The European Medicines Agency Committee for Medicinal Products for Human Use has recommended to approve venetoclax for use in combination with hypomethylating agents for the treatment of adult patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.
The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recommended to approve venetoclax (Venclyxto; Venclexta for US) for use in combination with hypomethylating agents for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The recommendation is based on data from the double-blind, placebo-controlled, phase 3 VIALE-A (M15-656; NCT02993523) and the phase 1b open-label, nonrandomized, multicenter M14-358 (NCT02203773) trials, both of which showed encouraging rates of efficacy with venetoclax with azacitidine and azacitidine or decitabine in this patient population, respectively.
The positive opinion will be used to inform a decision by the European Commission, which is expected to take place in the first half of 2021.
"AML is an incredibly aggressive form of cancer, and patients who are diagnosed with this disease are often so ill that they cannot tolerate the intensive chemotherapy that healthcare providers would typically prescribe," said Hartmut Döhner, MD, professor of medicine and director, Department of Hematology, Oncology, Palliative Care, Rheumatology and Infectious Diseases at University Hospital in Ulm, Germany. "Venclyxto combination therapy is a promising advancement for patients and their healthcare providers facing this challenging, lethal form of cancer."
In the double-blind, placebo-controlled, VIALE-A trial, investigators evaluated the efficacy and safety of venetoclax in combination with azacitidine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. The coprimary end points was overall survival (OS). Secondary end points were complete remission (CR) rate, and composite CR rate (CR + CR with incomplete hematologic recovery [CRi]) rate.
Results showed that the median OS was 14.7 months with venetoclax/azacitidine compared with 9.6 months for those who were on azacitidine/placebo. Venetoclax plus azacitidine led to a CR rate of 36.7% compared with 17.9% with placebo/azacitidine. The composite CR rates were 66.4% and 28.3%, respectively.
Regarding safety, venetoclax plus azacitidine was found to have an adverse event (AE) profile that was consistent with the know tolerability profiles of both agents, and the AEs were also similar and expected for an older patient population with AML. No differences in quality-of-life measures were reported.
The most commonly reported serious AEs were febrile neutropenia (30% with venetoclax/azacitidine vs 10% with placebo/azacitidine), pneumonia (17% vs 22%, respectively), sepsis (6% vs 8%), and hemorrhage (9% vs 6%).
In the nonrandomized, phase 1b M14-358 trial, researchers evaluated venetoclax with either azacitidine or decitabine in patients with newly diagnosed AML. Data showed that the patients on venetoclax/azacitidine demonstrated a 44% CR rate and a CR+CRi rate of 71%. Furthermore, the median duration of response (DOR) was 21.9 months, and the median time to first CR or CRi was 1.2 months (range, 0.7-7.7 months).
With the venetoclax/decitabine group, the CR rate was 55%, the CR+CRi rate was 74%, and the median DOR was 15 months; the median time to first CR or CRi was 1.9 months (range, 0.9-5.4 months).
Febrile neutropenia and pneumonia were the most commonly reported serious AEs with venetoclax/azacitidine, occurring in 31% and 26% of patients, respectively. For those who were treated with venetoclax/decitabine, the most frequent serious AEs were febrile neutropenia (42%), pneumonia (29%), bacteremia (16%), and sepsis (6%).
"This positive CHMP opinion for Venclyxto in acute myeloid leukemia is a critical step to providing new therapeutic options in the European Union for patients with this devastating disease," said Mohamed Zaki, MD, PhD, vice president and global head of oncology development at AbbVie, the codeveloper of venetoclax with Roche. "Enabling improved outcomes including potentially prolonging the lives of patients with malignant diseases such as acute myeloid leukemia is part of our mission and an objective we pursue relentlessly every day."
In October 2020, the FDA granted regular approval to venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for patients with newly diagnosed AML who are 75 years or older or who have comorbidities precluding intensive induction chemotherapy; an accelerated approval for this indication occurred in November 2018.2 The efficacy of venetoclax was confirmed in 2 randomized, double-blind, placebo-controlled trials in this patient population: VIALE-A (NCT02993523) and VIALE-C (NCT03069352).