1 Infections and infestations 18 15 • Infections and 2 0 •Pneumonia 4 4 infestations Metabolism, nutrition disorders* 12 6 • Neoplasms < 1 < 1 • Other reasons < 1 < 1 *P = .02

Fischer. NEJM. 2019;380:2225. 30 30

2020 PCE Spring Oncology Series 10 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Previously Treated CLL

31

Case Study 2: A Normal-Risk Patient Relapsing on Chemoimmunotherapy

• A 78-year-old female diagnosed with CLL (mutated IGHV and trisomy 12) ‒ Treated with obinutuzumab and chlorambucil ‒ She tolerated 4 cycles of treatment before developing prolonged cytopenias ‒ On exam, there was no adenopathy or splenomegaly • You chose to observe and initially cytopenias gradually resolved • However, over the next 12 months, the patient had a rising ALC and developed progressive anemia and thrombocytopenia ‒ Repeat FISH showed trisomy 12; TP53 status was negative

32 32

Phase III RESONATE: Ibrutinib vs in Previously Treated CLL/SLL

• At time of interim analysis, median time on study was 9.4 months

Stratified by refractory to purine analogue chemoimmunotherapy (no response or relapsed within 12 months); presence or absence of 17p13.1 (17p del)

Ibrutinib 420 mg/day PO until PD or unacceptable toxicity Enrollment dates: Patients with CLL/SLL (n = 195) June 2012 - April 2013 diagnosis; ≥ 1 prior therapy; ECOG PS 0/1; measurable Ofatumumab nodal disease IV starting dose of 300 mg Crossover to Ibrutinib (N = 391) followed by 2000 mg x 11 doses 420 mg/day following PD for 24 weeks (n = 122) (n = 196)

Protocol amended for crossover with support of data monitoring committee and discussion with health authorities.

Byrd. NEJM. 2014;371:213. 33 33

2020 PCE Spring Oncology Series 11 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

RESONATE: Final Analysis of PFS (Primary Endpoint) and OS

Median follow-up: 65.3 months

100 Ibrutinib Ofatumumab 100 (n = 195) (n = 196) Median PFS, mo 44.1 8.1 Ibrutinib 80 95% CI (38.5-55.2) (7.8-8.3) 80 HR (95% CI) 0.148 (0.113-0.195) Ofatumumab 60 60 OS (%) OS PFS (%) PFS 40 40 Ibrutinib Ibrutinib Ofatumumab (n = 195) (n = 196) Median OS, mo 67.7 65.1 20 20 Ofatumumab (95% CI) (61.0-NE) (50.6-NE) HR (95% CI) 0.810 (0.602-1.091) 0 0 0 3 6 91215 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 0 3 6 91215 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 Mos Mos Number at risk Number at risk Ibrutinib 195 189 179 171161154 149 146 138 123115 110 105 99 92 84 82 80 77 70 65 56 33 5 Ibrutinib 195 191 184 180 174166 164 160 156 147142 131 132 122120 117 112 110 108 106 100 84 50 11 Ofatumumab 196 159 120 67 34 22 19 14 10 9 6 5 5 4 4 4 4 4 3 3 3 3 Ofatumumab 196 183 165 154 148142 138 135 130 128121 115 112 109107 103 101 96 93 91 87 74 43 16 1

Munir. Am J Hematol. 2019;94:1353. 34 34

RESONATE Trials: Summary of AEs in the Ibrutinib Arm

Most Common AEs Any Grade 3/4 AEs of Interest (≥ 20% of Patients), % Grade Diarrhea 48 4 • Infection (all grade): 70% Fatigue 28 2 ̶ Grade ≥ 3: 24% (8% pneumonia) Nausea 26 2 • Bleeding/bruising (all grade): 44% Pyrexia 24 4 ̶ Grade ≥ 3: 1% (no grade 5) Most Common Grade ≥ 3 Grade 3/4 • Cardiac (all grade): 8% Hematologic AEs, % Neutropenia 16 ̶ Grade ≥ 3 cardiac: 3% (afib) Thrombocytopenia 6 ̶ 5% atrial fibrillation (all grades) Anemia 5

• Treatment-emergent AEs generally decreased over time (except HTN and bruising)

Byrd. NEJM. 2014;371:213. Munir. Am J Hematol. 2019;94:1353. 35 35

Phase III Trial of Venetoclax + Rituximab vs BR in Previously Treated CLL/SLL (MURANO): Study Design

• Multicenter, randomized, open-label phase III trial Stratified by del(17p), prior tx 28-day cycles response,* geographic region

Venetoclax dose ramp-up 20-400 mg PO daily for 5 wks then 400 mg PO daily for cycles 1-6 + Venetoclax monotherapy Rituximab 375 mg/m2 on Day 1 of cycle 1, until PD, unacceptable Adult patients with R/R CLL, then 500 mg/m2 Day 1 of cycles 2-6 toxicity, or maximum of 1-3 prior tx lines (with ≥ 1 (n = 194) 2 years from Day 1 of cycle 1 CT-containing regimen), prior bendamustine permitted Bendamustine 70 mg/m2 on Days 1, 2 of cycles 1- if DoR ≥ 24 months 6 + Rituximab 375 mg/m2 on Day 1 of cycle 1, *High-risk CLL defined as: del(17p); no (N = 389) then 500 mg/m2 Day 1 of cycles 2-6 response to first-line CT-containing tx; or relapsed in ≤ 12 months after CT or in (n = 195) ≤ 24 months after chemoimmunotherapy.

• Primary endpoint: investigator-assessed • Secondary endpoints: IRC-assessed PFS PFS and MRD negativity, IRC-assessed CR → ORR → OS (hierarchical testing), safety

Seymour. NEJM. 2018;378:1107. NCT02005471. 36 36

2020 PCE Spring Oncology Series 12 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

MURANO: Four-Year Analysis of PFS (Primary Endpoint) and OS

Treatment 4-Year PFS, % (95% CI) VenR 100 57.3 100 (n = 194) (49.4-65.3) BR 4.6 80 (n = 195) (0.1-9.2) 80 Median follow-up: 48 months 60 60 Treatment 4-Year OS, % VenR 85.3 (n = 194) OS(%) PFS(%) 40 40 BR 66.8 (n = 195)

20 20 Median follow-up: 48 months EOCT EOT EOCT EOT 0 0 0 3 6 91215 18212427 30 333639424548 51545760 0 3 6 9 121518212427 303336394245485154 5760 Number at Months Number at risk risk Months BR 195 178165143129 104 85 80 66 56 45 40 32 23 14 9 3 2 BR 195 181175167162 155 152150 147 141 140 138134 130116 94 58 29 7 VenR 194 190185179176 174 170167 161150 141134130 118 101 55 40 14 7 2 VenR 194 190185183182 179 178176 173 168 166 165164 163154 110 84 34 15 6 1 Seymour. ASH 2019. Abstr 355. 37 37

MURANO: Safety

Grade 3/4 AE With ≥ 2% Difference Between Venetoclax + Rituximab Bendamustine + Rituximab Arms, n (%) (n = 194) (n = 188) Neutropenia 114 (58.8) 75 (39.9) Anemia 22 (11.3) 26 (13.8) Thrombocytopenia 11 (5.7) 19 (10.1) Febrile neutropenia 7 (3.6) 18 (9.6) Pneumonia 10 (5.2) 15 (8.0) Infusion-related reaction 4 (2.1) 10 (5.3) TLS 6 (3.1) 2 (1.1) Hypotension 0 5 (2.7) Hyperglycemia 4 (2.1) 0 Hypogammaglobulinemia 4 (2.1) 0

Seymour. ASH 2019. Abstr 355. 38 38

Phase III Trial of Idelalisib + Rituximab in Relapsed CLL: Final Results of PFS (Primary Endpoint) and OS

• Phase III trial in patients with relapsed CLL after at least 1 prior line of tx ‒ Primary study 116 with idelalisib/rituximab followed by extension study 117 with single- agent idelalisib IDELA/R Placebo/R IDELA/R Placebo/R (n = 110) (n = 110) (n = 110) (n = 110) OS, median mos 40.6 34.6 100 PFS, median mos 19.4 6.5 100 (95% CI) (12.3-NR) (4.0-7.3) (95% CI) (28.5-57.3) (16.0-NR) 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 IDELA/R IDELA/R (to IDELA in the extension study) 10 (%)OS of Probability 10 Probability of PFS (%) PFS of Probability Placebo/R Placebo/R (to IDELA in the extension study) 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 4 8 12 16 20 24 28 32 40 44 52 56 60 64 68 Months Since Treatment Assignment Months Since Treatment Assignment

Sharman. JCO. 2019;37:1391. 39 39

2020 PCE Spring Oncology Series 13 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Phase III DUO Trial of Duvelisib vs Ofatumumab in R/R CLL

• Duvelisib is a dual inhibitor of PFS[2] [1] DUV OFA PI3K delta and PI3K gamma 100 Median PFS, mos (95% CI) 13.3 9.9 [1] (12.1-16.8) (9.2-11.3) • Administered orally twice daily 80 HR: 0.52; P < .0001 • Prolonged PFS compared with 60 [2] Duvelisib 25 mg BID ofatumumab in the DUO study Ofatumumab 40 • FDA approved for patients with 20

R/R CLL/SLL and ≥ 2 previous PFS(%)ICRby therapies in September 2018 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk Duvelisib 160 149 108 95 78 58 33 29 13 10 3 2 0 Ofatumumab 159 126 95 77 43 15 7 6 3 2 1 1 0

1. Flinn. Blood. 2018;131:877. 2. Flinn. Blood. 2018;132:2446. 40 40

Phase III ASCEND Trial of Acalabrutinib vs Idelalisib + Rituximab or BR in Previously Treated CLL

• Multicenter, randomized, open-label phase III trial

Acalabrutinib Adult patients with R/R CLL; (n = 155) ≥ 1 prior systemic therapies (no prior exposure to a BCL-2 inhibitor or B-cell receptor signaling inhibitor); ECOG PS 0-2 Idelalisib + Rituximab or (N = 310) Bendamustine + Rituximab (n =155)

• Primary endpoint: IRC-assessed PFS

Ghia. EHA 2019. Abstr LB2606. NCT02970318. 41 41

ASCEND: PFS (Primary Endpoint)

Patients, Median 12-Mo 100 n PFS, Mos PFS, % Acalabrutinib 155 NR 88 IdR or BR 155 16.5 68 80

60

PFS(%) 40

20

HR: 0.31 (95% CI: 0.20-0.49; P < .0001) 0 01 23 4 5 6 7 8 9 101112131415 16 1718 19 20 21 22 23 Months Number at risk Acalabrutinib 155 153 153 149 147 146 145 143 143139 139 137 118 116 73 61 60 25 21 21 1 1 1 0 Idelalisib + R or BR 155 156 150 146 144 142 136 130 129112 105 101 82 77 56 44 39 18 10 8 0

Ghia. EHA 2019. Abstr LB2606. 42 42

2020 PCE Spring Oncology Series 14 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

ASCEND: AEs of Clinical Interest for Acalabrutinib

Acalabrutinib (n = 154) Idelalisib + R (n = 118) BR (n = 35) AEs, % Any Grade ≥ 3 Any Grade ≥ 3 Any Grade ≥ 3

Atrial fibrillation 5 1 3 1 3 3

Bleeding 26 2 8 3 6 3

Hypertension 3 2 4 1 0 0

SPM (no NMSC) 6 3 3 0 3 3

Ghia. EHA 2019. Abstr LB2606. 43 43

AEs and Targeted Therapies in CLL

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Case Study 3: A Patient With Relapsed CLL Planning to Start Venetoclax Therapy

• A 69-year-old male with CLL currently taking ibrutinib reports increasing fatigue during routine follow up ‒ unmutated IGHV, trisomy 12 • PE: axillary lymphadenopathy has increased from 2 cm to 6 cm • Normal cardiac and kidney function • Lab results: ‒ Hgb 13.6, WBC 14K, PLT 400K, ALC 10.5, LDH normal • CT imaging: generalized lymphadenopathy, largest 6 cm in maximal dimension. • PET imaging: lymphadenopathy with FDG uptake slightly above hepatic reference • After consultation, the patient decides on treatment with venetoclax

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2020 PCE Spring Oncology Series 15 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Case Study 3 (cont’d): Patient Presents For Second Dose of Venetoclax

• The patient presents on day 8 of cycle 2 to receive his next dose of venetoclax (planned escalation to 100 mg) • Lab results show normal potassium, calcium, creatinine, uric acid, ANC 600/mL (grade 3 neutropenia)

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Venetoclax: TLS Prophylaxis and Monitoring

General Measures • Identify subjects at higher risk for TLS (see below) • Initiate prophylaxis with hydration and uric acid–reducing agent • Initiate venetoclax with 20-mg dose for 1 week, gradual stepwise ramp-up over 5 weeks to target dose of 400 mg/day Low Risk: Nodal Mass < 5 cm and ALC ≤ 25,000/L • Outpatient dosing at all dose levels, if no indication to hospitalize • Post dose 8- and 24-hour lab monitoring following initial dose and at dose increase Medium Risk: Nodal Mass ≥ 5 cm and < 10 cm or ALC > 25,000/L • Outpatient IV hydration at 20 and 50 mg • Inpatient if CrCl < 80 mL/min or high tumor burden • Post dose 8- and 24-hr lab monitoring following initial dose and at dose escalation High Risk: Nodal Mass ≥ 10 cm or Nodal Mass ≥ 5 cm and ALC > 25,000/L • Inpatient dosing and monitoring (4, 8, 12, and 24 hours) at 20 and 50 mg • Outpatient IV hydration for high-risk subjects at 100 mg and above, if no indication to hospitalize • Post dose 8- and 24-hour laboratory monitoring at 100 mg and above

Stilgenbauer. Lancet Oncol. 2016;17:768. Venetoclax PI. 47 47

AEs of Available BTK Inhibitors

Ibrutinib Acalabrutinib Cytopenias (grade 3/4) Cytopenias (grade 3/4) • Neutropenia 13% to 29% (with risk of febrile neutropenia) • Neutropenia 10% to 23% • Thrombocytopenia 5% to 17% • Thrombocytopenia 5% to 8% • Anemia 0% to 13% • Anemia 5% to 11% Hold BTK inhibitor for grade 3 neutropenia with infection or fever or grade 4 cytopenia Infections (grade 3-5) Infections (grade 3-5) • 14% to 29% of patients • 11% to 18% of patients Consider prophylaxis in patients who are at increased risk for opportunistic infections Other notable AEs Other notable AEs • Cardiac arrhythmia (5% in CLL) • Cardiac arrhythmia (3% in CLL) • Bleeding/bruising (grade 3 bleeding up to 6%) • Bleeding/bruising (grade 3 bleeding up to 3%) • Rash • Rash • Diarrhea, early self-limited, typically responds to loperamide • Headaches • Muscle cramping, late, can be very bothersome • Diarrhea • Pneumonitis, rare but serious, discontinue ibrutinib

Ibrutinib PI. Acalabrutinib PI. 48 48

2020 PCE Spring Oncology Series 16 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Future Directions in CLL

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Select Phase III Trials in Previously Untreated CLL

Primary Trial Phase Population Planned N Treatment Arm(s) Endpoint CLL13 Venetoclax + rituximab vs venetoclax + Untreated CLL (NCT02950051) obinutuzumab vs. venetoclax + III (no del[17p] or 920 PFS, MRD obinutuzumab + ibrutinib vs standard TP53 mutation) chemoimmunotherapy A041702 Untreated CLL Ibrutinib + obinutuzumab vs ibrutinib + III 454 PFS (NCT03737981) (≥ 70 years) obinutuzumab + venetoclax EA9161 Untreated CLL Ibrutinib + obinutuzumab vs ibrutinib + III 720 PFS (NCT03701282) (< 70 years) obinutuzumab + venetoclax FLAIR Untreated CLL FCR vs ibrutinib + rituximab vs ibrutinib (ISRCTN0184415 III 1576 PFS, MRD (≤ 75 years) vs ibrutinib + venetoclax 2)

50 50

Phase II Trial of Ibrutinib + Venetoclax in Previously Untreated High- Risk CLL: Study Design

• Investigator-initiated phase II trial ‒ Median follow-up: 14.8 months (range: 5.6-27.5) 3 cycles 24 cycles

Patients ≥ 18 years of age with treatment- Ibrutinib‡ 420 mg daily naive, high-risk Ibrutinib 420 mg daily + Venetoclax§ Until PD CLL/SLL* and adequate (n = 80) Dose-escalation to 400 mg daily organ function† (n = 75) (N = 80)

*Meeting 2008 IWCLL criteria; ≥ 1 high risk feature required: del(17p) or mutated TP53, del(11q), unmutated IGHV, or ≥ 65 years of age. †GFR > 50 mL/min; ALT/AST ≤ 3.0 x ULN; total bilirubin ≤ 1.5 x ULN; platelets > 20 K/μL. ‡Ibrutinib stopped at cycle 24 if BM MRD negative (by flow cytometry at 10-4), or if BM MRD positive, until PD. §Week 1: 20 mg daily; Wk 2: 50 mg daily; Week 3: 100 mg daily; Week 4: 200 mg daily; Week 5-27: 400 mg daily. Response evaluations Q3M in Yr 1, Q6M in Year 2. Any LN > 1.5 cm by CT considered PR. • Primary endpoint: CR/CRi by 2008 IWCLL criteria

Jain. NEJM. 2019;380:2095. 51 51

2020 PCE Spring Oncology Series 17 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Ibrutinib + Venetoclax in CLL: Response

100 1 • Addition of venetoclax to ibrutinib led to improved 80 responses with ongoing 57 73 therapy and rapid and 60 83 88 96 deep reductions in CLL 96 40 BM disease 69 61

Response(%) 52 20 43 40 27 17 17 0 12 0 4 3 Cycles 3 Cycles 6 Cycles 9 Cycles 12 Cycles 18 Cycles IBR VEN + IBR VEN + IBR VEN + IBR VEN + IBR VEN + IBR (n = 75) (n = 72) (n = 70) (n = 60) (n = 33) (n = 26) PR CR/CRi BM MRD negative*

*By flow cytometry at 10-4 sensitivity. Jain. NEJM. 2019;380:2095. 52 52

Ongoing Phase III Clinical Trials in R/R CLL

Trial Population N Status MRD Treatment Arms UTX-IB-301 del(17p), 120 Enrolled No Ublituximab + ibrutinib vs ibrutinib (NCT02301156) del(11q), and/or TP53 mutation ELEVATE-RR del(17p) 533 Enrolled No Acalabrutinib vs ibrutinib (NCT02477696) and/or del(11q) ALPINE All 400 Recruiting No vs ibrutinib (NCT03734016)

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Overcoming Acquired Resistance With Reversible BTK Inhibitors

• Resistance and intolerance can limit utility • Dose-escalation phase I trial of LOXO-305 of covalent BTK inhibitors (eg, ibrutinib, (N = 28, including 16 with CLL)[2] acalabrutinib)[1] — ≥ 2 lines of therapy, including BTKi intolerant ‒ BTK C481 mutations predominant reason for CLL progression after approved BTKi[1,2] — 25 mg up to 200 mg daily • Reversible, noncovalent BTK inhibitors in • Safety profile development with activity against WT and — No DLTs reported, MTD not reached [2-4] C481-mutant BTK — No reported atrial fibrillation or major ‒ LOXO-305 bleeding ‒ ARQ 531 • ORR (in CLL): 77% ‒ Vecabrutinib — Tumor shrinkage reported in all pts regardless of starting dose, previous therapy, or C481S mutation — Responses deepened over time 1. Kipps. Nat Rev Dis Primers. 2017;3:16096. 2. Mato. ASH 2019. Abstr 501. 3. Allan. ASH 2019. Abstr 3041. 4. Bond. Curr Hematol Malig Rep. 2019;14:197. 54 54

2020 PCE Spring Oncology Series 18 Advances in Chronic Lymphocytic Leukemia: Key Elements for Today’s Clinic

Chimeric Antigen Receptor T-Cell Therapy

 2011: first case report of successful CAR T-cell therapy Case Report: CAR T-Cell Therapy in CLL[1] in CLL[1] Bone Marrow Biopsy Specimens  Since then, multiple reports of sustained remissions after Day 1 (Baseline) Day 23 6 Mos CAR T-cell therapy[2]  Ibrutinib + anti-CD19 CAR T-cell therapy associated with 89% CR rate in CLL[3]  In pts with R/R CLL previously treated with ibrutinib (> 50% received venetoclax), anti-CD19 CAR T-cell therapy induced rapid and durable responses[4] Contrast-Enhanced CT Axial Coronal ‒ ORR: 82% (CR/CRi: 46%) Before Therapy ‒ MRD negativity rate (10-4): 75% in peripheral blood and 65% in bone marrow 1 Month of Treatment

3 Months of Treatment

1. Porter. NEJM. 2011;365:725. 2. Turtle. JCO. 2017;35:3010. 3. Gill. ASCO 2017. Abstr 7509. 4. Siddiqi. ASH 2019. Abstr 503. 55 55

PCE Action Plan

 Order karyotype and molecular analysis tests to identify prognostic and predictive biomarkers that inform treatment decisions  Consider targeted therapy options for all patients with newly diagnosed or relapsed/refractory CLL  Evaluate risk of and establish recommended monitoring practices for tumor lysis syndrome in patients being treated with venetoclax  Discuss clinical trial options for patients with progression following treatment with currently available targeted therapies for CLL

PCE Promotes Practice Change

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