The U.S. Food and Drug Administration (FDA) has granted full approval to Venclexta (venetoclax), in combination with Vidaza (azacitidine), Dacogen (decitabine), or low-dose cytarabine, for treating newly diagnosed adults with acute myeloid leukemia (AML).
The approval includes patients 75 and older, or who have simultaneous health conditions that disqualify them from receiving standard, intense chemotherapy.
The decision comes nearly two years after the FDA’s accelerated, conditional approval of Venclexta combinations for the same indication. Conversion to full approval was dependent on additional evidence of clinical benefit provided by two Phase 3 confirmatory clinical trials: VIALE-A (NCT02993523) and VIALE-C (NCT03069352).
“Today’s full approval is supported by the significant results that showed that Venclexta in combination with [Vidaza] extended overall survival for people with newly diagnosed acute myeloid leukaemia who cannot tolerate intensive induction chemotherapy,” Levi Garraway, MD, PhD, said in a press release. Garrawaay is chief medical officer and head of global product development at Roche, one of Venclexta’s developers.
“We are very pleased that this application was reviewed under the FDA’s Real-Time Oncology Review [RTOR] pilot and Project Orbis initiative, helping to bring this treatment option more rapidly to patients in the United States and other countries,” Garraway said.
The RTOR pilot program explores a more efficient review process to ensure safe and effective treatments are available to patients as early as possible, while the FDA’s recently established Project Orbis allows simultaneous submission and review of cancer treatments among multiple regulatory agencies worldwide. For this review, FDA collaborated with regulatory agencies in Australia, Brazil, Canada, and Switzerland, which are still reviewing the application.
Venclexta, developed by Roche and AbbVie and marketed as Venclyxto outside the U.S., is an oral small molecule that works by blocking the activity of B-cell lymphoma-2 (BCL-2), a protein that prevents apoptosis, or programmed cell death. Since cancer cells often produce high amounts of BCL-2 to escape death, by blocking BCL-2 Venclexta primes cancer cells for death.
The therapy previously received orphan drug designation in the U.S. and in Europe for the treatment of AML, as well as breakthrough therapy designation — in combination with azacitidine or decitabine, or low-dose cytarabine — in the U.S. for newly-diagnosed AML patients ineligible for standard chemotherapy.
The full approval was based mainly on results from the VIALE-A and VIALE-C multicenter studies, which are evaluating whether adding Venclexta to a chemotherapeutic agent (Vidaza or low-dose cytarabine) is superior to either agent alone at prolonging the survival of previously untreated AML patients ineligible for intensive chemotherapy.
VIALE-A is assessing the safety and effectiveness of the Venclexta-Vidaza combo in 431 AML adult patients who were assigned randomly to receive oral tablets of either Venclexta (286 patients) or a placebo (145 patients), in addition to Vidaza (given by intravenous or under-the-skin injections).
VIALE-A’s latest data showed that, at a median follow-up of 20.5 months (nearly two years), patients given the combination therapy lived longer (14.7 months) than those receiving Vidaza alone (9.6 months), corresponding to a 34% reduced risk of death.
Compared with the placebo group, a higher proportion of patients receiving the Venclexta-Vidaza combo achieved complete remission, or no signs of cancer (36.7% vs. 17.9%), and for a longer period of time (17.5 months vs. 13.3 months).
Similarly, more than twice as many patients in the Venclexta group achieved complete remission with incomplete hematologic recovery, compared with the placebo group (66.4% vs. 28.3%). This means that cancer was eradicated, but other blood parameters, such as the levels of neutrophils — a type of infection-fighting immune cell — were not within a normal range.
“Based on the results of this study, this treatment regimen represents a significant advance for older AML patients, including higher response rates, greater transfusion independence, longer durations of remission, and ultimately significantly improved overall survival compared to [Vidaza] alone,” said Courtney D. DiNardo, MD, associate professor of the department of leukemia at The University of Texas MD Anderson Cancer Center.
VIALE-C is evaluating the safety and effectiveness of a combination therapy of Venclexta and low-dose cytarabine in 211 AML adult patients assigned randomly to receive oral tablets of either Venclexta (143 patients) or a placebo (68 patients), in addition to low-dose cytarabine (given by an under-the-skin injection).
For this combo, the full approval was based on the rate and duration of patients’ complete responses, instead of overall survival.
At a median of one year of follow-up, data showed that a greater proportion of patients receiving the Venclexta combo (27.3%) achieved complete remission, compared with those in the placebo group (7.4%). Complete remission also lasted longer in the Venclexta group (11.1 months vs. 8.3 months in the placebo group).
Moreover, nearly four times more patients given the combination therapy achieved complete remission with or without complete hematologic recovery, compared with those treated with cytarabine alone (47.6% vs. 13.2%).
While participants treated with the Venclexta combo also lived longer than those given cytarabine alone (7.2 months vs. 4.1 months), these differences did not reach statistical significance, and the trial failed to meet its main goal.
Updated results from other Phase 1/2 trials of Venclexta in newly diagnosed AML patients also supported Venclexta’s full approval.
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