6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150)

Abstract

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1-23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Conflict of interest statement

AbbVie-sponsored the study (NCT03069352), contributed to its design, collection, analysis, and interpretation of the data, and participated in the writing, review, and approval of the manuscript. All authors had access to relevant data. No honoraria or payments were made for authorship. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech. A.H.W.: Consulting for AbbVie, Amgen, Astellas Pharma, Celgene, Janssen, MacroGenics, Novartis, Roche, and Servier; research funding from AbbVie, Celgene, Novartis, and Servier; former employee of Walter and Eliza Hall Institute of Medical Research, which receives royalties related to venetoclax, and Dr. Wei is entitled to a fraction of these payments. P.P.: Grant/research support from AbbVie, Genesis, Novartis, and Roche; honoraria from AbbVie, Genesis, Gilead, Janssen, Novartis, and Roche. P.M.: Grant/research support from Astellas Pharma, Celgene, Daiichi Sankyo, Janssen, Karyopharm Therapeutics, Novartis, Pfizer, and Teva; speaker/advisory role for AbbVie, Celgene, Daiichi Sankyo, Incyte, Janssen, Karyopharm Therapeutics, Novartis, Pfizer, Teva, and Tolero; consulting for Agios, Astellas Pharma, Celgene, Daiichi Sankyo, Oryzon, and Tolero. K.L.: Grant/research support from AbbVie, Novartis, Roche, Sandoz, and Takeda; personal fees from AbbVie, Astellas Pharma, BeiGene, Celgene, iQone Healthcare Switzerland, Janssen, Novartis, and Sandoz. V.I.: Investigator in AbbVie-sponsored clinical trials. I.K.: Investigator in AbbVie-sponsored clinical trials. J.N.: Consulting/advisory role for Amgen, Novartis, Pfizer, Roche, and Takeda; travel expenses from Amgen and Janssen. D.A.S.: Investigator in AbbVie-sponsored clinical trials. W.F.: Membership on an entity’s board of directors or advisory committee for AbbVie, Amgen, ARIAD/Incyte, Celgene, Jazz Pharmaceuticals, MorphoSys AG, Novartis, and Pfizer; patents and royalties from Amgen; support for meeting attendance Amgen, Daiichi Sankyo, Gilead, Jazz Pharmaceuticals, and Servier; research funding from Amgen and Pfizer. M.P.: Speaker/advisory role for AbbVie, Amgen, Astellas Pharma, Genesis, Janssen, Novartis, and Pfizer. J.B.: Consulting for AbbVie, Amgen, Astellas Pharma, BMS, Jazz Pharmaceuticals, Novartis, and Pfizer; travel support from Amgen and Novartis. S.B.T.: Consulting for AbbVie; investigator in AbbVie-sponsored clinical trials. J.Z.H., A.A., and A.M.: Investigator in AbbVie-sponsored clinical trials. V.M.: Conference attendance support from AbbVie, Celgene, Janssen, Novartis, and Takeda; consulting for Celgene, Novartis, and Janssen. T.Y.: Research support/honoraria from, and advisory role for AbbVie, Astellas Pharma, Gilead, Janssen, Nippon Shinyaku, Otsuka, Pfizer, Solasia, SymBio, and Takeda. J.W.: Advisory role for AbbVie; research support from Celgene. B.C., Y.S., Q.J., W.M., and J.H.: Employees of AbbVie and may hold stock or stock options. C.D.D.: Research support from AbbVie/Genentech, Agios, BMS/Celgene, Calithera, Cleave, Daiichi Sankyo, Immune-Onc, and Loxo; consulting/advisory board member for AbbVie, Agios, Aprea, BMS/Celgene, Immune-Onc, Kura, Novartis, Takeda, and Notable Labs.

© 2021. The Author(s).

Figures

Fig. 1. Overall Survival.

A OS at 6-month follow-up. Kaplan–Meier plot showing the OS rate of all patients over time, separated by treatment arm; the number of patients at risk for each time point is shown below the graph. Tick marks indicate censored data. Republished with permission of Elsevier Science & Technology Journals, from Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial, Wei et al., volume 135, issue 24, copyright 2021; permission conveyed through Copyright Clearance Center, Inc. B Subgroup analysis of investigator-assessed OS. HR is from the unstratified Cox proportional-hazards model. Data included are subjected to a cut-off date of August 15, 2019. Median (95% CI) and HR (95% CI) are calculated only for subgroups with available data. AML acute myeloid leukemia, CI confidence interval, HMA hypomethylating agent, HR hazard ratio, LDAC low-dose cytarabine, NA not assessed, OS overall survival.

Fig. 2. OS in patients treated with venetoclax +LDAC achieving CR/CRi by best post-baseline MRD value (−3 vs. ≥10−3).

Kaplan–Meier plot showing the OS rate in patients treated with venetoclax +LDAC who achieved a CR/CRi response, stratified by best post-baseline MRD value (−3 vs. ≥10−3). Unable to graph MRD data for placebo + LDAC arm due to small sample size (data summarized in Table 5). Tick marks indicate censored data. CI confidence interval, CR complete response, CRi CR with incomplete hematologic recovery, LDAC low-dose cytarabine, NR not reached, OS overall survival, VEN, venetoclax, MRD minimal residual disease.