11/9/2020 Disclosures • There are no relevant financial interests to disclose for myself or my spouse/partner from within the last 12 months New Drug Updates Brendan Mangan, PharmD Clinical Pharmacy Specialist Hospital of the University of Pennsylvania 1 2 Objectives New Drugs Explain the pharmacology of each new medication Malignant Hematology Medical Oncology Define indications, adverse effects and pertinent drug interactions Outline supportive care measures and clinical pearls Selinexor Tazemotostat Isatuximab-irfc Avapritinib Discuss the results of clinical trials and place in therapy Belantamab mafodotin-blmf Pexidartinib Fedratinib Entrectinib Polatuzumab vedotin-piiq Tafasitamab-cxix Zanubrutinib 3 4 Selinexor (XPOVIO®) Approval: July 3, 2019 Novel agent Exportin 1 inhibitor ▫ Reversibly inhibits nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins XPOVI™ [Prescribing Information] Newton, MA. Karyopharm Therapeutics. 2019. Picture: xpovio.com 5 6 1 11/9/2020 Selinexor Selinexor Indication Adverse Effects Clinical Pearls • In combination with dexamethasone for relapse refractory multiple myeloma after failing 4 prior therapies Thrombocytopenia (74%) GCSF and prophylactic antimicrobials Recommended Neutropenia (34%) Prophylactic anti-emetics First Reduction Second Reduction Third Reduction Starting Dosage Nausea (72%)/Vomiting (41%) IV fluids and electrolyte repletion may be Diarrhea (44%) warranted monitor closely 80 mg Discontinue Days 1 and 3 of each Anorexia (53%)/Weight loss (47%) Correct sodium levels for concurrent 100 mg once weekly 80 mg once weekly 60 mg once weekly week (160 mg weekly Hyponatremia (39%) hyperglycemia (>150 mg/dL) total) Infections (52%) TPO agonist may be warranted for Neurological toxicity (30%) thrombocytopenia GCSF = Granulocyte colony-stimulating factor XPOVI™ [Prescribing Information] Newton, MA. Karyopharm Therapeutics. 2019. XPOVI™ [Prescribing Information] Newton, MA. Karyopharm Therapeutics. 2019. TPO = Thrombopoietin receptor agonist 7 8 Selinexor – STORM Trial Isatuximab-irfc (Sarclisa®) Design • Approval: March 2, 2020 • Phase 2b, multicenter, open-label trial at 60 centers in the US and Europe • CD38-directed cytolytic Patients antibody • 122 patients with relapsed refractory multiple myeloma with previous exposure to bortezomib, ▫ CD38 expressed on the surface carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent of hematopoietic and tumor cells, including multiple Outcomes myeloma cells ▫ Induces apoptosis of tumor • ORR: 26% cells and activation of immune • Median duration of response: 4.4 months effector mechanisms • PFS: 3.7 months • OS: 8.6 months ORR = Overall response rate PFS = Progression free survival Chari A, et al. N Engl J Med. 2019. Sarclisa® [prescribing information]. Bridgewater, NJ. Sanofi. 2020. OS = Overall survival Picture: Frontiersin.org 9 10 Isatuximab-irfc Isatuximab-irfc Indication Adverse effects Clinical Pearls • In combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a Premedication with acetaminophen, H2- Infusion-related reactions (38%) proteasome inhibitor antagonist, diphenhydramine and Pneumonia (31%) dexamethasone warranted. Dosing Upper respiratory tract infections (57%) Can cause a false positive indirect Coombs test • In combination with pomalidomide and dexamethasone- C1 10 mg/kg as an intravenous infusion Febrile neutropenia (12%) Prior to treatment, consider phenotyping every week x4 weeks, then every 2 weeks until disease progression or unacceptable toxicity Dyspnea (17%) May interfere with Serum Protein Diarrhea (26%) Electrophoresis and Immunofixation Tests Dose Adjustments Nausea (15%) / Vomiting (12%) May infuse more rapidly on third infusion • No dosage adjustments recommended. Dosages may be delayed to allow for recovery of blood counts in the event of hematologic toxicity (Neutropenia: ANC < 1000/mm3) Sarclisa® [prescribing information]. Bridgewater, NJ. Sanofi. 2020. Sarclisa® [prescribing information]. Bridgewater, NJ. Sanofi. 2020. 11 12 2 11/9/2020 Isatuximab-irfc Trial Belantamab mafodotin- Design blmf (Blenrep®) • Phase 3, randomized, double-blind, open-label trial • Approval: August 5, 2020 • Class: B-cell maturation antigen Patients (BCMA)-directed antibody drug conjugate • 307 patients with relapsed refractory multiple myeloma who received at least 2 prior therapies, ▫ Conjugated to a microtubule including lenalidomide and a proteasome inhibitor One patient in the isatuximab group was inhibitor previously treated with daratumumab ▫ Antibody is conjugated by a Outcomes protease-resistant maleimidocaproyl linker to • PFS: 11.53 months vs 6.46 months (p = 0.001) microtubule-disrupting • ORR: 60.4% vs 35.3 % (p < 0.001) monomethyl auristatin F • Median time to response was 35 days in isatuximab-irfc group compared to 58 days in the Pd (MMAF) arm *Pd = pomalidomide + dexamethasone Attal M, et al. Lancet. 2017. Blenrep® [prescribing information]. Research Triangle Park, NC. GlaxoSmithKline. 2020. Picture: Oncozine.com 13 14 Belantamab mafodotin-blmf Belantamab mafodotin-blmf Indication Adverse effects Clinical Pearls • Treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and Ophthalmic examinations at baseline, prior an immunomodulatory agent Ocular toxicity (77%) BBW Keratopathy to each dose, and for worsening symptoms. Dosing Must be within 3 weeks of first dose Visual Acuity Changes • 2.5 mg/kg as an IV infusion over approximately 30 minutes once every 3 weeks Administer preservative-free lubricant eye Thrombocytopenia (69%) drops at least 4 times daily starting first Infusion-related reactions (18%) infusion and until the end of treatment Dose Adjustments Avoid the use of contact lenses during treatment • Based on toxicity: Immunogenicity (<1%) • Grade 2-3: Hold until Grade 1 or better • Grade 4: Consider permanent discontinuation REMS Program BBW = Black box warning Blenrep® [prescribing information]. Research Triangle Park, NC. GlaxoSmithKline. 2020. Blenrep® [prescribing information]. Research Triangle Park, NC. GlaxoSmithKline. 2020. 15 16 Belantamab mafodotin-blmf: DREAMM-2 Trial Fedratinib (Inrebic®) Design • FDA Approval: August 16, 2019 • Phase 2, open-label, two-arm, study Patients • Class: JAK inhibitor ▫ Oral TKI with activity against • 221 adult patients with multiple myeloma with disease progression after three or more lines of both wild type and mutated therapy (refractory to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 JAK2 and FLT3 monoclonal antibodies) Outcomes • Overall response rate: • 2.5 mg/kg group: 31% • 3.4 mg/kg group: 34% Lonial et al. Lancet. 2020 INREBIC™ [Prescribing Information] Summit, NJ, Celgene Corporation. 2019. Picture: sciencedirect.com 17 18 3 11/9/2020 Fedratinib Fedratinib Indication • Adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis Adverse effects Clinical Pearls Dosing Check thiamine levels and supplementation Encephalopathy (1.3%) BBW may be warranted • 400 mg daily in patients with baseline platelet count of > 50 x 10^9/L Anemia (74%) Must taper and discontinue ruxolitinib Dose Adjustments Thrombocytopenia (47%) according to package insert prior to starting • Reduce to 200 mg daily for: Neutropenia (23%) fedratinib • CrCl 15-20 ml/min Diarrhea (66%) Prophylactic anti-emetics may be warranted • Strong CYP3A4 inhibitors Nausea (62%)/Vomiting (39%) Monitor LFTs at baseline and when clinically • Reduce by 100 mg daily for: ALT (43%)/AST (40%) indicated • Grade 4 neutropenia once resolved to < 2 Amylase (2%) / Lipase (10%) Monitor amylase/lipase at baseline and when • Grade 3 AST/ALT once resolved to < 1 clinically indicated • Any grade 3 nonhematologic toxicity once resolved to < 1 BBW = Black box warning AST = Aspartate aminotransferase INREBIC™ [Prescribing Information] Summit, NJ, Celgene Corporation. 2019. ALT = Alanine aminotransferase INREBIC™ [Prescribing Information] Summit, NJ, Celgene Corporation. 2019. 19 20 Fedratinib: JAKARTA Trial Polatuzumab vedotin- piiq (POLIVY™) Design • Approval: June 10, 2019 • Phase 3, double-blind, placebo controlled trial Patients • Novel agent CD79b-directed antibody-drug conjugate • 289 patients not previously treated with a JAK inhibitor with intermediate-2 or high-risk primary ▫ Humanized IgG1 monoclonal or secondary myelofibrosis were randomized to receiver fedratinib 400 mg daily, fedratinib 500 antibody specific for CD79b mg daily, or placebo ▫ Small molecule anti-mitotic Outcomes agent MMAE ▫ A protease-cleavable linker • Spleen response at 6 months and confirmed 4 weeks later ( > 35% reduction in volume): maleimidocaproyl-valine- • 35% in 400 mg group citrulline-p- • 40% in 500 mg group 500 mg/day group: MRI confirmed aminobenzyloxycarbonyl that • 1% in placebo Wernicke encephalopathy in 4 covalently attaches MMAE to patients the polatuzumab antibody Pardanani A et al. JAMA Oncol. 2015. Polivy® [prescribing information]. San Francisco, CA: Genentech, Inc.: 2019 Picture: Polivy.com 21 22 Polatuzumab vedotin-piiq Polatuzumab vedotin-piiq Indication Adverse Effects (Incidence > 20%) Clinical Pearls • In combination with bendamustine and rituximab in adult patients with relapse or refractory DLBCL, not