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Home , Erdafitinib, Gilteritinib

Disclosures I have nothing to disclose. New Drug Update

JORDAN BASKETT, PHARMD, BCOP CLINICAL ONCOLOGY PHARMACIST DUKE UNIVERSITY HOSPITAL

Recently Approved Agents for & Objectives Duvelisib September 2018 CLL/SLL, FL Calaspargase pegol-mknl December 2018 ALL 1. Review pharmacology of newly approved oncology Blastic plasmacytoid agents Tagraxofusp-erzs December 2018 dendritic cell neoplasm 2. Discuss literature supporting approval of the agents July 2018 AML, IDH1+ 3. Identify clinical pearls for new agents November 2018 AML, FLT3+ 4. Evaluate place in therapy for newly approved agents November2018 AML Moxetumomab September 2018 Hairy cell leukemia pasudotox-tdfk Mycosis fungoides or -kpkc August 2018 Sézary syndrome

Duvelisib (Copiktra®) Compared to Idelalisib

Approved Duvelisib Idelalisib • September 2018 PI3K-δ and PI3K-γ inhibitor PI3K-δ inhibitor MOA • Inhibits PI3K-δ and PI3K-γ in normal and malignant B-cells Monotherapy In combination with for CLL/SLL Indication BBW: BBW: • Infection • Hepatotoxicity • Relapsed/refractory CLL/SLL and FL after ≥ 2 prior systemic therapies • Diarrhea, colitis (18%) • Diarrhea, colitis (14%) Dosing & Administration • Cutaneous reactions • Intestinal perforation • Pneumonitis (5%) • Pneumonitis (4%) • 25 mg PO BID Administer Pneumocystis jirovecii (PJP) prophylaxis during treatment and until absolute CD4+ T cell count is > 200 cells/uL

Consider antiviral prophylaxis for cytomegalovirus reactivation

Copiktra (duvelisib) [package insert]. Needham, MA: Verastem, Inc; 2018. Flinn IW, et al. Blood 2018;132(23):2446-2455. Furman RR, et al. N Engl J Med 2014;370(11):997-1007.

1 Calaspargase pegol-mknl Audience Response #1 (AsparlasTM)

How does the mechanism of action for duvelisib differ from idelalisib? Approved A. Duvelisib inhibits PI3K-δ alone • December 2018 B. In addition to inhibiting PI3K-δ, duvelisib also inhibits PI3K-γ MOA • Conjugated enzyme that reduces circulating levels of asparagine, resulting in cytotoxicity C. Duvelisib inhibits PI3K-γ alone to leukemic cells Indication • Treatment of ALL in pediatric & young adult patients age 1 month to 21 years Dosing & Administration • 2500 units/m2 IV over 1 hour, no more frequently than every 21 days

Asparlas (calaspargase pegol-mknl) [package insert]. Boston, MA: Servier Pharmaceuticals LLC; 2018.

Compared to Pegaspargase Tagraxofusp-erzs (ElzonrisTM) May be substituted for pegaspargase in multi-agent plans Approved Pegaspargase (SS-PEG) Calaspargase pegol (SC-PEG) • December 2018 E.coli L-asparaginase with a succinimidyl E.coli L-asparaginase with a succinimidyl MOA carbamate (SC) linker = succinate (SS) linker more stable molecule • CD123-directed cytotoxin

At least 14 days between doses At least 21 days between doses Indication Mean AUC from time 0-25 days: Mean AUC from time 0-25 days: • Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients ≥ 365 IU x h/mL 404 IU x h/mL 2 years old Mean half-life of plasma asparaginase Mean half-life of plasma asparaginase activity: 127 hr activity: 322 hr Dosing & Administration • 12 mcg/kg IV infusion over 15 minutes once daily on days 1-5 of a 21-day cycle

Asparlas (calaspargase pegol-mknl) [package insert]. Boston, MA: Servier Pharmaceuticals LLC; 2018. Angiolillo AL, et al. J Clin Oncol 2014;32(34):3874-3882. Elzonris (tagraxofusp-erzs) [package insert]. New York, NY: Stemline Therapeutics, Inc; 2018.

Tagraxofusp-erzs: Pearls & Place in Therapy Ivosidenib (Tibsovo®)

STML-401-0114 trial Approved • 29 treatment-naïve patients: • July 2018 (relapsed/refractory) • CR or clinical CR: 72% (95% CI, 52.8% to 87.3%) • May 2019 (front-line) • ORR: 90% (95% CI, 72.6% to 97.8%) MOA • 45% (13/29) were bridged to stem cell transplant • Mutated IDH1 inhibitor • OS: not reached (median f/u of 23 mo) • AEs (≥40%): increased ALT/AST, hypoalbuminemia, peripheral edema, Indication thrombocytopenia • Relapsed/refractory IDH1-mutated AML • Newly diagnosed IDH1-mutated AML in patients ≥ 75 years old or in patients who have •Premedicate with H1-histamine antagonist, acetaminophen, corticosteroids, and H2- comorbidities histamine antagonist prior to each infusion Dosing & Administration •Administer first cycle inpatient & monitor patient for a minimum of 24 hours •Warning: capillary leak syndrome (19% incidence) • 500 mg PO daily • Median onset: 5 days • Avoid taking with a high-fat meal • Duration: ~4 days • Monitor serum albumin & patient weight

Pemmaraju N, et al. N Engl J Med 2019;380(17):1628-1637. Tibsovo (ivosidenib) [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc; 2018. Elzonris (tagraxofusp-erzs) [package insert]. New York, NY: Stemline Therapeutics, Inc; 2018.

2 Ivosidenib in the… Ivosidenib: Relapsed/Refractory Setting Front-line Setting Pearls & Place in Therapy • Phase I/II dose-escalation & dose- • Ongoing phase I study •Available as 250 mg tablets expansion study • Determine safety & efficacy in patients •Increases risk for differentiation syndrome and hyperleukocytosis • Evaluate safety & efficacy in all with untreated AML •Reduce dose with strong CYP3A4 inhibitors & avoid concomitant use with CYP3A4 previously treated patients • CR + CRh: 41.2% (95% CI, 24.6 to 59.3) inducers • CR + CRh: 30.2% (95% CI, 23.5 to 37.5) • CR: 26.5% (95% CI, 12.9 to 44.4) •Dose adjust for differentiation syndrome, noninfectious leukocytosis not improved with • CR: 21.6% (95% CI, 14.7 to 29.8) • 38.1% of attained transfusion hydroxyurea, QTc prolongation • 35% of patients attained transfusion independence for ≥56 consecutive days •Recommended to treat for a minimum of 6 months independence on treatment • 500 mg daily was associated with • Induced durable remissions & AML, ≥ 60 yo, not a candidate for intensive remission induction therapy or declines transfusion independence, durable transfusion independence in an elderly - Ivosidenib IDH1 mutant remissions & a low frequency of ≥ grade patient population; also well tolerated - Low-intensity therapy (azacitidine, decitabine) 3 adverse events Relapsed/Refractory AML

Most common AEs (≥ 20%): diarrhea, leukocytosis, febrile neutropenia, nausea, fatigue, IDH1 mutant - Ivosidenib dyspnea, QT prolongation, peripheral edema, anemia, pyrexia, cough Note: All recommendations are category 2A unless otherwise indicated

Tibsovo (ivosidenib) [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc; 2018. DiNardo CD, et al. N Engl J Med 2018;378(25):2386-2398. National Comprehensive Cancer Network. (Version 3.2019) Roboz GJ, et al. Blood 2018;132:561; doi: https://doi.org/10.1182/blood-2018-99-110595. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 12, 2019.

Audience Response #2 Gilteritinib (Xospata®) Based on the trials discussed, what conclusions did authors make in Approved regards to using ivosidenib in the relapsed/refractory and front-line settings? • November 2018 A. Ivosidenib was associated with transfusion independence MOA • Selective inhibitor of multiple receptor tyrosine kinases, including FLT3 & AXL B. Ivosidenib induces durable remissions Indication C. Ivosidenib is well-tolerated • FLT3-mutated relapsed/refractory AML D. All of the above Dosing & Administration • 120 mg PO daily

Gilteritinib (Xospata) [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2018.

ADMIRAL Trial Phase III, open-label, multicenter, randomized trial (ongoing) Design TM - October 2015 to October 2019 Glasdegib (Daurismo ) Compare gilteritinib to salvage chemotherapy in patients with Objective relapsed/refractory FLT3 positive AML Approved Primary: OS Endpoints • November 2018 Secondary: safety MOA • Patients treated with gilteritinib had significantly longer OS than those who received standard • Selective inhibitor of Smoothened protein in Hedgehog signaling pathway salvage chemotherapy • OS: 9.3 mo vs. 5.6 mo (95% CI, 0.49 to 0.83; p=0.0007) Indication • 1 year survival rates: 37% vs. 17% • Less toxic compared to chemotherapy (serious side effects, 7.1% vs. 9.2%) • Newly diagnosed AML in adults ≥ 75 years old or in patients who have comorbidities that preclude the use of intensive induction chemotherapy • AEs occurring ≥ 10% in the first 30 days: anemia, increased ALT & AST, febrile neutropenia Dosing & Administration Relapsed/Refractory AML • 100 mg PO daily on days 1-28 in combination with low dose cytarabine (LDAC) 20 mg SC BID on days 1-10 of each 28 day cycle - Gilteritinib FLT3 mutant - Hypomethylating agents (azacitidine or decitabine) + (FLT3-ITD mutation only) Note: All recommendations are category 2A unless otherwise indicated

Gorcea CM, Burthem J, Tholouli E. Future Oncol 2018;14(20):1995-2004. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2019) Daurismo (Glasdegib) [package insert]. New York, NY: Pfizer Inc; 2018. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 12, 2019.

3 2 BRIGHT 1003 Trial Design Phase II, randomized, open-label, multicenter study Adverse Events Evaluate efficacy of glasdegib + LDAC vs. LDAC in patients with untreated AML Objective or high-risk myelodysplastic syndrome who are unsuitable for intensive chemotherapy n, (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total Primary: OS Endpoints Secondary: clinical efficacy, safety & tolerability, PK/PD, and effect on Any AE 0 1 (1.4) 11 (15.9) 52 (75.4) 5 (7.2) 69 (100) corrected QT interval Diarrhea 30 (43.5) 18 (26.1) 1 (1.4) 0 0 49 (71) OS, full analysis set OS, in patients with good/intermediate cytogenetic risk Febrile 0 0 42 (60.9) 2 (2.9) 0 44 (63.8) Neutropenia

Nausea 20 (29) 18 (26.1) 2 (2.9) 0 0 40 (58)

Hypokalemia 19 (27.5) 9 (13) 8 (11.6) 1 (1.4) 0 37 (53.6)

Cortes JE, et al. Leukemia 2019;33:379-389. Cortes JE, et al. Leukemia 2019;33:379-389.

Glasdegib: -tdfk Pearls & Place in Therapy (LumoxitiTM) •Available as 100 mg or 25 mg tablets •Consider avoiding co-administration with strong CYP3A4 inhibitors/inducers Approved • Dose adjust for QTc prolongation (>500 ms on at least 2 separate ECGs), • September 2018 thrombocytopenia, & neutropenia •Advise patients not to donate blood or blood products for at least 30 days after last dose MOA •Treat for a minimum of 6 months to allow time for clinical response • CD22-directed cytotoxin

AML, ≥ 60 yo, not a candidate for intensive remission induction therapy or declines Indication - Low-intensity therapy (azacitidine, decitabine) (preferred) • Treatment of relapsed/refractory hairy cell leukemia (HCL) after ≥ 2 prior systemic - once daily + IV decitabine therapies, including treatment with a purine nucleoside analog - Venetoclax once daily + SC or IV azacitidine AML without Dosing & Administration - Venetoclax once daily + SC low-dose cytarabine actionable - Glasdegib + low-dose cytarabine • 0.04 mg/kg IV infusion over 30 minutes on days 1, 3, and 5 of each 28-day cycle mutations - Low-dose cytarabine - (for CD33-positive) - Best supportive care Note: All recommendations are category 2A unless otherwise indicated

Daurismo (Glasdegib) [package insert]. New York, NY: Pfizer Inc; 2018. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2019) Lumoxiti (moxetumomab pasudotox-tdfk) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 12, 2019.

Kreitman RJ, et al. Leukemia 2018. Moxetumomab pasudotox-tdfk: Design Multicenter, single-arm open-label study Evaluate efficacy & safety of moxetumomab pasudotox in patients with Pearls & Place in Therapy Objective relapsed/refractory HCL who had ≥ 2 prior systemic therapies, including ≥ 1 purine nucleoside analog •BBW: capillary leak syndrome & hemolytic uremic syndrome •Premedicate with acetaminophen, antihistamine, and H2-receptor antagonist prior to all Primary: durable CR (hematologic remission > 180 days) infusions Endpoints Secondary: ORR, duration of complete & objective response, PFS, •Maintain adequate hydration throughout treatment (1 L NS over 2-4 hours before and safety/tolerability, immunogenicity, and pharmacokinetics after each infusion) •Advise all patients to adequately hydrate with up to 3 liters of oral fluids daily on days 1-8 of each cycle •Consider low-dose aspirin on days 1-8 of each 28-day cycle •Not recommended in patients with CrCl ≤ 29 mL/min

Relapsed/Refractory HCL after ≥ 2 prior therapies - Clinical trial - ± rituximab Progression - - Moxetumomab pasudotox Note: All recommendations are category 2A unless otherwise indicated

Lumoxiti (moxetumomab pasudotox-tdfk) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. Kreitman RJ, et al. Leukemia 2018;32:1768-1777. National Comprehensive Cancer Network. Hairy Cell Leukemia (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf. Accessed June 10, 2019.

4 Mogamulizumab-kpkc MAVORIC Trial Design Phase III randomized, open-label, multicenter controlled trial ® Compare efficacy of mogamulizumab with vorinostat in relapsed/refractory (Poteligeo ) Objective mycosis fungoides or Sézary syndrome Primary: PFS Approved Endpoints Secondary: ORR, safety • August 2018

MOA PFS: 7.7 mo vs. 3.1 mo • ORR: 28% vs. 5% (p<0.0001) • CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody o Higher in patients with Sézary syndrome than Indication mycosis fungoides • Treatment of mycosis fungoides or Sézary syndrome after at least 1 prior systemic (37% vs. 21%) therapy Dosing & Administration • Mostly grade 1-2 & manageable AEs: infusion • First 28-day cycle: 1 mg/kg IV infusion over at least 60 minutes on days 1, 8, 15, and 22 related reaction, skin • Subsequent cycles: 1 mg/kg IV infusion on days 1 and 15 eruption, diarrhea

• Most common grade 3 AEs: pyrexia, cellulitis

Poteligeo (mogamulizumab-kpkc) [package insert]. Bedminster, NJ: Kyowa Kirin, Inc.; 2018. Kim YH, et al. Lancet Oncol 2018;19(9):1192-1204.

Mogamulizumab-kpkc: Mogamulizumab-kpkc: Pearls Place in Therapy •Supplied in 20 mg/5 mL single-dose vials Mycosis Fungoides – Suggested Systemic Treatment Regimens •Store in refrigerator & protect from light Preferred regimens Other recommended regimens - - Acitretin •Monitor for infusion reactions, which usually occur during first administration - Bexarotene - All-trans retinoic acid • Premedicate with diphenhydramine and acetaminophen for the 1st infusion - Extracorporeal photopheresis - Isotretinoin - Interferons (IFN-alpha, IFN-gamma) Category A • If a reaction occurs, administer premeds with future infusions - Methotrexate (≤ 50 mg q week) - Mogamulizumab •Monitor for dermatologic toxicity - Romidepsin - Vorinostat •Increased risk of severe acute GVHD, steroid-refractory GVHD and transplant- - Idelalisib + rituximab related death in patients who receive mogamulizumab within approximately 50 days prior to allogeneic stem cell transplant Sézary Syndrome – High burden (eg, absolute Sézary cell > 5 K/mm3) - Combination therapies (phototherapy + ECP/IFN/retinoid; ECP + IFN ± retinoid) - Mogamulizumab ± skin-directed therapies - Romidepsin ± skin-directed therapies Note: All recommendations are category 2A unless otherwise indicated

Poteligeo (mogamulizumab-kpkc) [package insert]. Bedminster, NJ: Kyowa Kirin, Inc.; 2018. National Comprehensive Cancer Network. Primary Cutaneous (Version 2.20190). Fuji S, et al. J Clin Oncol 2016;34:3426-3433. https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf. Accessed June 12, 2019.

® Recently Approved Agents for Solid Tumors (Braftovi ) + ® Encorafenib + June 2018 Melanoma Binimetinib (Mektovi ) Cutaneous squamous cell -rwlc September 2018 carcinoma (CSCC) Approved September 2018 Metastatic NSCLC • June 2018 November 2018 ALK+ metastatic NSCLC MOA April 2019 Urothelial carcinoma • BRAF V600E/D/K inhibitor + MEK1/2 inhibitor Indication Talazoparib October 2018 BRCA-mutated breast cancer • Treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K PIK3CA-mutated breast mutation Alpelisib May 2019 cancer Dosing & Administration Solid tumors with a • Encorafenib 450 mg PO daily + binimetinib 45 mg PO q12h neurotrophic receptor November 2018 (NTRK) gene fusion

Braftovi (encorafenib) [package insert]. Boulder, CO: Array BioPharma Inc.; 2018. Mektovi (binimetinib) [package insert]. Boulder , CO: Array BioPharma Inc.; 2018.

5 Compared to other BRAF/MEK inhibitors Cemiplimab-rwlc (Libtayo®)

Approved AEs Median Median PFS Median OS Trial Phase Treatment Arms Response Rate Grade 3- • September 2018 f/u (mo) (mo) (mo) 4 MOA 11 Dab + tram (n=352) 64% p<0.001 11.4 p<0.001 NR p=0.005 52% COMBI-v III 10 Vem (n=352) 51% 7.3 17.2 63% • Programmed death-receptor 1 (PD-1) inhibitor 14.2 Vem + cobi (n=247) 70% p<0.0001 12.3 p<0.001 22.3 p=0.005 75% Co-BRIM III 18.5 Vem + pbo (n=248) 50% 7.2 17.4 61% Indication COLUM- 32.1 (PFS) Encor + bini (n=192) 64% 14.9 p<0.001 33.6 p<0.001 64% III • Treatment of metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced BUS 36.8 (OS) Vem (n=191) 41% 7.3 16.9 66% CSCC who are not candidates for curative surgery or radiation Dosing & Administration • 350 mg IV infusion over 30 minutes every 3 weeks

National Comprehensive Cancer Network. Cutaneous Melanoma (Version Dummer R, et al. Lancet Oncol 2018;19:603-615. 2.2019). Dummer R, et al. Lancet Oncol 2018;19:1315-1327. Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY, and Bridgewater, NJ: Regeneron Pharmaceuticals and https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pd Sanofi-Aventis US, LLC; January 2019. f. Accessed June 10, 2019.

R2810-ONC-1450 Trial Cemiplimab-rwlc: Design Phase II, nonrandomized, open-label, global trial Estimate clinical benefit of cemiplimab monotherapy in patients with metastatic Objective Pearls & Place in Therapy CSCC or with unresectable locally advanced CSCC Primary: ORR (CR + PR) •First & only PD-1 inhibitor approved this metastatic or locally advanced CSCC Endpoints Secondary: duration of response, durable disease control rate, time to response, safety •Supplied as 350 mg/7mL vial •Dilute in 0.9% sodium chloride or 5% dextrose Median Most common Grade ≥ 3 Median •Administer via a 0.2- to 5-micron filter Durable disease observed treatment- immune- ORR duration of control rate time to emergent AEs related AEs response •Monitor for immunotherapy-related AEs response (all grades) Primary Treatment for Squamous Cell Skin Cancer 49.2% (95% CI, 35.9 to 62.5) Has not been 61% 1.9 months Diarrhea, RT &/or systemic treatment options or clinical trial 13.6% reached (95% CI, 47 to 74) fatigue, rash Inoperable - Cemiplimab 10 CR + 19 PR disease - Cisplatin ± 5-FU - EGFR inhibitors () Note: All recommendations are category 2A unless otherwise indicated

National Comprehensive Cancer Network. Squamous Cell Skin Cancer (Version 2.2019). https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf. Migden MR, et al. N Engl J Med 2018;379:341-351. Accessed June 10, 2019. Libtayo (cemiplimab-rwlc) [package insert]. Tarrytown, NY, and Bridgewater, NJ: Regeneron Pharmaceuticals and Sanofi-Aventis US, LLC; January 2019.

Solomon BJ, et al. Lancet Oncol 2018. ® Design Phase II Evaluate efficacy & safety of lorlatinib in ALK-positive or ROS1-positive metastatic Lorlatinib (Lorbrena ) Objective NSCLC who had progressed after ALK inhibitor therapy Primary: overall & intracranial tumor response Approved Endpoints Secondary: safety • November 2018 MOA • Objective response with ≥ 1 previous ALK inhibitor rd •3 generation tyrosine kinase inhibitor with activity against ALK and ROS1 as well as • 47% (93/198; 95% CI, 39.9% to 54.2%) various others • 4 CR + 89 PR Indication • Effective in patients who had received up to 3 previous ALK inhibitors • • Treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following Objective intracranial response in those with measureable baseline CNS lesions disease progression on and ≥ 1 other ALK inhibitor, or or as • 63% (51/81; 95% CI, 51.5% to 73.4%) first therapy • Intracranial response with previous crizotinib: 87% • Intracranial response with previous 2nd generation ALK inhibitors: >50% Dosing & Administration • Grade 3-4 AEs: • 100 mg PO daily • Hypercholesterolemia (16%) • Hypertriglyceridemia (16%) Developed to better penetrate the blood-brain barrier & to retain potency to acquired resistant mutations that developed during therapy with 1st and 2nd generation agents

Lorbrena (lorlatinib) [package insert]. New York, NY: Pfizer Inc.; 2018. Solomon BJ, et al. Lancet Oncol 2018;19(12):1654-1667.

6 ARCHER 1050 ® Design Phase III, head-to-head trial Evaluate efficacy & safety of dacomitinib vs. as first-line therapy for newly Dacomitinib (Vizimpro ) Objective diagnosed, locally advanced or metastatic NSCLC with EGFR activating mutations Primary: PFS Approved Endpoints Secondary: ORR, OS • September 2018 MOA • PFS: 14.7 mo vs. 9.2 mo (95% CI, 0.47 to 0.74; •2nd generation tyrosine kinase inhibitor that irreversibly inhibits EGFR, HER1, HER2, and p<0.001) HER4 • ORR: 74.9% vs. 71.6% Indication • First-line treatment of metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R • OS: 34.1 mo vs. 26.8 mo substitution mutations (95% CI, 0.582 to 0.993; p=0.0438) Dosing & Administration • 45 mg PO daily • Grade 3-4 AEs: rash (21%) & diarrhea (11%)

Vizimpro (dacomitinib) [package insert]. New York, NY: Pfizer Inc.; 2018. Mok TS, et al. J Clin Oncol 2018;36(22):2244-2250.

BLC2001 Trial TM Design Phase II global, open-label study Erdafitinib (Balversa ) Evaluate the safety & efficacy of erdafitinib in locally advanced or metastatic Objective urothelial cancer with an FGFR gene mutation or fusion following at least 1 prior therapy Approved Endpoints Primary: ORR • April 2019

MOA ORR (n=87) ORR with prior immune • Fibroblast growth factor receptor (FGFR) kinase inhibitor • 42% confirmed checkpoint inhibitors (n=21; 24%) • 3% CR, 39% PR Indication • 70% •2nd-line treatment of locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or FGFR2 genetic alterations & progressed during or following ≥ 1 line of prior platinum-containing chemotherapy Disease control rate Most common AEs: Dosing & Administration • 80% • Hyperphosphatemia 69% • Starting dose: 8 mg tablets PO daily • Stomatitis 47% • Dose increase to 9 mg PO daily based on serum phosphate levels & tolerability at 14-21 • Diarrhea 42% days

Balversa (erdafitinib) [package insert]. Horsham, PA: Janssen Products, LP; 2019. Siefker-Radtke AO, et al. J Clin Oncol 2018;36(supple15):4503. Available at http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_supple.4503.

Erdafitinib: Pearls & Place in Therapy Audience Response #3 •Available in 3 mg, 4 mg, and 5 mg tablets In addition to restricting phosphate intake, what does the manufacturer • 3 mg: bottle & dose pack of 56 and 84 tablets recommend doing if the serum phosphate is above 7 mg/dL? • 4 mg: bottle of 56 and 84 tablets, starter pack of 14 tablets, dose pack of 28 and 56 tablets • 5 mg: bottle and dose pack of 28 tablets A. Continue erdafitinib as current dose •Avoid concomitant use with strong CYP2C9 or CYP3A4 inducers • Increase dose up to 9 mg with moderate CYP2C9 or CYP3A4 inducers B. Add an oral phosphate binder until serum phosphate returns to <5.5 •Restrict phosphate intake to 600-800 mg daily & dose adjust based on serum phosphate level mg/dL C. Hold erdafitinib and reassess serum phosphate weekly, then restart Subsequent systemic therapy for locally advanced or metastatic disease (post-platinum) at the same dose level once phosphate returns to < 5.5 mg/dL Preferred Alternative preferred regimens • • D. Both B & C • • • • Erdafitinib* *Only for patients with susceptible FGFR3 or FGFR2 genetic alterations Note: All recommendations are category 2A unless otherwise indicated

Balversa (erdafitinib) [package insert]. Horsham, PA: Janssen National Comprehensive Cancer Network. (Version 3.2019). Products, LP; 2019. https:///www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed June 8, 2019.

7 Compared to Olaparib ® Talazoparib (Talzenna ) Talazoparib Olaparib • ~100-fold more potent at trapping PARP- Approved • Lower PARP trapping potency DNA complexes • Lower cytotoxic potency • October 2018 • Higher cytotoxic potency Locally advanced & metastatic disease Metastatic disease MOA EMBRACA trial OlympiAD trial • Poly (ADP-ribose) polymerase (PARP) 1 and 2 inhibitor • Median PFS: 8.6 mo vs. 5.6 mo • Median PFS: 7 mo vs 4.2 mo (95% CI, 0.41 to 0.71; p<0.0001) (95% CI, 0.43 to 0.80; p<0.0009) Indication • ORR: 50.2% vs. 18.4% • ORR: 52% vs. 23% • Grade 3/4 thrombocytopenia: 14.7% • Treatment of deleterious or suspected deleterious germline BRCA-mutated, HER2- • Grade 3/4 anemia: 16.3% • Grade 3/4 anemia: 39.2% negative locally advanced or metastatic breast cancer • Grade 3/4 neutropenia: 9.3%% • Grade 3/4 neutropenia: 20.1% • Any grade nausea: 58% Dosing & Administration • Any grade nausea: 49% • Any grade fatigue: 28.8% • Any grade fatigue: 62% • 1 mg PO daily • Alopecia: 25% • 0.75 mg PO daily if CrCl 30-59 mL/min Preferred, category 1 NCCN recommendation

Litton JK, et al. N Engl J Med 2018;379:753-763. Talzenna (talazoparib) [package insert]. New York, NY: Pfizer Inc.; 2018. Robson M, et al. N Engl J Med 2017;377:523-533.

Audience Response #4 Alpelisib (Piqray®) While both agents are preferred, category 1 recommendations per the Approved NCCN guidelines for HER2-negative, germline BRCA 1/2 mutated breast cancer, talazoparib may be preferred over olaparib in all of the following • May 2019 women except: MOA A. A 32 year old who does not want to lose her hair • α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor B. A 45 year old who had experienced significant morning sickness with pregnancy and is very concerned about nausea/vomiting Indication C. A 40 year old with locally advanced disease • In combination with fulvestrant for the treatment of postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen Dosing & Administration • 300 mg PO daily with food • Fulvestrant 500 mg IM on days 1, 15, and 29 &then monthly thereafter

Piqray (alpelisib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.

SOLAR-1 Trial Alpelisib: Design Phase III, randomized trial Compare efficacy & safety of alpelisib + fulvestrant with placebo + fulvestrant in Objective Pearls & Place in Therapy HR-positive, HER2-negative advanced breast cancer following endocrine therapy Primary: PFS •Available in 50 mg, 150 mg, and 200 mg tablets Endpoints Secondary: OS, safety •Warnings/Precautions: severe cutaneous reactions (SJS, TEN); hyperglycemia & ketoacidosis; pneumonitis; diarrhea 341 of 572 patients had confirmed PIK3CA mutations •Avoid coadministration with strong CYP3A4 inducers and BCRP inhibitors •PFS: 11 mo vs. 5.7 mo (95% CI, 0.5 to 0.85; p<0.001) •Majority of patients in study had not received a CDK4/6 inhibitor •Overall response: 36% vs. 16% (p=0.0002)

Most frequent Grade 3/4 AEs Upfront, in combination •Hyperglycemia FPG > 250 mg/dL: 36.6% vs. 0.7% with endocrine therapy + •Rash: 9.9% vs. 0.3% CDK4/6 inhibitor? When should this •Diarrhea: 6.7% vs. 0.3% be incorporated Hyperglycemia into the current treatment algorithm •65% of patients reported any hyperglycemia Sequentially, after disease •Median time to occurrence: 15 days progression on endocrine •87% managed with anti-diabetic medication therapy + CDK4/6 inhibitor? •76% reported use of metformin as single agent or in combination with other anti-diabetic medication (insulin, DPP-4 inhibitors, sulfonylureas)

Piqray (alpelisib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. André F, et al. N Engl J Med 2019;380:1929-1940. André F, et al. N Engl J Med 2019;380:1929-1940.

8 New Drug Update

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