Combining venetoclax with low-dose cytarabine (LDAC) did not lead to a statistically significant improvement in overall survival compared with LDAC alone in newly-diagnosed patients with acute myeloid leukemia who are ineligible for intensive chemotherapy, according to findings from the phase III VIALE-C (M16-043) trial.
Combining venetoclax (Venclexta) with low-dose cytarabine (LDAC) did not lead to a statistically significant improvement in overall survival (OS) compared with LDAC alone in newly-diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, according to findings from the phase III VIALE-C (M16-043) trial.1
The findings showed that the combination did lead to a 25% reduction in the risk of death, with median OS of 7.2 months compared with 4.1 months with LDAC alone; however, the numerical increase was not statistically significant (HR, 0.75; 95% CI, 0.52-1.07; P = .11). The codevelopers of venetoclax, AbbVie and Genentech, also reported in a press release that a posthoc analysis after an additional 6 months of follow-up showed a median OS of 8.4 months with the combination versus 4.1 months in the control arm (HR, 0.70; 95% CI, 0.50-0.99).
"We remain committed to AML patients and our research in AML and other blood cancers," Neil Gallagher, MD, PhD, chief medical officer and vice president of development, AbbVie, said in the press release. "The study results, while not statistically significant, are indicative of the clinical activity of venetoclax in combination with low-dose cytarabine."
The double-blind phase III VIALE-C study evaluated venetoclax in combination with LDAC (n = 142) compared with LDAC plus placebo (n = 68) in 210 newly-diagnosed patients with AML who are ineligible for intensive chemotherapy. The primary endpoint was OS, and secondary endpoints included remission rates, transfusion independence, and event-free survival. The median follow-up was 12 months in both arms for this planned interim analysis.
The complete remission (CR) rate was 27.3% with the combination compared with 7.4% with LDAC alone, and the rate of CR or CR with incomplete blood count recovery (CRi) was 47.6% versus 13.2%, respectively. The rate of CR or CR with partial hematologic recovery (CRh) was 46.9% versus 14.7%, respectively, and the CR plus CRi rate by the start of cycle 2 was 34.3% versus 2.9%.
The safety data were consistent with prior research with these treatments in patients with AML. The most common non-serious adverse events (AEs) in the combination versus the control arm were neutropenia (45.8% vs 17.7%), thrombocytopenia (40.9% vs 36.8%), anemia (26.1% vs 22.1%), and febrile neutropenia (15.5% vs 11.8%). Rates of serious AEs for these 4 side effects were also, for the most part, higher with the combination: neutropenia (2.8% vs 0), thrombocytopenia (4.9% vs 2.9%), anemia (2.8% vs 0), and febrile neutropenia (16.9% vs 17.7%).
In November 2018, the FDA granted an accelerated approval to venetoclax for use in combination with azacitidine or decitabine or LDAC for the treatment of adult patients with newly-diagnosed acute myeloid leukemia who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
The approval was based on 2 phase Ib/II trials in this setting, the M14-358 study and the M14-387 study. In M14-358, combining venetoclax with azacitidine led to a CR rate of 37% and a CRh rate of 24%.2 The rates were 54% and 7.7%, respectively, with the combination of venetoclax and decitabine. M14-387 examined venetoclax in combination with LDAC. The CR and CRh rates with the combination were both 21%.2
This accelerated approval of venetoclax in AML is contingent on the results of a confirmatory trial.
The ongoing phase III VIALE-A trial (NCT02993523) is examining venetoclax in combination with azacitidine compared to azacitidine plus placebo in newly-diagnosed patients who are ineligible for intensive chemotherapy.