1/30/18 2018 BMT Pharmacists Conference New and Emerging Drugs Arpita Gandhi, PharmD, BCOP Hematology/Oncology Clinical Pharmacy Specialist Augusta University Medical Center, Augusta, GA Disclosure • Arpita Gandhi has nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors mentioned in this presentation). Objectives • Review new drug approvals and investigational new drugs relevant to the field of hematopoietic stem cell transplantation • Describe mechanisms of action and evaluate the toxicity profile of newly approved agents • Analyze clinical data supporting the approval and proposed benefit of these drugs • Identify clinical pearls and potential place in therapy for these novel agents 1 1/30/18 New Drug Approval Gemtuzumab (AML) Copanlisib (FL) March-July August September October 2017 2017 2017 2017 Midostaurin CPX-351 (AML) Acalabrutinib (MCL) (AML) Enasidenib (AML) Pembrolizumab (HL) Inotuzumab (ALL) Oral glutamine AML: acute myeloid leukemia ALL: acute lymphocytic leukemia powder (SCD) FL: follicular lymphoma HL: hodgkin’s lymphoma MCL: mantle cell lymphoma SCD: sickle cell disease Outline Expanded Sickle Cell Indications/ Leukemia Lymphoma HCT Disease Emerging Drugs HCT: hematopoietic stem cell transplantation Acute Myeloid Leukemia 2 1/30/18 Midostaurin: FLT3 inhibitor Multi-targeted kinase inhibitor (VEGF, PDGFR, stem cell factor, and FLT3) Approval: April 2017 Labeled indication: FLT3-positive AML Dosage and administration: 50 mg oral twice daily WITH FOOD on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation cycle (in combination with high-dose cytarabine) Hepatically metabolized, but no dosage adjustment required for baseline hepatic impairment (note: patients with bili > 2.5 X ULN were eXcluded from RATIFY study) FLT: FMS-like tyrosine kinase; PDGFR: platelet derived growth factor; ULN: upper limit of normal; VEGF: vascular endothelial growth factor; Midostaurin (Rydapt® ). Package Insert. Novartis Pharmaceutical Corporation, East Hanover, NJ. Accessed Nov 2017 FLT3 • FLT3 gene Located on chromosome 13 and encodes for FLT3 receptor tyrosine kinase, which is expressed on majority of the leukemic blasts Mutated gene: proteins that spontaneously dimerize causing factor independent growth and fatal myeloproliferative neoplasm in murine models • Mutations Internal tandem duplication (ITD) • 25-30% of de novo AML and 15% of MDS derived AML • Increased risk of relapse, reduced survival and inferior clinical course overall Tyrosine kinase domain (TKD) • 10% of de novo AML • Unclear if confers poor prognosis • Clinical outcomes better than FLT3-ITD AML, however less clear clinical implications Stone RM, et al. N Engl J Med 2017;377:454-64 Stansfield LC, et al. Pharmacotherapy 2017 Oct 4 [Epub] RATIFY: Midostaurin in FLT3+ AML Patients Treatment Groups Results (n= 717) Placebo (n = 357) Induction (up to 2 cycles): 7+3 Overall survival (median): 25.6 Consolidation (4 cycles): HiDAC* months R Maintenance: placebo for twelve 28-day Phase III, A cycles 4 yr. OS: 44.3% randomized, double- N blind, placebo controlled study D O Midostaurin (n = 360) Age 18-59 years with Induction (up to 2 cycles): 7+3 + Overall survival newly diagnosed M midostaurin** days 8-21 (median): 74.7 AML (t-AML I Consolidation (4 cycles): HiDAC* + months excluded) with FLT3 Z midostaurin** days 8-21 4 yr OS: 51.4% mutation Maintenance: midostaurin* for twelve E 28-day cycles HR 0.78, p = 0.009 ⁋ cytarabine 200 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3 *HiDAC: high dose cytarabine (3 gm/m2 IV q12H days 1, 3, 5) ** Midostaurin 50 mg PO BID Stone RM, et al. N Engl J Med 2017;377:454-64 3 1/30/18 RATIFY: Efficacy Midostaurin + Placebo + Outcomes Chemotherapy Chemotherapy P Value (n = 360) (n = 357) Median OS, mos (range)* 74.7 (31.7-NR) 25.6 (18.6-42.9) 0.009 4-yr OS, % (95% CI) § Uncensored 51.4 (46.0-57.0) 44.3 (39.0-50.0) 0.0074 § Censored for SCT 63.7 (56.0-71.0) 55.7 (47.0-63.0) 0.08 HCT, (%) § Any time 59 55 0.28 § CR1 onLy 28.1 22.7 0.10 CR (by day 60), % 59 54 0.15 Median EFS, mos 8.2 3.0 0.002 4-yr EFS rate, % 28.2 20.6 0.002 Median DFS, mos 26.7 15.5 0.01 CR: complete remission, DFS: disease free survival, EFS: event free survival, HCT: hematopoietic stem cell transplantation, NR: not reached, OS: overall survival * OS also longer in the midostaurin group compared with placeBo among patients with a FLT3 TKD and FLT3 ITD mutation with either a high ratio (>0.7) or low ratio (0.05-0.7) of mutant to wild-type allele Stone RM, et al. N Engl J Med 2017;377:454-64 RATIFY: Safety Midostaurin + Placebo + Select Grade 3-4 Adverse Chemotherapy Chemotherapy P Value Events, % (n = 360) (n = 357) Thrombocytopenia 97 97 0.52 Neutropenia 95 96 0.82 Anemia 93 88 0.03 Febrile neutropenia 82 82 0.84 Infection 52 50 0.60 Diarrhea 16 15 0.92 Hypokalemia 14 17 0.25 Rash/desquamation 14 8 0.008 Increased alanine 13 9 0.19 aminotransferase Nausea 6 10 0.05 Stone RM, et al. N Engl J Med 2017;377:454-64 Midostaurin Key Points • Midostaurin added to standard chemo • Interaction with strong CYP3A4 in patients with newly diagnosed inhibitors FLT3-mutated AML 1.44 fold increase in midostaurin Improved OS and EFS, regardless of exposure; no notable increase in ITD/TKD stratification group midostaurin related AEs Reduced risk of death by 23% compared with placebo • Interaction with NPM1 mutation EFS and OS benefit most pronounced in • Benefit derived early in therapy NPM1wt/FLT3-ITD high group (median exposure: 42 days) • Take with food; Anti-emetic • Not approved for use as maintenance prophylaxis recommended therapy • QTc prolongation 11% vs. 6% in • Age/Gender placebo (consider interval assessment of QTc if taken in combination with No age restriction in FDA labeling medications that can prolong QT Differences in outcomes based on gender interval) • Cons • Area of ongoing investigation How to best combine midostaurin with Lack of IV formulation other agents Midostaurin combined with Role of maintenance therapy in high-risk daunorubicin 60 mg/m2 instead of 90 patients mg/m2 Concurrent vs. sequential therapy Midostaurin (Rydapt® ). Package Insert. Novartis Pharmaceutical Corporation, East Hanover, NJ. Accessed Nov 2017 Taoufik O, et al. ASH 2017, Abstract 3814 4 1/30/18 CPX-351 A Nanoscale Delivery Complex Liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio Approval: August 2017 Labeled indication: treatment of adults with newly diagnosed therapy related AML or AML with myelodysplasia-related changes • Dosing and administration: • Induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 liposome via intravenous infusion over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction, if needed • Consolidation: daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 liposome via intravenous infusion over 90 minutes on days 1 and 3 • Hepatic/renal impairment: not studied in patients with T.bili > 3 mg/dL, GFR < 30 mL/min and end stage renal disease • Full course: 1-2 cycles of induction and up to 2 cycles of consolidation Vyxeos® . Jazz Pharmaceuticals, Inc. Palo Alto, CA. Accessed November 2017 CPX-351 A Nanoscale Delivery Complex Liposomal Formulation • Synergistic effect at killing leukemia cells in-vitro and murine models • Liposome retains drug in the synergistic ratio, minimizes first pass metabolism and delivers drugs preferentially at tumor site • Effective drug exposure of leukemia cell extended by days beyond what’s possible with conventional chemotherapy Image credit: clinicaloptions.com Raut LS, et al. South Asian J Cancer 2015;4(1):38-40 CPX-351: Clinical Data Patients Treatment Groups Results (n= 309) 7+3 (n = 156) 1st induction: 7+3 à cytarabine 100 Overall survival Phase III, mg/m2 + daunorubicin 60 mg/m2 (median): 9.6 randomized, open- R 2nd induction AND consolidation: 5+2 months label study (cytarabine 100 mg/m2 + daunorubicin A 2 Age 60-75 years with N 60 mg/m ) sAML (t-AML, antecedent MDS or D CMML, AML with O CPX-351 (n = 153) MDS-related 1st induction: 100 units/m2 on Overall survival cytogenetic M days 1, 3, 5 (median): 5.9 abnormalities) I 2nd induction: 100 unit/m2 on months Z days 1 and 3 Consolidation: 65 unit/m2 on day • t-AML (20%) • AML with antecedent E 1 and 3 HR 0.69, p = 0.005 hematological disorder (54%) • De novo AML with MDS related cytogenetic abnormalities (25%) CMML: chronic myelomonocytic AML, MDS: myelodysplastic syndrome, sAML: secondary 1 unit = 1 mg cytarabine + 0.44 mg daunorubicin AML, t-AML: therapy related AML, Lancet JE, et al. ASCO 2016. Abstract 7000. 5 1/30/18 CPX-351: Outcomes CPX-351 7+3 Outcomes P Value (n = 153) (n = 156) Median overall survival, mos 9.56 5.95 0.005 Complete remission, % 38 26 0.036 CR + CRi, % 47.7 33.3 0.016 Event free survival Data not reported Data not reported 0.021 Rate of transplantation, % 34 29 - OS post-transplantation, mos Not reached 10.25 0.0046 Prolonged thrombocytopenia* (grade 3-5) - During induction 28 13 - - During consolidation 25 16 (with 5+2) Prolonged neutropenia* (grade 3-5) - During induction 17 3 - - During consolidation 10 3 CRi: complete remission with incomplete count recovery;*defined as PLT < 50K, ANC < 500 lasting past cycle day 42 in the absence of leukemia Lancet JE, et al. J Clin Oncol 2016;24: Abstract 7000 Vyxeos® . Jazz Pharmaceuticals, Inc. Palo Alto, CA. Accessed November 2017 CPX-351: Key Points 1.0 De novo AML • CPX-351 superior to 7 + 3 for OS, EFS, CR, CR + CRi sAML, MDS 30- and 60-day mortality rates lower with CPX-351 0.8 sAML, non-MDS OS after transplantation improved tAML with CPX-351 vs 7 + 3 • High frequency of sAML in older 0.6 population; CPX-351 new standard for older, fit, patients with previously untreated high- risk AML 0.4 • An effective bridge to HCT Probability Survival • Can not be substituted for 0.2 standard 7+3 • 1 unit = 1 mg cytarabine + 0.44 mg daunorubicin 0 1 3 5 7 9 11 13 • Substantially longer half life compared with non-liposomal Yrs Since AML DiaGnosis formulations likely leading to longer time to neutrophil (36 vs.