Background: Mantle Cell Lymphoma (MCL) has no established standard of care (SOC) in the front-line (1L) setting. Recent studies - TRIANGLE1 and ECHO2 - affirmed the role of BTKi's in younger and older MCL patients (pts), respectively. The BOVEN study demonstrated impressive efficacy with the combination of BTKi, BCL2i, and anti-CD20 antibody in pts with a TP53 mutation. However, short follow-up limits applicability of this regimen, with the development of novel therapeutics still needed for patients with high-risk MCL. Given the efficacy of bispecific antibodies in patients with relapsed/refractory (R/R) MCL, and pre-clinical data showing their synergy with small molecules, we designed a phase 1/2 trial combining the cd20/cd3 bispecific antibody glofitamab (Glofit), with the BCL-2i venetoclax (ven), and the immunomodulatory drug lenalidomide (len), for 1L high-risk MCL (GLOVe).

Methods: This trial included patients with treatment-naïve MCL, who had high risk features defined as complex cytogenetics (CK; 3 or more cytogenetic abnormalities in addition to t(11:14)), TP53 mutation (mTP53), del17p, high risk MIPI, blastoid/pleomorphic variant or Ki67≥50%. Ven 50 mg started on cycle 1 day 1 (C1D1) of a 3-week cycle with weekly escalation to a target of 400 mg. Once ven 200 mg was reached, Obinutuzumab 1000 mg was given over two days (C1D15-16). Starting with C2D1, standard step-up dosing (SUD) of glofitamab was started and administered weekly x 3 to the target dose of 30 mg, concurrent with daily ven 400 mg. Thereafter Glofit is given every 3 weeks for a total of 12 cycles. On C3D8 len is started at a dose of 10 or 20 mg, based on creatinine clearance and given for 1 week with C3, and on days 1-14 of C4-C12. The first 6 patients were evaluated for a safety cohort with a DLT period that extended to C4D1. Response was measured every 3 cycles during induction per Lugano criteria and included measurable residual disease (MRD) testing by ClonoSEQ (undetectable [uMRD]<10-6).

Results: Twenty-five pts were enrolled. Median age was 65 years (range, 53-76), 11 (48%) were male, 20 (87%) were White, 5 (22%) were Hispanics, 22 (96%) had stage III/IV disease, 21 (91%) had marrow involvement, 11 (48%) had GI involvement, 10 (43%) had mTP53, 9 (39%) had del17p, 6 (26%) had both mTP53 and del17p, 4 (17%) had blastoid histology, 19 (83%) were MIPI high risk, 19 (83%) had CK, 11 (48%) had Ki67 ≥50%.

Twenty-two pts are evaluable for toxicities. Twenty pts are still on treatment. The median number of cycles received thus far was 11 (range, 2-22). Ten (45%) had required dose reduction of len during study treatment and 3 (14%) started reduced dose of len due to age and creatinine. The most common treatment-related any grade (gr) adverse events were CRS (55%), thrombocytopenia (41%), fatigue (36%), and neutropenia (36%). The most frequent treatment related gr3-4 adverse events were neutropenia (23%) and leukopenia (23%). Cytokine release syndrome (CRS) of any gr was observed in 12 (55%) of patients: 4 (18%) gr 1, 7 (32%) gr 2, and 1 (5%) gr 3. One ICANS (grade 2) was reported (resolved).

Twenty pts were evaluable for response, all had CR (100%) and 18 (95%) uMRD-6. The median time to best response was 53 days. 1 pt was inevaluable for response (death during ven escalation due to multi-organ failure that was unrelated to treatment); 4 pts are pending response assessment. No pt at the time of submission has had disease progression on study. Two deaths occurred during treatment. One patient in a CMR died due to treatment related sepsis after C3 and multi-organ failure during C1. Median follow-up among survivors was 7.1 month (range 0.7-21). The PFS and OS at 6 months was 90% (95% CI: 64%-97%). DOR at 6 months was 95% (95% CI: 68%-99%).

Conclusions: Herein we report the 1st known study to evaluate the efficacy and safety of the bispecific antibody glofit in a 1L high-risk MCL patient population. Data thus far after the completion of the 1st stage of the study indicates that CRS associated with glofit can be mitigated using targeted therapies as a debulking strategy. This is evident with the modest rates of CRS noted in the pt treated to date, with only one gr 3 event and no CRS events observed beyond SUD. Initial efficacy of this regimen is very promising with 100% CR rate and 95% uMRD-6. Median follow-up is short, the study remains open, and we will provide updated results of the study at the time of presentation.

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2025
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