Subgroup analyses from the randomized, Phase 3 VERONA study of venetoclax with azacitidine (Ven+Aza) versus placebo with azacititine (Pbo+Aza) in patients with treatment-naive, intermediate and higher-risk Myelodysplastic Syndromes (HR-MDS)
In the VielEA clinical trial that led to the approval of azoytidine and the selective oral BCL-2 inhibitor phennetalax for the treatment of patients with newly diagnosed AML or acute myeloid leukemia ineligible for intensive chemo, um, it taught us that the combination approach might be a way to help to improve responses and survival. We next confirmed this regimen or combination. Um, in terms of safety and dosing in a separate higher risk myelodysplastic syndrome or MDS clinical trial in the phase 1B setting, and this was a global study that we've gone on to publish. In that trial, we showed promising overall survival, excellent safety, and patients who were maybe 85 to 90% were high and very high risk by IPSSR classification. And the majority had greater than 5% blasts or had higher risk MDS. Based on the AML and then this high risk phase 1B study, it led us to develop the Verona study, which was a global phase 3 trial for patients with intermediate and high risk. Myelodysplastic syndrome who are randomized 1 to 1 to azacytin plus veneta clocks for 14 days, that's the study arm versus azoytine plus placebo, and this occurred with about 509 patients. The primary endpoint of the study was overall survival. After a 41 month follow up, unfortunately we did not meet the primary endpoint of overall survival with a 22 months versus 21, 21 month overall survival in both arms. Here at AS we presented additional subgroup analysis to try to see if there was a signal of benefit. What did we find? We found that with the study treatment or Vennetoclex combination, there was a numerically lower rate of AML transformation, 15% versus 20%. We saw an overall response rate that was higher with CR plus PR plus marrow CR with study treatment. We saw a statistically significant higher transfusion or blood and platelet. Independence compared to the standard of care arm and a trend towards higher hematologic improvement. However, one of the issues with this trial is that the core was not overall high risk. 28% were intermediate risk. Nearly 20% had less than 5% blasts, and 20% on the azoytine placebo arm. Uh, ultimately received Vennetalax off trial since it's available in some countries. Essentially it was almost like a crossover which was not provided on the clinical trial, but a therapy that was provided to the patients who needed therapies. Um, and further, twice as many patients had azacytidine dose reduction in the study arm, nearly 49%, compared to azathytine plus placebo, 27%, which led us to the question of maybe we underdoseed the azacytidine in the combination. So between these these variables, it asked us whether or not we would be able to tease out a signal among subgroups knowing that there was more heterogeneity in this population than we had wanted. Um, so here at ASH we show that in the subgroup analysis there were overall trends towards a response benefit, overall response benefit with the study treatment across the majority of the subgroups under study, from issues such as age, greater than 5% blast, to higher risk disease and the presence of mutations that are common like ASXO1 and Run-X1. However, none were significant. Importantly, further subgroup analysis based on overall survival also showed only trends, none significant, for a study arm versus azo citing plus placebo. It is worthwhile to note that in the group that we thought might have benefited the most but was underpowered on this study, Uh, because of the nature of the trial enrolling intermediate plus higher risk patients, we found that for patients with excess blasts over 5%, the hazard ratio was 0.83, uh, favoring the study arm, and the hazard ratio was 0.88 for those with greater than 10% blasts, again favoring the study arm, but the hazard ratio range overall crossed one. And thus likely because the study was underpowered for these subgroups of interest, we were unable to show a benefit, and I think this is one of the challenges to try and interpret the study. Now numerically, more went to transplant, and the time to transplant was sooner on the study arm. Sir, what are some surprises? Well, we, we enrolled, as I mentioned, patients that didn't have excess blasts and patients who are intermediate risk who might not have needed more therapy other than azacytidine. Only 15% overall went to transplant, although this is now the standard of care is to get our patients a transplant as soon as possible. In a really great way, we found that the combination of venetalax did not cause excess toxicities, no new toxicities, and things that are important that people are worried about is with combination febrile neutropenia was only 23% with the venetalax combo and 16% with azocity alone, so not too much difference. And importantly, there was a low rate of disease progression on study overall. So what's the immediate or future impact on patient and standard of care? Well, we have been eagerly waiting for the results of this trial, and I think that we can at least conclude that Venetta Clock's combination is not meant for all patients with MDS, should not be given blanketly. However, we do need further analysis on what happened for those that went to transplant. And we do need to take a look when we compile data from this perspective trial, plus other real world data which will also be presented at Ash for groups of interest, including those with excess blasts or those that have the MDS AML classification with greater than 10% blasts who behave more like AML than they do like MDS. So in terms of next steps for us, I think we are taking a close look at what the appropriate endpoints are for high risk MDS, who are the subgroups that should be studied based on the type of drug that is under consideration, and we should also keep in mind that MDS is not like AML. And so consideration of novel therapies for this particular disease is extremely important.
