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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
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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
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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
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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
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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
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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 otherwise specified, after at least two prior therapies Peripheral neuropathy Studied in combination with bendamustine Infusion-reactions and rituximab Dosing Myelosuppression Pre-medications needed with an antipyretic • 1.8 mg/kg as an IV infusion over 90 minutes every 21 days for 6 cycles Serious and opportunistic infections and antihistamine Progressive multifocal leukoencephalopathy All patients should receive PJP and HSV Tumor lysis syndrome prophylaxis throughout treatment Dose Adjustments Hepatotoxicity GCSF may be used • Not studied in patients with a CrCl < 30 ml/min
PJP = Pneumocystis jiroveci pneumonia
Polivy® [prescribing information]. San Francisco, CA: Genentech, Inc.: 2019 Polivy® [prescribing information]. San Francisco, CA: Genentech, Inc.: 2019 HSV = herpes simplex virus 23 24
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Polatuzumab vedotin-piiq: G029365 Trial Polatuzumab vedotin-piiq – G029365
Design • Phase 1b/2, randomized, multicenter trial Response per IRC,n (%) Polatuzumab+ BR (n=40) BR(n=40)
Patients Objective Response at End of 18 (45) 7 (18) Treatment (95% CI) (29, 62) (7, 33) • The trial randomized 80 patients with relapsed or refractory DLBCL after at least one prior regimen were randomized to receive either polatuzumab in combination with bendamustine and rituximab (BR) or BR alone CR 16 (40) 7 (18) • No HCT candidates at study entry (95% CI) (25,57) (7, 33) Outcomes Differencein CR rates, % (95% CI) 22, (3, 41) Best Overall Response of CR or PR 25 (63) 10 (25) Duration of PR or CR Polatuzumab+ BR (n=25) BR (n=10) (95% CI) (46, 77) (13, 41) Response, n (%) Best Response of CR 20 (50) 9 (23) 6 months 16 (64%) 3 (30%) (95% CI) (34, 66) (11, 38) 12 months 12 (48%) 2 (20%)
Sehn LH, et al. J Clin Onc. 2020 Sehn LH, et al. J Clin Onc. 2020 25 26
Tafasitamab-cxix Tafasitamab-cxix (Monjuvi™) Indication • Approval: July 31, 2020 • In combination with lenalidomide for the treatment of relapsed or refractory DLBCL who are not eligible for autologous stem cell transplant • Novel agent CD19-directed cytolytic antibody Dose Cycle1 Cycle2 and 3 Cycle4 and Beyond ▫ Mediates B-cell lysis through apoptosis and immune 12 mg/kg Days:1, 4, 8, 15 and 22 Days:1, 8, 15, and 22 Days:1 and 15 effector mechanisms ▫ Antibody-dependent cellular cytotoxicity Dose Adjustments ▫ Antibody-dependent cellular phagocytosis • Myelosuppression • Platelets: hold until platelets > 50,000/mcL and resume at same dose • Hold until ANC > 1000/mcL and resume at same dose
Monjuvi® [prescribing information]. Boston, MA: Morphosys, Inc.: 2020 Monjuvi® [prescribing information]. Boston, MA: Morphosys, Inc.: 2020 Picture: SEC.gov 27 28
Tafasitamab-cxix Tafasitamab-cxix: L-MIND Trial
Adverse effects Clinical Pearls Design Infection-related deaths occurred in 2.5% of • Phase 2, multicenter, open-label, single-arm trial Infusion-related reaction (6%) patients Myelosuppression Administer prophylactic medications Patients Neutropenia (25%) Granulocyte colony-stimulating factor • 81 adult patients with DLBCL relapsed or refractory to at least one, but no more than three Thrombocytopenia (12%) administration can be considered in patients regimens and were not candidates for autologous stem cell transplant Anemia (7%) at risk for prolonged neutropenia Infections (73%) Premedications (30 minutes to 2 hours prior) Outcomes Acetaminophen, H1-antagonist, H2- • Primary endpoint of objective response: 60% antagonist, +/- glucocorticosteroids • Partial response: 18% Median line of therapy: 2 (1-4) Can be withheld if no reaction during first 3 • Complete response: 43% 1 line: 50% administrations 2 lines: 43%
Monjuvi® [prescribing information]. Boston, MA: Morphosys, Inc.: 2020 Salles, et al. Lancet. 2020 29 30
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Zanubrutinib Zanubrutinib (Brukinsa®) Indication • Approval: November 14, 2019 • Adults patients with mantle cell lymphoma (MCL) who have received at least one prior therapy
• Small-molecule inhibitor of Dosing Bruton’s tyrosine kinase • 160 mg orally twice daily or 320 mg orally once daily ▫ Key component of B-cell receptor or signaling pathway Dose Adjustments that regulates cell proliferation • Strong CYP3A4 inhibitors: 80 mg once daily and cell survival in B-cell malignancies • Moderate CYP3A4 inhibitors: 80 mg twice daily • Strong or moderate CYP3A4 inducer: Avoid use • Severe hepatic impairment: 80 mg twice daily • Dose reductions: febrile neutropenia, thrombocytopenia
BRUNKINSA™ [package insert]. San Mateo, CA. BeiGene USA Inc. 2019. BRUNKINSA™ [package insert]. San Mateo, CA. BeiGene USA Inc. 2019. Picture: Journal.lww.com 31 32
Zanubrutinib Dose Reduction Schedule Zanubrutinib
Adverse Effects Clinical Pearls Dose 1st Occurrence 2nd Occurrence 3rd Occurrence 4th Occurrence Neutropenia (38%) Hold 3-7 days pre- and post-surgery 160 mg BID 160 mg BID 80 mg BID 80 mg daily Stop Thrombocytopenia (27%) Risk vs. benefit in combination with any other 320 mg daily 320 mg daily 160 mg daily 80 mg daily Stop Upper respiratory tract infection (39%) antiplatelet or anticoagulant Rash (36%) Consider HSV, PJP prophylaxis in patients Diarrhea (23%) Risk of secondary malignancies (skin cancers) Hypertension (12%) Monitor EKG throughout therapy as Infection (23%) appropriate for atrial fibrillation or atrial flutter
BRUNKINSA™ [package insert]. San Mateo, CA. BeiGene USA Inc. 2019. BRUNKINSA™ [package insert]. San Mateo, CA. BeiGene USA Inc. 2019. 33 34
Zanubrutinib Clinical Trials BTK-Inhibitor Comparison Design Ibrutinib Acalabrutinib Zanubrutinib • BGB-3111-206: Phase 2, open-label, multicenter, single arm Indications: MCL, CLL/SLL, MZL, WM, cGVHD MCL MCL • BGB-3111-AU-003: Phase 1/2, open-label, dose escalation, global, multicenter, single arm trial Target BTK BTK BTK Off-Targets ITK, EGFR, TEC, BMX Minimal ITK (weak) Patients Anti-platelet activity Yes No No • BGB-3111-206: 86 patients with MCL who have received at least one prior therapy Bleeding, > grade 3 6% 0.8% 3% • BGB-3111-AU-003: B-cell malignancies 32 patients with previous treated MCL Atrial fibrillation, > grade 3 4.6% None 3% Outcomes Hematologic, > grade 3 Neutropenia 17% 10% 9% • BGB-3111-206: FDG-PET scans required for ORR: ORR: 85% Thrombocytopenia 13% 5% 9% • CR: 59% Anemia 11% 12% 11% • Median duration of response: 19.5 month Diarrhea, all grade 54% 31% 23% • BGB-3111-AU-003: FDG-PET scans not required for ORR: ORR: 85% Fatigue, all grade 50% 31% 23% • CR: 22% MCL = Mantle cell lymphoma; CLL = Chronic lymphocytic leukemia; SLL = Small lymphocytic lymphoma; WM = Waldenstrom’s macroglobulinemia; MZL = Marginal zone lymphoma; cGVHD = Chronic graft versus host disease • Median duration of response: 18.5 month
BRUNKINSA™ [package insert]. San Mateo, CA. BeiGene USA Inc. 2019. Owen, C et al. Current Oncol. 2019. 35 36
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Malignant Hematology Approval Review Drug Drug Class Indication Notable Adverse Effects Selinexor Exportin 1 inhibitor R/r Multiple myeloma Thrombocytopenia, N/V/D, anorexia, hypernatremia, infection Belantamab mafodotin-blmf BCMA-directed antibody drug R/r Multiple myeloma Ocular toxicity, conjugate thrombocytopenia, infusion reactions Isatuximab-irfc CD38-directed antibody R/r Multiple myeloma Infusion reactions, pneumonia, upper respiratory tract infections Polatuzumab vedotin-piiq CD79b-directed antibody drug R/r DLBCL Peripheral neuropathy, infusion conjugate reactions, infections
Tafasitamab-cxix CD-19-directed cytolytic R/r B-celllymphomas Infusion reactions, antibody myelosuppression, infections
Fedtratinib JAK2 inhibitor Myelofibrosis Encephalopathy, N/V/D, LFTs, amylase/lipase elevations
Zanubrutinib BTK inhibitor R/r MCL Rash, infection, neutropenia/thrombocytopenia
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Tazemetostat Tazemetostat (Tazverik®) Indication • Approval: January 23, 2020 • Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection • Novel agent Histone Dosing methyltransferase, EZH2 • 800 mg taken orally twice daily without regards to food inhibitor ▫ No specific mutations required Dose Adjustments for use • Avoid with strong or moderate CYP3A4 inhibitors. • 50% dose reduction • Avoid with strong or moderate CYP3A4 inducers • Dose adjusted based off toxicities: First: 600 mg BID, Second: 400 mg BID, Third: Discontinue • Grade 3 Neutropenia, Thrombocytopenia, Anemia, Any other grade 3-4 adverse effect
Tazverik® [prescribing information]. Cambridge, MA. Epizyme. 2020. Tazverik® [prescribing information]. Cambridge, MA. Epizyme. 2020. Picture: semanticscolar.org 39 40
Tazemetostat Tazemetostat – EZH-202 Trial
Adverse Effects Clinical Pearls Design • Phase 2, open-label, single-arm cohort of a multicenter trial Pain (52%) Risk of secondary malignancies (AML/MDS in Fatigue (47%) 0.6% of patients) Gastrointestinal (13-36%) Has not been studied in patients with Patients Decreased appetite (26%) moderate (tbili > 1.5 – 3x ULN) or severe (tbili • 64 patients with histologically confirmed, metastatic or locally advanced epithelioid sarcoma > 3x ULN) hepatic impairment Cough (18%) / Dyspnea (16%) Outcomes Hemorrhage (18%) Anemia (16%) • ORR: 15% • CR: 1.6% • PR: 13% • Duration of Response • % with duration > 6 months: 67% • Range: 3.7 – 24.5+
Tazverik® [prescribing information]. Cambridge, MA. Epizyme. 2020. Tazverik® [prescribing information]. Cambridge, MA. Epizyme. 2020. 41 42
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Avapritinib Avapritinib (Ayvakit™) Indication • Approval: January 9, 2020 • The treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including the PDGFRA D842V mutations • Oral TKI inhibitor that targets: Dosing ▫ PDGFRA and PDGFRA D842 ▫ KIT exon 11, 11/17, and 17 • 300 mg orally once daily on an empty stomach mutations Dose Adjustments • Avoid with strong or moderate CYP3A4 inhibitors. Avoid with strong or moderate CYP3A4 inducers • 100 mg daily if must be used in the presence of a moderate CYP3A4 inhibitor • Dose adjusted based off toxicities: First: 200 mg daily, Second: 100 mg daily, Third: Discontinue • Intracranial hemorrhage, CNS effects, other grade 3-4 adverse effects
Ayvakit® [prescribing information]. Cambridge, MA. Blueprint Medicines Corporation. 2020. Ayvakit® [prescribing information]. Cambridge, MA. Blueprint Medicines Corporation. 2020. Picture: sec.gov 43 44
Avapritinib Avapritinib – NAVIGATOR Trial
Adverse effects Clinical Pearls Design Take at least one hour before and two hours • Phase 1, multi-center, open-label, single-arm trial CNS effects 58% after a meal Intracranial hemorrhage (1% in GIST) First effective treatment for patients with a Patients Edema (72%) PDGFRA D842V GIST • 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V Nausea (64%) / Vomiting (38%) Inhibits autophosphorylation of KIT D816V, mutations Diarrhea (37%) which is associated with resistance to other • Median number of prior kinase inhibitors: 3 (range 0-7) Increased lacrimation (33%) approved TKIs Outcomes Imatinib is ineffective with this mutation Rash (23%) • PDGFRA exon 18 mutation • ORR: 85%, CR: 7%, PR: 77% • Subgroup of PDGFRA D842V • ORR: 89%, CR: 8%, PF 82% • Median duration of response: 10.6 months
Ayvakit® [prescribing information]. Cambridge, MA. Blueprint Medicines Corporation. 2020. Heinrich MC, et al. Lancet Oncol. 2020. 45 46
Pexidartinib Pexidartinib (Turalio™) Indication • Approved: August 2,2019 • Adult patients with symptomatic tenosynovial giant cell tumor (TGCT) not amenable to improvement with surgery • Tyrosine kinase inhibitor that targets: Dosing ▫ Colony stimulating factor 1 • 400 mg orally twice daily on an empty stomach receptor (CSF1R) ▫ KIT Dose Adjustments ▫ FLT3-ITD • Avoid use with concomitant hepatotoxic medications • Strong CYP3A4 inducers: Avoid • Acid reducing agents: Avoid with concomitant PPIs • Dose reductions: Hepatotoxicity
TURALIO™ [package insert] Basking Ridge, NJ. Daiichi Sankyo. 2019. TURALIO™ [package insert] Basking Ridge, NJ. Daiichi Sankyo. 2019. 47 48
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Pexidartinib Modifications for Strong CYP3A4 Inhibitors or Pexidartinib UGT Inhibitors Adverse effects Clinical Pearls Avoid with pre-existing increase LFTs > ULN Administration of Modified Total Planned Total Daily Dose Modified Total Daily Dose Hepatotoxicity (Grade > 3, 5%) BBW Daily Dose Monitor AST/ALT, tbili, d-bili, ALP, CGT at Hair color changes (67%) baseline weekly for first 8 weeks every Rash (28%) 800 mg 400 mg 200 mg twice daily two weeks for next month every 3 weeks Peripheral edema (20%) thereafter 600 mg 400 mg 200 mg twice daily Eye edema (30%) Taking with food increase exposure by 100% Hypertension (15%) and increases risk of hepatoxicity 400 mg 200 mg 200 mg once daily Take 1 hour before food, or 2 hours after food REMS Program due to hepatoxicity www.turalioREMS.com or 1-833-887-2546
BBW = Black box warning TURALIO™ [package insert] Basking Ridge, NJ. Daiichi Sankyo. 2019. TURALIO™ [package insert] Basking Ridge, NJ. Daiichi Sankyo. 2019. 49 50
Pexidartinib – ENLIVEN Trial Entrectinib (Rozlytrek®) Design • Phase 3, international, multi-center, double-blind, placebo-controlled trial • Approved: August 15, 2019
• Tropomyosin receptor tyrosine Patients kinases (TRK) • 120 patients with TGCT not amenable to surgical resection ▫ Neurotrophic tyrosine receptor kinas [NTRK] genes ▫ Proto-oncogene tyrosine- Outcomes protein kinase ROS1 (ROS1) • ORR at 25 weeks: 38% vs 0% (p<0.001) ▫ Anaplastic lymphoma kinase • CR: 15% (ALK) • PR: 23% • 13/13 responders who were followed for > 12 months maintained the response for > 12 months
ROZLYTREK® [package insert] San Francisco. Roche Group. 2109. Tap, WD, et al. Lancet. 2019 Picture: FDA.gov 51 52
Entrectinib Entrectinib Dose Reductions
Indication Dose Level • Adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive Starting dose 600 mg daily • Adult and pediatric patients > 12 years of age with solid tumors that have NTRK gene fusion without resistance, First dose reduction 400 mg daily are metastatic or have progressed following treatment with no alterative therapy Second dose reduction 200 mg daily Dosing Third dose reduction Discontinue • 600 mg orally once daily *Always discontinue for any grade 4 event • Pediatric dosing is based on BSA Dose Adjustments • Moderate and strong CYP3A4 inhibitors: Moderate: 200 mg daily; Strong; 100 mg daily • Moderate and strong CYP3A4 inducers: Avoid • Dose adjustments: CHF, CNS, Hepatoxicity, Hyperuricemia, QTc prolongation, Visual disorders, Hematologic, Any other grade 3-4 adverse effects
ROZLYTREK® [package insert] San Francisco. Roche Group. 2109. ROZLYTREK® [package insert] San Francisco. Roche Group. 2109. 53 54
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Entrectinib – ALKA, STARTRK-1, STARTRK-2 Entrectinib
Adverse effects Clinical Pearls Design • ALKA – Phase 1, multicenter, single-arm trial Congestive heart failure (3.4%) ECHO at baseline and as clinically indicated • STARTRK-1 and STARTRK-2 – Phase 2, multicenter, basket trial Cognitive impairment (27%) Monitor LFTs at baseline every 2 weeks Patients Skeletal fractures (5%) during the first month monthly after • Patients with NTRK1/2/3, ROS, or ALK mutation were screened and included. Hepatotoxicity (Grade > 3, 2.8%) Monitor uric acid at baseline and as Prior treatment with crizotinib indicated (ALK/ROS) and only CNS progression Hyperuricemia (9%) Outcomes were included Baseline EKG and electrolytes and as QT prolongation (3.1%) • ORR for 54 adults: 57% indicated Vision disorders (21%) • Duration > 6 months: 68% If visual changes, hold entrectinib until 51 adults with ROS1-positive NSCLC had an ORR • Duration > 12 months: 45% of 78% with a duration of response > 12 months resolution and conduct an eye exam of 55%
Drilon, A et al. AACR Abstract. 2017. ROZLYTREK® [package insert] San Francisco. Roche Group. 2109. Patel, M et al. Journal of Clinical Oncology suppl. 2017. 55 56
Medical Oncology Approval Review What A Year!
The landscape of treatment is continuously evolving Drug Drug Class Indication Notable Adverse Effects New medications and expanded indications are allowing for increased Tazemetostat Methyltransferase, EZH2 inhibitor Advanced epithelioid sarcoma GI (N/V/D), risk of hemorrhage treatment options for patients Avapritinib TKI (PDGFRA, KIT) GIST harboring PDGFRA exon 18 + CNS, edema, N/V/D, rash, ICH PDGFRA 842V mutations
Pexidartinib CSF1R inhibitor Symptomatic TGCT Hepatotoxicity, rash, edema, hypertension
Entrectinib TKI targeting NTRK, ROS1, ALK ROS1-positive NSCLC, NTRK gene CHF, CNS effects, QTc prolongation, fusion tumors vision disorders
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Assessment 1 Assessment 2
Which medication does not function as a drug-antibody conjugate to Which medication has a REMS program due to the high incidence of exert its action? hepatotoxicity?
A. Tafasitamab-cxix A. Avapritinib B. Selinexor B. Pexidartinib C. Polatuzumab vedotin-piiq C. Polatuzumab vedotin-piiq D. Belantamab mafodotin-blmf D. Belantamab mafodotin-blmf
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Assessment 3 Assessment 4
In patient receiving selinexor, what supportive care measure can be LM is a 68 year old M with DLBCL who recently relapsed after receiving R-CHOP therapy. LM is currently not a candidate for autologous stem cell transplant but warrented? would like to pursue therapy. He states he has read of two new therapies that may be for him. What would you tell him about these options? A. Avapritinib A. Polatuzumab vedotin-piiq is a CD-19-directed agent indicated after failure B. Pexidartinib of one line of treatment C. Polatuzumab vedotin-piiq B. Polatuzumab vedotin-piiq is indicated as he is not a stem cell transplant candidate D. Belantamab mafodotin-blmf C. Tafasitamab-cxix is indicated as he has only failed one line of therapy D. Tafasitamab-cxix can be used as a bridge to transplant in patient who failed one line of therapy
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References References
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