Abstract Background: Patients with HR MDS face poor prognosis and are often ineligible for hematopoietic cell transplantation (HCT). After encouraging safety and efficacy in a phase 1b study (Garcia Blood 2025), Ven+Aza was evaluated against Pbo+Aza in patients with treatment-naïve HR MDS in the randomized, phase 3 VERONA study (NCT04401748). Primary analysis at 41.2 months median follow-up showed no difference in overall survival (OS) with Ven+Aza (22.18 mo) vs Pbo+Aza (21.68 mo; HR=0.908 95% CI, 0.733–1.126; P=.38), but modified overall response (mOR) was higher with Ven+Aza vs Pbo+Aza (76.2% vs 57.7%; nominal P.0001; Garcia-Manero SOHO 2025). Here, we present additional outcomes and pre-planned subgroup analyses from VERONA with the aim of identifying patient subsets that may have received clinical benefit from Ven+Aza. Methods: VERONA enrolled patients aged ≥18 years with a diagnosis of MDS (WHO 2016), Revised International Prognostic Scoring System (IPSS-R) score 3 (intermediate, high, very high), ECOG PS 0–2, not immediately SCT eligible, and had no prior MDS therapy and no therapy-related MDS. Patients were randomized 1:1 to receive oral Ven 400 mg or Pbo once daily on Days 1–14 combined with IV or SC Aza 75 mg/m2 for 7 days in each 28-day cycle. Primary endpoint was OS. Patients were stratified by IPSS-R risk (very high, high, intermediate), region (North America, Europe, Japan, China, rest of world), and HCT eligibility. Pre-planned subgroup analyses were conducted for the primary endpoint of OS by unstratified Cox proportional hazards model and for mOR (sum of complete remission CR, partial remission, and marrow CR mCR) by risk difference. Data cutoff was 4/10/2025. Results: A total of 509 patients were randomized (Ven+Aza, n=256; Pbo+Aza, n=253) and included in efficacy analysis. Of these, 255 patients in the Ven+Aza arm and 246 in the Pbo+Aza arm received ≥1 dose of study drug and were evaluable for safety. Baseline patient and disease characteristics were well balanced between arms (Ven+Aza vs Pbo+Aza): median age 72 vs 72 years, 66% vs 59% aged 18 to 75 years, 93% vs 92% ECOG PS 0–1, 7% vs 8% ECOG PS 2, 22% vs 22% North America, 78% vs 78% outside of North America. IPSS-R risk group was very high in 36% vs 32%, high in 37% vs 39%, and intermediate in 27% vs 28%. There was a balanced distribution of poor prognostic and frequently mutated genes between study arms, including TP53 (25% vs 19%), ASXL1 (30% vs 33%), RUNX1 (15% vs 24%), and EZH2 (3% vs 6%). Reasons for treatment discontinuation (Ven+Aza, n=231 91%; Pbo+Aza, n=234 95%): HCT (16% vs 8%), progressive disease (30% vs 45%), adverse event (20% vs 15%), and patient withdrawal (14% vs 17%). Overall, Ven was used as post-study therapy in 16% of patients (Ven+Aza, n=27 11%; Pbo+Aza, n=53 21%). Rate of AML transformation was 15% with Ven+Aza vs 20% with Pbo+Aza. There were no differences in OS across subgroups, though trends favoring Ven+Aza were observed in younger patients (18 to 75 years, HR=0.835 95% CI, 0.630–1.107; ≥75 years, HR=1.160 95% CI, 0.834–1.613) and those with excess blasts (≥5% to 20% blasts, HR=0.858 95% CI, 0.676–1.090; 5% blasts, HR=1.313 95% CI, 0.795–2.169). Subgroup analysis showed patients with TP53 mutation had an HR of 1.064 (95% CI, 0.670–1.688). Post-study HCT was received by 17% of patients (43/256) in the Ven+Aza arm and 13% (33/253) in the Pbo+Aza arm at a median of 5.6 months (range, 2.9–18.1) for those treated with Ven+Aza and 6.7 months (range, 2.2–33.9) for those treated with Pbo+Aza. The best response on study treatment prior to HCT were CR 25.6%, mCR 60.5%, and stable disease (SD) 14.0% in the Ven+Aza arm and CR 27.3%, mCR 33.3%, and SD 39.4% in the Pbo+Aza arm. Additional post-study therapy was given prior to HCT in 4/43 (9%) in the Ven+Aza arm and 10/33 (30%) in the Pbo+Aza arm. Subgroup analyses showed trend toward higher mOR with Ven+Aza vs Pbo+Aza in patients 75 years and those with very high IPSS-R, 5% blasts, and mutations in ASXL1, TP53, or RUNX1. mCR with hematologic improvement (mCR+HI) was higher with Ven+Aza vs Pbo+Aza (27.3% vs 18.2%). Conclusions: VERONA did not meet the primary endpoint of OS. A higher proportion of patients treated with Ven+Aza achieved mOR, mCR+HI, and numerically lower risk of AML transformation vs those treated with Pbo+Aza. Subgroup analyses showed favorable trends in response for Ven+Aza vs Pbo+Aza in younger patients, excess blasts, and select mutations.
Garcia‐Manero et al. (Mon,) studied this question.
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