Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naïve Patients Aged 65 Years With Acute Myeloid Leukemia

Transcription

1 Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naïve Patients Aged 65 Years With Acute Myeloid Leukemia Abstract 102 Wei AH, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, Martinelli G, Walter RB, Enjeti A, Fakouhi KM, Darden DE, Dunbar M, Jia J, Agarwal S, Salem AH, Mabry M, Hayslip J

2 Introduction Older patients ( 65 years) with acute myelogenous leukemia (AML) who are often unfit for intensive chemotherapy have limited treatment options 1 Reported CR+CRi rates for low-dose cytarabine (LDAC) are modest (11%- 18%), and median survival is 5 months [95% CI = ] in this population 2,3 Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies 4,5 Venetoclax (VEN) is a potent, orally bioavailable selective BCL-2 inhibitor 5,6 with demonstrated single-agent activity in AML cell lines and primary patient samples 7 Heavily pretreated patients with relapsed/refractory AML 8 1. Thein MS, et al. Cancer. 2013;119(15): Kantarjian HM, et al. J Clin Oncol. 2012;30(21): Burnett AK, et al. Cancer. 2007;109(6): Thomas S, et al. Expert Opin Ther Targets. 2013;17(1): Roberts AW, et al. N Engl J Med. 2016;374(4): Souers AJ, et al. Nat Med. 2013;19(2): Pan R, et al. Cancer Discov. 2014;4(3): ; 8. Konopleva M, et al. Cancer Discov. 2016; 6(10):

3 Venetoclax Is a BCL-2 Selective Inhibitor Promotes apoptosis through selective inhibition of BCL-2 BCL-2 Pro-apoptotic protein BCL-2 venetoclax Pro-apoptotic protein Apoptosis initiation BIM BAX Cancer Cell Survival Cancer Cell Death BAK BAX Activation of caspases Cytochrome c BCL-2 overexpression allows cancer cells to evade apoptosis by sequestering pro-apoptotic proteins 1-3 Venetoclax binds selectively to BCL-2, freeing pro-apoptotic proteins that initiate programmed cell death (apoptosis) Leverson JD, et al. Sci Transl Med 2015;7(279):279ra Czabotar PE, et al. Nat Rev Mol Cell Biol. 2014;15(1): Plati J, et al. Integr Biol (Camb). 2011;3(4): Certo M, et al. Cancer Cell. 2006;9(5): Souers AJ, et al. Nat Med. 2013;19(2): Del Gaizo Moore V, et al. J Clin Invest. 2007;117(1):

4 Phase I/II, Open-label, Multicenter, 2-Stage Study Phase I (3+3 design) Phase II VEN + LDAC N = 18 n = 8, 600 mg VEN n = 10, 800 mg VEN* RP2D 600 mg VEN + LDAC N = 53 All patients 600 mg VEN VEN: once daily LDAC: 20 mg/m 2 D1 10, SC 28-D cycles Inclusion criteria Adults 65 years with untreated AML, not eligible for standard induction therapy, ECOG PS 0-2 Exclusion criteria Previous cytarabine for pre-existing myeloid disorder Acute promyelocytic leukemia Active CNS involvement with AML *2 patients had dose-limiting toxicity (DLT) at 800 mg dose Objectives Safety: Safety, PK, MTD, RP2D Efficacy: Response rates, DOR, OS Exploratory: biomarkers predictive of outcome CNS, central nervous system; D, day; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; LDAC, low-dose cytarabine; MTD, maximum tolerated dose; OS, overall survival; PK, pharmacokinetics; PS, performance status; RP2D, recommended phase II dose; SC, subcutaneous; VEN, venetoclax

5 Dosing Schema in Cycle 1 for Venetoclax and LDAC All patients were hospitalized and received prophylaxis for tumor lysis syndrome (TLS) prior to cycle 1 day 1 Each cycle was 28 days in length Venetoclax Dose (Cycle 1)* Day 1 - Day 2 50 mg Day mg Day mg LDAC 20 mg/m 2 daily SC; Days 1-10 of all cycles Day mg Day 6 Day mg *subsequent cycles 600 mg venetoclax days 1-28 LDAC, low-dose cytarabine; SC, subcutaneous

6 Patient Demographics and Characteristics Characteristics VEN 600 mg (N = 61) Age, median (range), years 74 (66-87) Males, n (%) 39 (64) ECOG status, n (%) (30) 30 (49) 13 (21) Secondary AML, n (%) 27 (44) Prior HMA treatment for MDS, n (%) 17 (28) Cytogenetics, n (%) Intermediate Adverse No mitoses 37 (61) 19 (31) 5 (8) Baseline bone marrow blast count, n (%) >50 20 (33) 12 (20) 29 (48) Either age 75 years, or ECOG 2, or secondary AML or adverse karyotype 51 (84) ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agent; MDS, myelodysplastic syndrome; VEN, venetoclax Data cutoff date: 31AUG2016

7 Treatment-Emergent Adverse Events (TEAEs) Excluding Cytopenias TEAEs of Any Grade Grade 3/4 TEAEs TEAE (in 30% patients), n (%) VEN 600 mg (N = 61) Nausea 44 (72) Hypokalemia 28 (46) Diarrhea 27 (44) Fatigue 26 (43) Decreased appetite 25 (41) Constipation 22 (36) Febrile neutropenia 22 (36) Hypomagnesemia 20 (33) TEAE (in 10% patients), n (%) VEN 600 mg (N = 61) Febrile neutropenia 21 (34) Hypokalemia 9 (15) Hypophosphatemia 8 (13) Hypertension 6 (10) 2 (3%) deaths 30 days of start of treatment 9 (15%) deaths 60 days of start of treatment Vomiting 19 (31) VEN, venetoclax Data cutoff date: 31AUG2016

8 LDAC Did Not Appear to Affect Venetoclax Exposures Parameters, Units VEN 600 mg + LDAC n = 7 VEN 600 mg n = 7 T max, median (range), (h) 4 (4-6) 8 (4-8) C max (µg/ml) 2.04 ± ± 2.15 AUC 24 (µg h/ml) 33.3 ± ± 36.8 C max /Dose (µg/ml)/mg ± ± AUC 24 /Dose (µg h/ml)/mg ± ± Values presented as mean ± SD AUC, area under the curve; C max, maximum concentration; LDAC, low-dose cytarabine; VEN, venetoclax Data cutoff date: 31AUG2016

9 Response Rates for Patients Treated With Venetoclax + LDAC Overall Response, n (%) VEN 600 mg N = 61 Complete remission (CR) 13 (21) CR with incomplete marrow recovery (CRi) 20 (33) Partial remission (PR) 4 (7) Resistant/progressive disease 23 (38) Incomplete data due to discontinuation 1 (2) CR+CRi* 33 (54) Overall response rate (CR+CRi+PR) 37 (61) *23/33 (70%) of CR/CRi achieved during cycle1 and cycle 2 VEN, venetoclax Data cutoff date: 31AUG2016

10 Venetoclax + LDAC Is Active Across a Wide Variety of Cytogenetic Mutations and Patient Profiles Characteristics, n (%) VEN 600 mg (N = 61) ORR (CR + CRi + PR) Age (70) Secondary AML HMA for MDS Prior MPN (52) 9 (53) 0 Adverse karyotype 19 9 (47) FLT3 (ITD or TKD) mutation* 3 3 (100) IDH1/2 mutation* 7 5 (71) Data cutoff date: 31AUG2016 HMA, hypomethylating agent; ITD, internal tandem duplication; LDAC, low-dose cytarabine; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; ORR, overall response rate; TKD, tyrosine kinase domain; VEN, venetoclax

11 Overall Survival (OS) at RP2D (600 mg) ORR (CR+CRi+PR) is highly correlated with OS All patients, n = 61 Responders (CR + CRi + PR), n = 37 Nonresponders, n = 24 Data cutoff date: 31AUG2016

12 Conclusions Co-administration of venetoclax (600 mg) with LDAC showed a tolerable safety profile CR + CRi was seen in 33/61 (54%) patients; ORR (CR + CRi + PR) in 37/61 (61%) patients Median overall survival has not been reached Clinical activity and tolerability was seen in patients with: age 75 years secondary AML (prior treatment with HMA for MDS) adverse karyotype FLT3-ITD mutation IDH 1/2 mutation Venetoclax plus LDAC demonstrates significant and durable activity in elderly patients with treatment-naïve AML ineligible to receive intensive induction chemotherapy A future randomized trial is planned HMA, hypomethylating agent; LDAC, low-dose cytarabine; MDS, myelodysplastic syndrome