VERONA trial misses primary endpoint of OS benefit with azacitidine/venetoclax in high-risk MDS

In patients with newly diagnosed high-risk myelodysplastic syndrome (MDS), the combination of venetoclax and azacitidine did not provide an overall survival (OS) advantage compared with placebo plus azacitidine, failing to meet the primary endpoint of the phase 3 VERONA trial (NCT04401748). The hazard ratio for OS was 0.908 (stratified log-rank P=0.3772). Investigators found no new safety signals, according to the release.

The results of the VERONA trial will be announced and/or published. In addition, any patient who receives venetoclax plus azacitidine through participating VERONA will have their primary care physician informed of the trial results. Of note, these data do not affect any currently approved indications for venetoclax.

VERONA enrolled patients with MDS who were at least 18 years old according to the 2016 World Health Organization classification and who had less than 20% bone marrow blasts in each bone marrow biopsy/aspirate at screening. Patients needed to have an overall Revised International Prognostic Scoring System score greater than 3 (moderate, high, or very high); an ECOG performance status of 0 to 2; and be eligible for hematopoietic stem cell transplantation (HSCT) on study day 1 without a pre-scheduled HSCT, or without an HSCT planned on study day 1 and not eligible for HSCT.

Patients were randomly assigned to receive 75 mg/m2 of subcutaneous or intravenous azacitidine daily for 7 of the first 9 days of each 28-day cycle, and 400 mg of venetoclax or placebo orally once daily on days 1 to 14 of each cycle. Patients are scheduled to receive study treatment until disease progression, unacceptable toxicity, hematopoietic cell transplantation, withdrawal of consent, or study termination.

Secondary endpoints of the trial include modified overall response, percentage of patients achieving global hematological improvement, complete response (CR), percentage of transfusion-dependent patients at baseline achieving transfusion independence, time to worsening of physical function as measured by the physical function domain of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire scale, changes in the Patient-Reported Outcomes Measurement Information System, Fatigue Short Form 7a scale score and overall response.

Previously, one itemA phase 1b study (NCT02942290) showed that venetoclax combined with azacitidine has good efficacy and safety in untreated high-risk MDS patients. At the data cutoff point, among the 107 patients who received combination therapy, the best response of CR or myeloid CR was 29.9% (95% CI, 21.4%-39.5%) and 50.5% (95% CI), 40.6%-60.3%, respectively; the median overall response rate was 80.4% (95% CI, 71.6%-87.4%). The median OS was 26.0 months (95% CI, 18.1-51.5), and the estimated 1- and 2-year OS rates were 71.2% (95% CI, 61.4%-78.9%) and 51.3% (95% CI-41.2%-60.5%), respectively.

In addition, among patients who were red blood cell and/or platelet transfusion dependent at baseline (n=59), 40.7% (95% CI, 28.1%-54.3%) achieved transfusion independence during the study period, and 18.6% (95% CI, 9.7%-30.9%) of these patients also achieved CR. Additionally, 49.0% (95% CI - 39.1% - 59.0%) of all evaluable patients in the overall population (n = 104) achieved hematologic improvement. Excluding transplantation, the median time to next treatment was 13.4 months (95% CI, 9.7-17.7).

The safety results from this study reflect the known safety profiles of venetoclax and azacitidine. The most common adverse reactions included constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%). The VERONA trial was designed to confirm the OS benefit observed in the phase 1b trial of azacitidine plus venetoclax.

Reference materials:https://www.venclexta.com/