Pivotal phase III VERONA trial results presented at the American Society of Hematology annual meeting show no overall survival improvement, but potential for sub-group benefit and no added side effects.
Based on a subgroup analysis of the phase III VERONA trial data, treatment with venetoclax, a BCL-2 inhibitor, plus azacitidine showed no differences in overall survival across subgroups compared to standard of care treatment with placebo plus azacitidine.
The venetoclax combination treatment did show favorable trends in overall survival among patients under age 75 and patients with excess blasts, which are immature blood cells in the bone marrow, according to Dana-Farber Cancer Institute’s Dr. Jacqueline S. Garcia, principal investigator on the study.
Although there were significantly higher rates of overall response (a combined measure of complete remission, partial remission, and marrow complete response) and blood and platelet transfusion independence on venetoclax combination compared to azacitidine alone, subgroup analysis showed positive trends toward higher overall responses that did not meet significance with the venetoclax combination compared to placebo plus azacitidine across multiple subgroups including those 18-74 years, with excess blasts, with higher cytogenetic risks, and with mutations in ASXL1, TP53, and RUNX1. Marrow complete response with hematologic improvement also trended higher in those subgroups with the venetoclax combination. Additional analyses are planned.
Jacqueline Garcia, MD
The findings were presented by first author Dr. Guillermo Garcia-Manero of University of Texas MD Anderson Cancer Center at the 67th American Society for Hematology Annual Meeting and Exposition on December 6 in Orlando, FL.
“While we have observed trends suggesting that the study treatment might have been better for certain subgroups, there aren’t enough patients in each subgroup to make a conclusion,” says senior author Garcia, a medical oncologist at Dana-Farber Cancer Institute. “However, the venetoclax plus azacitidine treatment did not cause new unexpected or excess toxicities including febrile neutropenia (23% vs 16%).”
Standard of care for patients with high-risk MDS has been treatment with azacitidine (in intravenous or subcutaneous formulations) or decitabine (in intravenous or oral formulations) for the past two decades. Based on real world observations, survival with this treatment regimen is approximately 16 to 17 months.
“There’s been a real urgency to think about adding to that treatment to extend survival for these patients especially if a stem cell transplant is not an option,” says Garcia.
Research from the Dana-Farber lab of Dr. Anthony Letai, now director of the National Cancer Institute, contributed to the development of BCL-2 inhibitors and the rationale to combine venetoclax with azacitidine in MDS. Based on that rationale, Garcia led a phase 1b trial investigating treatment of newly diagnosed patients with high-risk MDS with venetoclax plus azacitidine.
That trial showed promising results and provided the foundation for this phase III VERONA trial. The VERONA trial randomized 500 patients with intermediate, high or very high risk MDS from around the world who had not yet received treatment. However, while the phase 1b trial primarily enrolled patients with high or very high-risk disease (86%) and excess blasts (90%), the VERONA trial included patients with intermediate risk-MDS (28%) or without excess blasts (27%).
“In the VERONA trial, it is possible that signals of an improved benefit in patients with high-risk disease, those patients who really need escalated treatment, could be buried by responses in patients with intermediate disease who would have done well on either regimen,” says Garcia. “Future MDS trials need to be designed to focus on the patient sub-groups that stand to benefit most.”
Importantly, combination therapy with venetoclax was very similar to that of azacitidine alone and did not prevent or delay patients who were eligible from receiving stem cell transplantation, and transplant is the recommended therapy for eligible patients with higher risk MDS. Overall, regardless of the treatment received, patients who later received a stem cell transplant had better survival.
Post-study stem cell transplant was received by 17% of patients who received venetoclax plus azacitidine at a median of 5.6 months, and 13% of patients who received placebo plus azacitidine at a median of 6.7 months. Prior to stem cell transplant, 25.6% of patients on the venetoclax treatment had a complete response, 60.5% had a marrow complete response, and 14% had stable disease compared to 27.3%, 33.3%, and 39.4%, respectively, on the placebo plus azacitidine regimen.
“Our analysis is still ongoing,” says Garcia. “We would really like to understand more about the patients who had better responses. However, combination therapy with venetoclax does not blanketly replace the standard of care for all patients with intermediate or higher risk MDS. Further, additional studies including real-world or retrospective studies may fill these gaps in patient numbers to identify sub-groups and we look forward to seeing what is presented at this year’s ASH to complement this randomized trial.”
Funding for this research was provided by AbbVie, Inc.