Ibrutinib, venetoclax plus CD20 monoclonal Ab: Initial results of OASIS II, a prospective randomized phase 2 trial in previously untreated mantle cell lymphoma patients.

7044 Background: Ibrutinib is approved in R/R MCL. Enrich trial (Lewis, ASH 2024, abst 235) showed that Ibrutnib/CD20mAb outperforms chemotherapy front-line. We demonstrated that Ibrutnib/CD20mAb plus Venetoclax has a good safety profile in R/R and untreated MCL (Le Gouill, Blood 2021). Whether or not Ibrutnib/CD20mAb is superior to Ibrutnib/CD20/Venetoclax front-line is a key question. OASIS 2 (NCT04802590) is a phase 2 prospective randomized international trial that investigates Ibrutinib/CD20mAb (Arm A) plus Venetoclax (Arm B) in untreated MCL. Methods: Patients were stratified by country, age (< / >=66 years) and MIPI. All patients (18-80y) with untreated MCL, stage II-IV and nodal disease were eligible. Treatment consisted of Ibrutinib (560 mg/d, C1-24) and anti-CD20mAb (C1-6), then 2 monthly (C7-42). In Arm B, Venetoclax was added for a fixed duration of 2y (400 mg/d). The study uses a two-stage Simon’s design. A preplanned interim futility analysis occurred after 39 pts with informative MRD were randomized in each arm. The primary endpoint of the futility analysis is the measurable residual disease (MRD) negativity rate assessed by digital-droplet PCR technique at the end of C6. Each treatment arm was to be considered effective if the 80% upper CI MRD negativity percentage was ≥ 64%. The interim analysis result was mandatory to re-open the trial (only for effective arms) for the second phase of recruitment. Herein, we present the results of the futility pre-planed interim analysis. Results: 102 pts were randomized (51 in each arm, 78 were MRD informative). Pts’ characteristics were comparable between the two arms. One patient in arm B withdrew consent before any treatment. 46 in arm A and 45 in arm B completed the first 6 cycles. The median dose intensity for CD20mAb was 100%, 96% for Ibrutinib in arm A and 90% in Arm B, 91% for Venetoclax. At least one dose adjustment of Ibrutinib was more frequent in Arm B (28% vs 15.7%). At least one Venetoclax dose reduction was needed in 24% of patients in Arm B. AE, AESI, AE grade ≥ 3 were more frequent in Arm B (92% vs 82.4%; 82% vs 52.9%; 64% vs 47.1%) but not for SAE grade ≥ 3 (32% vs 31.4%). The most frequent grade 3 AE was neutropenia (11.8% vs 34%). MRD negativity was obtained in 53.8% (CI 80% 42.4% - 65%) in Arm A and 82.1% (CI 80% 71.7% - 89.7%) in Arm B. According to Lugano criteria at the end of C6, 21 out of 39 (54%) pts were in a complete metabolic remission in Arm A vs 27 out of 39 (69%) in Arm B. The export in Oct 2024 showed that the 2-y PFS and OS were 87.9% (95%CI, 79.7-92.9) and 91.9% (95%CI, 84.5-95.9). Conclusions: Ibrutinib/CD20mAb /Venetoclax frontline provides very high MRD negativity rate. According to the statistical analysis plan, both arms were thus re-opened for inclusion on 02APR24 and 102 new patients have been included (end of inclusion DEC 2024). Clinical trial information: NCT04802590 .