FDA Grants Full Approval to Roche/AbbVie’s Venclexta in Combination with Azacitidine for Newly Diagnosed AML Patients Ineligible for Intensive Chemotherapy

Compiled by Keke

Recently, Genentech, a member of the Roche Group, announced that the U.S. FDA has granted full approval for Venclexta® (venetoclax) in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for the treatment of patients aged 75 years or older with newly diagnosed acute myeloid leukemia (AML) who have comorbidities that preclude the use of intensive induction chemotherapy.

It is understood that Venclexta had previously received provisional approval in November 2018 under the U.S. FDA’s Accelerated Approval Program. The FDA has now converted the accelerated approval of Venclexta to full approval. This approval is primarily based on the results of two Phase 3 clinical studies (VIALE-A and VIALE-C).

VIALE-A (NCT02993523) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 clinical study evaluating the efficacy and safety of Venclexta in combination with the hypomethylating agent azacitidine versus placebo in combination with azacitidine. The study enrolled 431 patients who were previously untreated and ineligible for intensive chemotherapy. Two-thirds of the patients (n=286) received 400 mg of Venclexta daily in combination with azacitidine, while the remaining patients (n=145) received placebo tablets in combination with azacitidine. The AML patients in the study exhibited a range of mutational subtypes, including IDH1/2 and FLT3 mutations.

The results of the VIALE-A study, published in The New England Journal of Medicine in August 2020, met its primary and key secondary endpoints. Specific data showed that, compared with azacitidine monotherapy:

• Venclexta in combination with azacitidine significantly reduced the risk of patient death by 34% (median overall survival [OS]: 14.7 months vs. 9.6 months; HR=0.66; 95% CI: 0.52–0.85; p<0.001).
• The complete remission (CR) rate in patients treated with Venclexta in combination with azacitidine was 37% (95% confidence interval [CI]: 31–43), which was significantly higher than that in patients treated with azacitidine alone (CR rate: 18%; 95% CI: 12–25) (p<0.001).
• The Venclexta plus azacitidine treatment group also demonstrated a higher rate of complete remission (CR) and CR with partial hematologic recovery (CR+CRh), at 65%, compared to 23% in the azacitidine monotherapy group (p<0.001).

The National Comprehensive Cancer Network (NCCN) Guidelines recently recommend Venclexta in combination with azacitidine as a Category 1 preferred treatment regimen for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Among patients treated with Venclexta in combination with azacitidine, the most common serious adverse reactions (≥5%) observed in 83% of patients were febrile neutropenia (30%), pneumonia (22%), bloodstream infections (excluding fungal; 19%), and hemorrhage (6%).

VIALE-C (NCT03069352) was also a randomized, double-blind, placebo-controlled, multicenter Phase 3 clinical study designed to evaluate the efficacy and safety of Venclexta in combination with low-dose cytarabine (LDAC) versus placebo in combination with LDAC in 211 patients with previously untreated acute myeloid leukemia (AML). The patients were ineligible for intensive chemotherapy; two-thirds of the patients (n=143) received 600 mg of Venclexta daily in combination with LDAC, while the remaining patients (n=68) received placebo in combination with LDAC.

For the VIALE-C study, approval was primarily based on the rate and duration of complete response (CR) in patients treated with Venclexta. Among patients receiving Venclexta in combination with low-dose cytarabine (LDAC), 27% (95% CI: 20–35) achieved CR [mean duration of complete response (DOCR) = 11.1 months], whereas the CR rate in patients receiving LDAC alone was 7.4% (95% CI: 2.4–16) (median DOCR = 8.3 months). The median overall survival (OS) was 7.2 months for patients treated with Venclexta plus LDAC, compared with 4.1 months for those treated with LDAC alone (HR = 0.75; 95% CI: 0.52–1.07; p = 0.114). The OS results were not statistically significant.

It is reported that this marks the second time Venclexta has undergone review under the Real-Time Oncology Review (RTOR) and Assessment Aid pilot program established by the U.S. FDA. The RTOR pilot project explores a more efficient evaluation process, providing a framework for the simultaneous submission and review of an oncology drug by multiple regulatory agencies worldwide. For this application, Venclexta was submitted concurrently to the drug regulatory authorities in the United States, Australia, Canada, Brazil, and Switzerland. Furthermore, in the materials submitted to the U.S. FDA, Roche included updated data from an additional Phase 1/2 study on Venclexta treatment in patients with newly diagnosed acute myeloid leukemia (AML) as supporting evidence.

Venclexta (Venetoclax) Molecular Structure (Source: Wikipedia)

Venclexta is a first-in-class targeted therapy designed to selectively bind to and inhibit the B-cell lymphoma-2 (BCL-2) protein. In certain hematologic cancers and other tumors, BCL-2 prevents cancer cells from dying or undergoing self-destruction, a process known as apoptosis. The drug blocks the BCL-2 protein, helping to restore the apoptotic process. Venclexta was co-developed by AbbVie and Genentech. The two companies are jointly responsible for commercialization in the U.S. market, while AbbVie is responsible for commercialization in markets outside the United States.

In the United States, Venclexta has received five Breakthrough Therapy Designations from the U.S. FDA: one for previously untreated patients with chronic lymphocytic leukemia (CLL), two for patients with relapsed or refractory CLL, and two for previously untreated patients with acute myeloid leukemia (AML).

Reference Sources:

1. Wikipedia

2.AbbVie, Roche's Venclexta garners full FDA approval for AML

3.Genentech Announces Full FDA Approval for Venclexta Combinations for Acute Myeloid Leukemia