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Home , Daratumumab, Fedratinib, Ivosidenib, Polatuzumab vedotin, Zanubrutinib

2/17/20

We Have a Pill for That! Objectives New Drugs, New Indications, 1. Describe the mechanism of action of the anticancer therapy and New Hope for Patients 2. Discuss supporting literature leading to with Hematological approval of anticancer therapies 3. Identify common and serious toxicities Malignancies associated with therapies

Susanne Liewer, PharmD, BCOP, FHOPA 4. Outline management strategies for UNMC College of Pharmacy toxicities associated with anticancer February 20, 2020 therapies 5. Identify any barriers to patient access of anticancer therapies

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/ Cancer Incidence…The Cancer Incidence…The Bad and the Good Bad and the Good American Cancer Society 2020 Statistics Decrease in mortality! – 1.8 million new cancer diagnoses – 29% – 606,000 cancer deaths – 2.9 million fewer deaths Hematologic malignancies Why? – Acute – Lung cancer • 26,090 new cases; 10,370 deaths • Decrease smoking – • Decrease mortality • 85,720 new cases; 20,910 deaths – Breakthroughs! – • Hematological & lymphoid • 32,270 new cases; 12,830 deaths

Siegel R. Ca Cancer J Clin 2020; 70-7-30 Siegel R. Ca Cancer J Clin 2020; 70-7-30 3 4

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/ US Food and Drug Hematology/Oncology New Administration (FDA) Drug Approvals 2019 Standards for drug safety & efficacy February August and – 1906 Pure Food and Drug Act hyaluronidase-oysk • List ingredients Caplacizumab-yhdp – 1938 Food, Drug & Cosmetic Act April November • Nontoxic • No efficacy data May Luspatercept-aamt Alpelisib Crizanlizumab-tmca – 1962 thalidomide crisis Givosiran • Demonstrate efficacy June Voxelotor -piiq Significant impact on US economy (Polivy) December Fam-trastuzumab – $400 billion in 2016 July deruxtecan-nxki -ejfv – 48 new drugs approved in 2019 Darolutamide – 17 cancer agents

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 5 6

Hematology/Oncology Drug with Expanding Indications from the FDA Let’s Narrow This Down January June: → hepatocellular carcinoma → first line treatment with metastatic HNSCC Multiple Myeloma February Pembrolizumab →recurrent small cell lung cancer Lymphoma Pembrolizumab → adjuvant treatment → combination therapy in newly diagnosed MM (transplant ineligible) Daratumumab Trifluridine/tipiracil → metastatic gastric or GEJ junction adenocarinoma July Polatuzumab vedotin- Selinexor March Pembrolizumab → advanced esophageal squamous cell cancer piiq → locally advanced/metastatic triple negative September Myelofibrosis breast cancer Pembrolizumab + → advanced endometrial cancer Atezolizumab → combination with for extensive Zanubrutinib stage small cell lung cancer Apalutamide → metastatic castration-sensitive prostate cancer Fedratinib Pembrolizumab→ stage III non-small cell lung cancer Daratumumab → combination therapy for newly diagnosed MM (transplant eligible) Pembrolizumab April October Pembrolizumab → combination with for advanced renal cell carcinoma Niraparib→ recurrent advanced ovarian, fallopian tube, or primary Duvelisib peritoneal cancer associated with HRD positive status May November Brentuximab vendotin * Ivosidenib → newly diagnosed AML with IDH1 mutation (select patients) → adults with CLL or SLL * Ado- → adjuvant treatment HER2 positive Atezolizumab→ combination therapy for metastatic non- Acalabrutinib early breast cancer (residual disease following neoadjuvant squamous NSCLC * therapy) Enzalutamide → metastatic castration-sensitive prostate cancer Zanubrutinib → hepatocellular carcinoma Olaparib→ maintenance treatment adults with gBRCAm Acute GVHD → combination with axitinib for advanced renal cell metastatic pancreatic adenocarcinoma carcinoma (Jakafi) Venetoclax → chronic lymphocytic leukemia or small lymphocytic lymphoma Venetoclax Ruxolitinib → steroid refractory acute graft-versus-host disease Lenalidomide→ combination with for previously treated and marginal zone lymphoma Gilteritinib → relapsed or refractory AML with FLT3 mutations *=approved late 2018 https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 7 8

2 2/17/20

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Selinexor Karyopharm Therapeutics – July 3, 2019 – First in class Multiple Myeloma Indication Selinexor – Relapsed refractory multiple myeloma (RRMM) Daratumumab – Combination with – At least four prior therapies • Two proteasome inhibitors • Two immunomodulatory agents • Anti-CD38

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 9 10

/ Selinexor Selective Inhibition of Mechanism of Action Nuclear Export (SINE) Selective inhibitor of nuclear export (SINE) – Exportin 1 (XPO1 or CRM1) • Transporter proteins that encourage proliferation – Tumor suppressor proteins, glucocorticoid receptor and onco-protein mRNa • Overexpression correlates with poor survival – Blockade of XPO1 • Reversibly inhibits nuclear export of proteins • Build up of tumor suppressors in nucleus • Triggering

Talati C et al. In J Hematol Oncol. 2018;7(30):IJH04.8;7 Vogl D. J Clin Oncol, 2018; 36(9) 859-866 11 12

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/ / Selinexor Selinexor Dosing Recommendations STORM Trial Design Recommended First Reduction Second Third starting dose Reduction Reduction – Phase 2b open label multi-center study 80 mg days 1 and 3 100 mg once 80 mg once 60 mg once Discontinue – Triple-refractory disease • Refractory to one proteasome inhibitor, one (160 mg per week) weekly weekly weekly immunomodulatory agent and daratumumab Supplied Treatment – 20 mg tablets – Selinexor 80 mg and dexamethasone 20 mg – Dispensed in blister packs • Days 1 and 3 weekly of a 4 week cycle Administration End Point – Primary – overall response rate (OR) – Take same time each day – Secondary – duration, clinical benefit, progression – Swallow whole, do not crush or break free survival and overall survival Patient access – Available through specialty pharmacies

Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 Chari A. New Engl J Medicine 2019;381:727-738 13 14

Selinexor Selinexor STORM Trial Warnings and Precautions Characteristics Value (range) Toxicity Overall Grade 3 / 4 Median time to (N= 122) Incidence (%) Incidence (%) onset (days) Age 65.2 (40-86) Thrombocytopenia 74 61 22 High risk chromosomal 65 (53%) Neutropenia 34 21 25 abnormality Nausea 72 9 3 Median number of past 7 (3-18) treatments Vomiting 41 4 5 Overall Response and Partial Response or Minimal Response or Diarrhea 44 6 15 Clinical Benefit Better Better Anorexia/Weight Loss 53/47 5/1 8/15 Total (N= 122) 32 (26%) 48 (39%) Hyponatremia 39 22 8 High risk chromosomal 12 (18%) 24 (37%) Infections 52 25 abnormality (N= 65) Neurological 30 9 15 Overall response = partial response (≥50% reduction in serum level of myeloma protein) Clinical benefit = as minimal response (≥25% to < 50% reduction in serum level of protein

Chari A. New Engl J Medicine 2019;381:727-38 Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 15 16

4 2/17/20

Selinexor Selinexor GI Toxicity Management GI Toxicity Management

Nausea and Vomiting Occurrence Action Diarrhea Occurrence Action Grade 1 or 2: Decreased oral intake without Any Maintain dose Grade 2: increase of 4 to 6 stools per day over First Maintain dose and start significant weight loss, dehydration or Add anti-nausea baseline supportive care malnutrition OR 5 or fewer Second and Reduce by 1 dose level vomiting episodes subsequent Start supportive care Grade 3: inadequate oral caloric or Any Interrupt selinexor Grade 3 or higher: increase of 7 stools or more Any Interrupt dose fluid intake Monitor until resolution to per day over baseline Monitor until resolution to grade 2 grade 2 or lower Restart 1 dose level lower Start anti-nausea medications Weight loss and Anorexia Restart at 1 dose level lower Weight loss 10-20% OR significant weight loss or Any Interrupt dose malnutrition Monitor until weight returns to Management strategies 90% of baseline Restart at 1 dose level lower • Schedule anti-emetics Management strategies – 5HT3 • Diarrhea: anti-diarrheal agents, IV fluids – Additional agents as needed • Anorexia/weight loss: appetite stimulants, Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 nutritional support Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 17 18

Selinexor Selinexor Hematologic Management Non-Hematologic Management

Thrombocytopenia Occurrence Action Hyponatremia Occurrence Action Platelet count 20,000- <75,000/mcl Any Reduce by 1 dose level Sodium level 130 mmol/L or less Any Interrupt therapy Supportive care until > 130 Platelet count 20,000- <75,000/mcl with Any Interrupt therapy mmol/L concurrent bleeding Restart at 1 dose level lower Restart at 1 dose level lower Platelet count < 25,000/mcl Any Interrupt therapy Fatigue Monitor until platelet count > Grade 2 lasting greater than 7 days OR grade 3 Any Interrupt therapy 50,000/mcl Monitor until resolution Restart 1 dose level lower Restart at 1 dose level lower Neutropenia ANC* 0.5-1.0 x 109/L Any Reduce by 1 dose level

ANC < 0.5 x 109/L OR febrile neutropenia Any Interrupt therapy Monitor until ANC > 1 x 109/L *ANC = Absolute neutrophil count Restart 1 dose level lower

Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 Xpovio [package insert]. Newton MA: Karyopharm Therapeutics; 2019 19 20

5 2/17/20

/ / Selinexor Clinical Practice Daratumumab Prior to therapy Janssen Biotech – Lab evaluation – CBC, sodium levels – Original approval November 16, 2015 – Optimize hydration status – Evaluate for potential drug interactions – Expanded indications • Hepatic metabolism through CYP3A4 • September 26 and June 27, 2019 Monitor Expanded Indications – Toxicity evaluation: • Myelosuppression – In combination with lenalidomide and • Nausea dexamethasone in newly diagnosed patients NOT • Maintain caloric intake eligible for autologous transplant – In combination with , thalidomide and dexamethasone in newly diagnosed patients who ARE eligible for autologous transplant

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Chari A. New Engl J Medicine 2019;381:727-38 Darzalex [package insert]. Horsham PA: Janssen Biotech, Inc.; September 2019 21 23

/ / Daratumumab Daratumumab Mechanism of Action Dosing Recommendations CD38 monoclonal antibody Lenalidomide & dexamethasone Week Schedule – CD38 transmembrane glycoprotein 16 mg/kg weeks 1 to 8 Weekly (total 8 doses) – Hematopoietic cells Weeks 9 to 24 Every two weeks (total of 8 doses) Induces apoptosis Week 25 onwards Every 4 weeks – Cross linking Bortezomib, thalidomide & dexamethasone Treatment Phase Weeks Schedule – Complement dependent cytotoxicity (CDC) Induction Weeks 1 to 8 Weekly (total 8 doses) – Antibody cell mediated cytotoxicity (ADCC) Weeks 9 to 16 Every 2 weeks (total of 4 doses) – Antibody dependent cellular phagocytosis Stop for high dose chemotherapy and autologous transplant Consolidation Weeks 1 to 8 Every 2 weeks (total of 4 doses)

Darzalex [package insert]. Horsham PA: Janssen Biotech, Inc.; September 2019 Darzalex [package insert]. Horsham PA: Janssen Biotech, Inc.; September 2019

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/ / Daratumumab, Lenalidomide and Daratumumab, bortezomib, Dexamethsone (DRd) thalidomide, dexamethasone (D- MAIA Trial VTd) Cassiopeia Trial Phase III Phase III with 2 parts – Part 1: 4 cycles pre-transplant + 2 cycles post-transplant – Newly diagnosed, no transplant – Part 2: maintenance • 737 patients included – 1085 patients included Treatment Treatment – D-VTd vs VTd – DRd: lendalidomide 25 daily + dexamethasone 40 • Bortezomib 1.3 mg/m2 days 1,4 and 8,11 weekly vs Rd • Thalidomide 100 mg daily Outcomes • Dexamethasone 40 days 1,2; 8,9; 15,16; 22,23 Outcomes – Improved progression free survival – Improved response • 30 months 70.6% vs 55.6% • CR 64% D-VTd vs 44% VTd • Hazard ratio = 0.56, P <0.001 • MRD 64% vs 44% – Adverse events – Complete response (CR) • Neutropenia 28 vs 15% • 47.6% vs 24.9% • Lymphopenia 17 vs 10% – P <0.001 • Stomatitis 13% vs 16%

Facon N Engl J Med. 2019 30;380(22): 2104-2115 CR = complete response; MRD Minimal residual disease Mooreau Lancet. 2019; 394: 29-38

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/ / Daratumumab Daratumumab Administration Warnings & Precautions Pre-medications Infusion reactions – Steroid, acetaminophen, antihistamine – Anaphylactic Infection prophylaxis – ~50% experienced infusion related reaction – Acyclovir Interference with serological testing – Positive indirect Coombs test Infusion • Binds to CD38 on red blood cells – First dose Neutropenia • Split over 2 days or given full dose in 1 day – Dose delay to allow recovery of neutrophils • Must be completed within 15 hours Interference with response determination – Infusion related reactions – Detected on serum protein electrophoresis • Monitor vital signs • Emergency medications – Detected on immunofixation assays

Darzalex [package insert]. Horsham PA: Janssen Biotech, Inc.; September 2019 Darzalex [package insert]. Horsham PA: Janssen Biotech, Inc.; September 2019

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Ruxolitinib Incyte Corporation – Original approval June 21, 2012 for MF Graft versus Host – Expanded GVHD indications Disease (GVHD) • May 24, 2019 Ruxolitnib – JAK inhibitor Indication – Steroid refractory acute GVHD in adult and pediatric patients 12 years and older

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 30 31

/ Ruxolitinib GVHD Janus-Activated Kinase (JAK) Dosing Recommendations Adult Recommended First Second Third starting dose Reduction Reduction Reduction 5 mg twice daily consider 5 mg twice daily 5 mg daily Interrupt therapy JAK1 and JAK2 increasing to 10 twice daily after 3 until recovery days if ANC & platelets are stable • Signaling for cytokines and growth factors Taper – Decrease one dose level every 8 weeks Ruxolitinib • Inhibits JAK1 and JAK2 Renal dose modifications – CrCl 15-59 mL/min: 5 mg once daily – CrCl <15 mL/min on dialysis: 5 mg once after dialysis Hepatic dose modifications – Mild, moderate or severe - no dose change – Stage 3 or 4 liver GVHD

Vainchenker Oncogene 2013; 32: 2601-2613 • Monitor CBC for toxicity and consider 5 mg daily Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 32 33

8 2/17/20

/ / Ruxolitinib GVHD Ruxolitinib GVHD Dose Modifications Dosing Considerations Parameter Dose Recommendation Supplied Clinically significant Reduce by 1 dose level; upon – 5, 10, 15, 20 and 25 mg tablets thrombocytopenia platelet recover may return to prior – Supplied by specialty pharmacy dose level Administration ANC < 1X109 related to ruxolitinib Hold 14 days, resume 1 dose level lower upon recovery – Swallow whole, do not crush or break Total bilirubin (bili); No liver GVHD 3-5 X ULN: reduce 1 dose level lower – NG tube (> 8 Fr) ULN = upper limit of normal >5-10 X ULN: hold up to 14 days until • Suspend tablet in 40 mL water stir 10 minutes bili is <1.5 X ULN then resume at • Administer within 6 hours current dose • Rinse NG with ~75 mL water >10 X ULN: hold up to 14 days untl bili <1.5 X ULN then start 1 dose level lower Total bili with liver GVHD > 3 X ULN: continue 1 dose level lower

Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 34 35

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Ruxolitinib GVHD Ruxolitinib Drug Interaction Considerations REACH1 Trial Design – Open label, single arm Dose Recommendation – Steroid refractory disease Ketoconazole 5 mg once daily • Grades 2 to 4 Other CYP3A4 inhibitors* No dose adjustment Treatment – Ruxolitinib 5 twice daily *co-administration with itraconazole • Increase to 10 twice daily if no toxicity monitor more frequently for toxicity and adjust dose as necessary End Point – Primary – overall response rate (ORR) – Secondary – 6 month duration of response (DOR)

Shah N et al. Abstracts/Biol Blood Marrow Transplant 2019 (25) S7-S75, Abstract 66 Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 36 37

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/ / Ruxolitinib Ruxolitinib REACH1 Trial Warnings and Precautions Characteristic n=71 Thrombocytopenia, anemia and neutropenia Overall Day 28 Response 54.9% – Dose reductions or temporarily interrupting therapy Complete response 26.8% – May require transfusions Median time to response (range days) 7 days (6-49) Infection – Active surveillance and prophylactic antibiotics Median duration of response* 345 days *(minimum 6 months follow up) • According to clinical guidelines Treatment Emergent Adverse Effects n=71 – Reported infections • Tuberculosis, herpes zoster, hepatitis B Anemia 64.8% Non-Melanoma skin cancer Thrombocytopenia 62% – Perform periodic skin exmainations Neutropenia 47.9% Lipid elevations Infections – Monitor 8-12 weeks following initiation CMV, Sepsis and bacteremia 12.7%, 12.7% and 9.9% Fatal treatment adverse effects 1 patient each Pulmonary hemorrhage and sepsis

Shah N et al. Abstracts/Biol Blood Marrow Transplant 2019 (25) S7-S75, Abstract 66 Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2019 38 39

/ Ruxolitinib Clinical Practice Prior to therapy – Lab evaluation – CBC, renal and liver function – Skin examination – Talk about adherence – Evaluate for potential drug interactions • Hepatic metabolism through CYP3A4 Myelofibrosis (MF) Monitor Fedratinib – Toxicity evaluation • Platelets, neutrophils • Infections • Changes in skin • Changes in other mediations Adherence

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10 2/17/20

/ / Fedratinib Fedratinib Mechanism of Action Celgene JAK/STAT pathway – August 16, 2019 – Key regulator of cytokine receptor signaling pathway – Critical role in hematopoiesis and immune response – JAK Inhibitor class • JAK2 V617F variant : 50-60% • Fedratinib: JAK2 selective inhibitor • Drive proliferation • Ruxolitinib: JAK1/2 inhibitor Fedratinib – JAK2 selective inhibitor Indication • Inhibits JAK2 v617F or wild type JAK2 – Inhibits FLT3 – Intermediate-2 or high-risk primary or – Decrease in phosphorylation of STAT proteins secondary (post- or post- – Inhibited cell proliferation essential thrombocythemia) myelofibrosis – Apoptotic cell death

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Bewersdor J. Cancer Management and research 2019: 11 10777-10790 Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 43 44

/ / Fedratinib Fedratinib Dosing Recommendations Clinical Studies Adult Recommended First Second Third JAKARTA starting dose Reduction Reduction Reduction – Double blind, randomized, placebo controlled 400 mg by mouth daily 100 mg below 100 mg 100 mg below the last given below the last the last given – Patient population dose given dose dose • Intermediate or high risk MF, polycythemia vera MF or post- Supplied essential thromobocythemia MF with – 100 mg capsules • Patients received 500 mg, 400 mg or placebo daily for 6 cycles – Dispensed by specialty pharmacy – Outcomes Renal dose modifications • Proportion of patients >35% spleen reduction – CrCl >30 mL/min: no dose adjustment – Measured by MRI – CrCl 15-29 mL/min: 200 mg daily • Decrease in symptom score Hepatic dose modifications – Avoid use in severe impairment Metabolized 3A4 – Strong inhibitor decrease to 200 mg daily Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 45 46

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/ / Fedratinib Fedratinib Clinical Studies Warnings & Precautions Encephalopathy including Wernicke’s Response Fedratinib (N= 96) Placebo (N=96) – Reported in 8/608 (1.3%) Spleen reduction of 35 (37)* 1 (1) • 1 case fatal >35% (%) – Wernicke’s Decrease in symptom 36 (40)* 7 (9) • Neurologic emergency due to vitamin B1 deficiency score of >50% (%) • Ataxia, mental status changes, nystagmus, diplopia *= p <0.0001 – Mental status changes Adverse Fedratinib Fedratinib Placebo Placebo • Full neurologic exam Reaction All Grades (%) > Grade 3 (%) All Grades (%) > Grade 3 (%) • Thiamine levels • Imaging Diarrhea 66 5 16 0 – Thiamine level Nausea 62 0 15 0 • Documents prior to initiation Anemia 40 30 14 7 – Periodically through treatment • Replete if low Vomiting 39 3.1 5 0

Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019

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/ / Fedratinib Fedratinib Warnings & Precautions Warnings & Precautions Anemia Gastrointestinal toxicity – Median time to onset 2 months – Most common • Nadir after 12 to 16 weeks • Diarrhea 66% • Nausea 62% – Transfusions 51% • Vomiting 39% – Dose reductions for patients transfusion dependent – Median time to onset 1 day Thrombocytopenia • 75% occur in the first 2 weeks – Median time to onset 1 month Treatment – Schedule antiemetic prophylaxis – Transfusions 3.1% • 5-HT3 antagonist • Discontinuation due to bleeding 2% – Anti-diarrheal agents – Dose adjustment • Grade 3 thrombocytopenia with bleeding Dose adjustment • Grade 4 – Symptoms not resolving in 48 with supportive care • Hold until resolution and restart at lower dose • Interrupt therapy until resolved • Restart at lower dose

Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019 Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019

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/ / Fedratinib Fetratinib Warnings & Precautions Clinical Practice Amylase and lipase elevation Prior to therapy – Lab evaluation – CBC, thiamine levels, liver function, – 2 and 10% of patients lipase and amylase – Median time to onset 15 days – Evaluate for potential drug interactions • 1 case pancreatitis • Hepatic metabolism through CYP3A4 Hepatic Toxicity Monitor – ALT and AST 43 and 40% – Toxicity evaluation: – Median time to onset 1 month • Nausea, vomiting and diarrhea – Ask about anti-emetic regimen – Monitor labs during therapy • Bleeding Dose adjustment • Change in mental status – Interrupt therapy until resolved – New medications – Restart at lower dose – Adherence

Inrebic [package insert]. Summit, NJ: Celgene Corporation; 2019

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Zanubrutinib BeiGene, Ltd. – November 14, 2019 – Bruton Tyrosine Kinase (BTK) inhibitor • (1st generation) Zanubrutinib • Acalbrutinib (2nd generation) Indication – Patients with mantle cell lymphoma (MCL) who have received at least one prior therapy

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 54 55

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/ / Zanubrutinib Zanubrutinib Mechanism of Action Dosing Recommendations

Starting dose BTK is a signal for B-cell receptor 160 mg by mouth twice daily OR 320 mg daily • Activation of pathways Supplied • Proliferation – 80 mg capsules • Chemotaxis – Available through specialty pharmacies • Adhesion Renal dose modifications – CrCl >30 mL/min no dose adjustment Hepatic dose modifications – Severe impairment 80 mg twice daily Drug-drug interaction modifications – Substrate of CYP3A4 – Dose adjust for inhibitors

Liang C. et al European J Med Chem (2018);151:315-326 Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 56 57

/ / Zanubrutinib Zanubrutinib Dosing Modifications Dosing Modifications Event Adverse Reaction Dose Modification Occurrence Co-administered drug Recommended Dose Grade 3 or higher First Interrupt, resume upon Strong CYP3A4 inhibitor 80 mg daily non-hematological toxicity resolution to grade 1 at 160 mg twice daily or Monitor for adverse reactions and 320 mg daily interrupt therapy and modify dose as Second Interrupt, resume upon necessary Grade 3 febrile neutropenia resolution to grade 1 at Moderate CYP3A4 inhibitor 80 mg twice daily 80 mg twice daily or 160 Monitor for adverse reactions and mg daily modify dose as necessary Grade 4 neutropenia* Third Interrupt, resume upon resolution to grade 1 at Moderate or strong CYP3A4 inducer Avoid concomitant use 80 mg daily Fourth Discontinue Grade 4 thrombocytopenia (>10 days)* zanubrutinib Intracranial hemorrhage Any Discontinue * = May require transfusion OR growth factor support

Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 58 59

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/ / Zanubrutinib Zanubrutinib Clinical Studies Clinical Studies Phase 1/2 open label, single arm, dose escalation – B-cell malignances Response Phase 1 /2 (N = 32) Phase 2 (N=86) • 32 patients with MCL previously treated – Patient population Overall Response Rate 84% 84% • Received 160 mg twice daily or 320 mg daily CR 22% 59% • Median age 70 years (42-86) PR 62% 24% – Phase 2 open label, single arm – Patient population • Previously treated MCL • 160 mg twice daily • Median age 65 years (34-75) • Number of prior therapies 2 (1-4)

Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 60 61

/ Zanubrutinib Toxicities Zanubrutinib Reported toxicity All Grades Grade > 3 Warnings & Precautions Neutropenia 38 15 Hemorrhage Thrombocytopenia 27 5 – Any grade 50% Leukopenia 25 5 – Grade 3 and higher Anemia 14 8 • Intracranial, GI, hematuria and hemothorax Upper respiratory tract 39 0 – Increased risk combined with anti-platelet, anticoagulants infection Infections Pneumonia 15 10* – Pneumonia Rash 36 0 – Opportunistic infections Diarrhea 23 0.8 – Hepatitis B virus reactivation Constipation 13 0 – Anti-microbial prophylaxis Hemorrhage 11 3.4* • Pneumocystis jiroveci • Herpes simplex virus Musculoskeletal pain 14 3.4 Hypokalemia 14 1.7

* = includes fatal adverse reaction Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 62 63

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/ / Zanubrutinib Zanubrutinib Warnings & Precautions Clinical Practice Cytopenia Prior to therapy – Lab evaluation – CBC, renal and liver function – Neutropenia – Evaluate for potential drug interactions • Consider growth factor • Hepatic metabolism through CYP3A4 – Thrombocytopenia and anemia Monitor • Consider transfusions – Toxicity evaluation: Cardiac arrhythmias • Diarrhea or constipation • Bleeding – Atrial fibrillation and atrial flutter – 2% • Afib/flutter • Underlying cardiac conditions may increase risk • Infections Second primary malignancies – Lymphocytosis – Skin cancer most common • Asymptomatic, not a toxicity – • Basal cell and squamous cell New medications • Sun protection! – Adherence

Brukinsa [package insert]. San Mateo: BeiGene, Ltd; 2019 64 65

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Polatuzumab vedotin-piiq Genetech, Inc. – June 10, 2019 Diffuse Large B-Cell – Antibody drug conjugate Lymphoma (DLBCL) • Toxin – monomethylauristatin E (MMAE) Polatuzumab vedotin-piiq Indication – Patients with relapsed or refractory DLBCL after at least two prior therapies

https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed 1/19/20 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 67 68

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/ Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Mechanism of Action Dosing Recommendations Initial dose – 1.8 mg/kg IV over 90 minutes every 21 days for 6 cycles – In combination with • 90 mg/m2/day days 1 and 2 • Rituximab 375 mg/m2 – Administered • Low-protein binding in-line or add-on 0.2 or 0.22 filter – Pre-medications • Antipyretic and antihistamine – Anti-microbial prophylaxis • Pneumocystis jirovici • Herpes simplex virus https://www.researchgate.net/figure/Structure-and-mechanism-of-action-of-ADC-A-A-general-structure-of-an-ADC-containing-a_fig7_309141197 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 69 70

Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Dose Modifications Dose Modifications Event Dose Modification Event Dose Modification Grade 2 – 3 Peripheral Neuropathy Hold until grade 1 or lower Grade 1-3 Infusion related reaction Stop infusion, supportive care -Before day 14 restart next cycle at 1.4 mg/kg First time grade 3 wheezing or urticarial or recurrence any grade 3 -Prior dose reduction to 1.4 mg/kg – permanently discontinue discontinue Resolution of symptoms, resume at 50% of rate, if tolerated may escalate -Not recovered by day 14 to grade 1 by 50 mg/hour every 30 minutes or lower discontinue Next cycle, administer over 90 Grade 4 peripheral neuropathy Discontinue minutes if tolerated next cycle over 30 minutes Grade 4 infusion related reaction Stop infusion, give supportive care and discontinue permanently

Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 71 72

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Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Dose Modifications Dose Modifications Event Dose Modification Event Dose Modification Grade 3 – 4 neutropenia* Hold until ANC > 1000/microliter Grade 3 – 4 thrombocytopenia* Hold treatment until platelets recover to > 75,000/microliter ANC >1000 by day 7 resume without any additional dose reduction and consider colony If platelets recover > 75,000 on or before day 7 stimulating factor resume all treatment without any additional ANC > 1000 after day 7 dose reductions -restart treatment, consider colony stimulating factor, if growth factor was given consider dose If platelets recover to >75,000 after day 7: reduction of bendamustine -restart all treatment with a reduction of -dose reduction of bendamustine already bendamustine occurred, consider dose reduction to 1.4 -If bendamustine dose reduction has already * = severity on day 1 of any cycle mg/kg * = severity on day 1 of any cycle occurred, consider dose reduction of polatuzumab to 1.4 mg/kg

Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 73 74

Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Clinical data Clinical data Multi-center trial relapsed refractory DLBCL Response Polatuzumab + BR BR n = 40 n=40 – Polatuzumab + bendamustine and rituximab Median number of 5 3 • At least 1 prior regimen cycles • Not eligible for transplant Objective response at 18 (45%) 7 (18%) – Efficacy the end of treatment • Complete response CR 16 (40%) 7 (18) • Duration of response Duration of response - 6 months 16 (64%)* 3 (30%)^ – Patient characteristics - 12 months 12 (48%)* 2 (20%)^ • Median age 69 years (30-86) * Of patients with a CR ^ Of patients with a CR • Median number of prior therapies 2 (1-7) or PR (n=25) or PR (n=10)

Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 75 76

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/ Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Clinical data Warnings and Precautions Adverse Reaction All Grades Grade >3 All Grades Grade >3 Peripheral neuropathy P+BR P+BR BR BR – 40% in clinical trials Neutropenia 49 42 44 36 – Median time to onset 2.1 months Thrombocytopenia 49 40 33 26 Anemia 47 24 28 18 – Sensory: paresthesia, dysesthesia, burning weakness Peripheral 40 0 8 0 – Generally reversible neuropathy • 65% reported improvement after 1 month Diarrhea 38 4.4 28 5 Myelosuppression Infusion reactions 18 2.2 8 0 – Neutropenia, anemia and thrombocytopenia Pyrexia 33 2.2 23 0 • 42% received primary prophylaxis with GSCF Pneumonia 22 16^ 15 2.6^ – Most common reason for treatment discontinuation

^ = fatal outcomes; 2 P+BR; 1 BR Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 Polivy [package insert]. South San Francisco CA: Genetech, Inc.; 2019 77 78

/ / Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Warnings and Precautions Warnings and Precautions Infections Tumor lysis syndrome – Grade >3: 32% – Monitor patients with high tumor burden • Pneumocystis jiroveci, fungal pneumonia, or rapidly proliferative tumors cytomegalovirus and herpes infections Hepatotoxicity – Infection related deaths 2.9% – Transaminases & bilirubin Progressive multifocal Leukoencephalopathy (PML) – Preexisting liver disease may increase risk of hepatotoxicity – Monitor for new or worsening neurological changes

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/ Polatuzumab vedotin-piiq Clinical Practice You made it! Prior to therapy New options are available – Lab evaluation – CBC, liver function – Current role – active treatment of disease – Evaluate for potential drug interactions • MMAE hepatic metabolism through CYP3A4 – Future studies could look at maintenance therapies Monitor Educate and follow up – Toxicity evaluation: • Myelosuppression – Ask about toxicities • Peripheral neuropathy – Oral agents • Infection • Ask about adherence • TLS – cycle 1 • Mental status changes - PML • Ask about drug dispensing – New medications • Ask about co-pays – Adherence

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