Venetoclax-Based Combos Approved in Europe for Intensive Chemo–Ineligible Newly Diagnosed AML

The European Commission has approved venetoclax (Venclyxto) for use in combination with azacitidine and decitabine in the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates to receive intensive chemotherapy.¹

The regulatory decision is supported by data from 2 trials: the phase 3 VIALE-A trial (NCT02993523) and the phase 1/2 M140358 trial (NCT02203773). Both efforts evaluated the use of venetoclax in combination with hypomethylating agents in this patient population.

“This [venetoclax] approval is a critical step in providing new therapeutic options for patients in the European Union [EU] newly diagnosed with AML who cannot tolerate the side effects of, or are ineligible for, intensive chemotherapy,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “[Venetoclax]-based combinations continue to show meaningful clinical benefits in [patients with] AML, who would otherwise have a poor prognosis.”

The multicenter, double-blind, placebo-controlled VIALE-A trial examined the safety and efficacy of venetoclax plus azacitidine vs azacitidine plus placebo in patients who were at least 18 years of age and had a confirmed diagnosis of treatment-naïve AML per World Health Organization criteria.² These patients were ineligible for standard induction treatment if they were aged 75 years or older or if they had certain coexisting conditions that precluded intensive chemotherapy, such as a history of congestive heart failure for which treatment was needed or an ejection fraction of 50% or less, or chronic stable angina, among others.

Study participants were randomized 2:1 to receive venetoclax/azacitidine (n = 286) or azacitidine/placebo (n = 145). Venetoclax was given at a dose of 100 mg on day 1 cycle 1 and 200 mg on day 2; on day 3, the target dose of 400 mg was reached and continued until day 28. In all subsequent 28-day treatment cycles, venetoclax was initiated at a daily dose of 400 mg. Those in the control arm were given placebo on the same schedule. In both arms, azacitidine was administered at a dose of 75 mg/m2 on days 1 through 7, every 28-day cycle.

The primary end point of the trial was overall survival, while secondary end points included composite complete remission, complete remission with our without partial hematologic recovery, complete remission by initiation of cycle 2, as well as red cell and platelet transfusion independence, among others.

Results from VIALE-A indicated that when venetoclax was paired with azacitidine, it led to a significant 34% reduction in the risk of death vs azacitidine alone (HR, 0.66; 95% CI, 0.52-0.85; P <.001). The median overall survival in the investigative and control arms was 14.7 months (95% CI, 11.9-18.7) and 9.6 months (95% CI, 7.4-12.7), respectively.

Moreover, the venetoclax combination was noted to more than double the complete responses (CRs) experienced, with a 37% CR rate (95% CI, 31%-43%) vs an 18% CR rate (95% CI, 12%-25%) with the control (P <.001). The venetoclax also resulted in higher rates of composite complete remission (CR + CR with incomplete blood count recovery [CR + CRi]) vs azacitidine alone, at 66% (95% CI, 61-62) and 28% (95% CI, 21-36), respectively (P <.001).

Regarding safety, the most common serious adverse effects (AEs) reported with the venetoclax/azacitidine regimen included febrile neutropenia, pneumonia, sepsis, and hemorrhage.

The large, multicenter, phase 1b, M140358 study evaluated the safety and efficacy of venetoclax plus either decitabine (n = 31) or azacitidine (n = 84) in patients who were at least 65 years of age, had treatment-naïve AML, and were not candidates for intensive chemotherapy.³

During the dose-escalation portion of the trial, venetoclax was given at daily doses of 400 mg, 800 mg, or 1200 mg in combination with either decitabine at 20 mg/m2 on days 1 through 5 or azacitidine at 75 mg/m2 on days 1 through 7. In the expansion phase of the research, venetoclax was given at either 400 mg or 800 mg with either of the hypomethylating agents.

Results indicated that patients who venetoclax with decitabine had a CR + CRi rate of 74% (95% CI, 55%-88%). The most frequently experienced serious AEs included febrile neutropenia, pneumonia, bacteremia, and sepsis.

"[Venetoclax] has proven incremental overall survival in treating newly diagnosed AML in patients who are ineligible for intensive chemotherapy when treated with [venetoclax] plus azacitidine compared to those treated with azacitidine alone," said Mohamed Zaki, MD, PhD, vice president and head, global oncology development, AbbVie, stated in a press release.⁴ "We look forward to bringing [venetoclax] to more AML patients who can potentially benefit from this important new treatment option in EU countries."

References

1. European Commission approves Venclyxto-based combinations for adults with newly diagnosed acute myeloid leukaemia who are ineligible for intensive chemotherapy. News release. May 25, 2021. Accessed May 25, 2021. https://bit.ly/34i09Gw
2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
3. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-2018-08-868752
4. AbbVie receives European Commission approval of VENCLYXTO (venetoclax) in combination with a hypomethylating agent for patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy. News release. AbbVie. May 25, 2021. Accessed May 25, 2021. https://bit.ly/3fm6cAw