Efficacy and safety of molto, a multicenter, open label, phase ii clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in richter syndrome

Introduction: Chemoimmunotherapy is the standard first line treatment of diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). However, response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti-tumor immune response. MOLTO is a multicenter international phase 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 q21 cycles with obinutuzumab (1000 mg C1–8), atezolizumab (1200 mg C1–18) and venetoclax (400 mg/d C1–35). Primary endpoint was ORR ≥67% at C6. RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by 8 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: Overall 28 planned pts were enrolled from October 2019 to October 2022 (Table 1). Three were not evaluable for primary endpoint due to G5 infection (n = 1) or early withdrawn (n = 2). As per intention-to-treatment ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6% (8/28). No clinical characteristics influenced ORR at C6. After a median follow-up of 11.6 months, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS), among them 6 for ≥24 months. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response was 11.7 months, median PFS was 16.2 months and median OS 31.6 months. Out of the 13 pts who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 months. Bulky disease and ECOG PS >1 affected PFS. Rate of unmeasurable MRD and impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. A total of 43 G3–4 adverse events (AE) occurred in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs was reported in 6 pts (G3–4 in 2), none led to discontinuation. No tumor lysis was observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 years in one third of responders. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Roche Keywords: combination therapies, immunotherapy, molecular targeted therapies Conflicts of interests pertinent to the abstract A. M. Frustaci Other remuneration: Abbvie, AstraZeneca, Janssen, Beigene; advisory boards, travel grants, speaker invitations