Mosunetuzumab (Mosun) or glofitamab (Glofit) in combination with golcadomide (Golca) demonstrates a manageable safety profile and encouraging efficacy in patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL)

Abstract

Abstract Background: Mosun and Glofit, both CD20xCD3 T-cell engaging bispecific antibodies, have demonstrated high response rates and manageable safety in patients (pts) with R/R follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Golca, a CELMoDTM agent, drives the closed active conformation of cereblon inducing rapid degradation of Ikaros and Aiolos, and has shown promising efficacy and a manageable safety profile. We report preliminary safety and efficacy data from a Phase Ib study (NCT05169515) of Golca combined with Mosun (Arm 1) or Glofit (Arm 2) in pts with R/R B-NHL. Methods: Pts with R/R B-NHL (DLBCL, FL Grade [Gr]1–3a, transformed [tr]FL) received treatment for up to 12 cycles. In Arm 1, subcutaneous Mosun was given with step-up dosing in Cycle (C)1 (Day [D]1, 5mg; D8 and D15, 45mg; 21-day cycle), then 45mg on D1 of subsequent cycles (28-day cycles); concurrently, oral Golca (0.1, 0.2, or 0.4mg) was given daily from C1 or C2 onwards (D1–14; 28-day cycles). In Arm 2, pts received intravenous obinutuzumab pretreatment on C1D1 and Glofit on C1D8 (2.5mg), D15 (10mg), then D1 of subsequent cycles (30mg); oral Golca was given daily from C2 or C3 onwards (D1–10; 21-day cycles) in dose escalation (0.2 or 0.4mg). Prophylactic G-CSF was mandatory for the first cycle of combination therapy. Primary endpoints were safety including DLTs and Golca RP2D selection. Secondary endpoints included investigator-assessed overall response rate (ORR) and complete response rate (CRR; Lugano 2014 criteria). Results: As of May 5, 2025, 35 (10 DLBCL; 20 FL; 4 trFL; 1 composite FL/DLBCL) and 12 (3 DLBCL; 9 FL) pts were enrolled in Arms 1 and 2, respectively (safety-evaluable population). In Arms 1 and 2, median age was 63 (range: 30–83) and 60 years (range: 37–76), 29% and 42% of pts had prior CAR T-cell therapy, respectively. Median number of prior therapies was 3 (range: 1–6) in Arm 1 and 2 (range: 1–4) in Arm 2. Gr ≥3 AEs occurred in 74% and 67% of pts in Arms 1 and 2, respectively; there were no Gr 5 AEs. Serious AEs occurred in 66% of pts in Arm 1 and 50% of pts in Arm 2. Most common AEs in Arms 1 and 2, respectively, were neutropenia (Gr ≥3: 57% and 58%), injection site reactions (57%; all Gr 1/2 in Arm 1 only), CRS (Gr 1/2: 43% and 33%, no Gr ≥3), rash (Gr ≥3: 3% and 0%), and infections (Gr ≥3: 11% and 8%). Gr ≥3 neurological AEs occurred in 3% of pts (n=1; Gr 3 presyncope) in Arm 1 and 17% of pts (n=2; Gr 3 cognitive disorder and Gr 4 spinal cord compression) in Arm 2. ICANS as a preferred term was reported in one patient in Arm 2 (Gr 2); suspected ICANS was observed in 11% of pts (all Gr 1: cognitive disorder, n=1; lethargy, n=1; syncope, n=2) in Arm 1 and 17% of pts (Gr 3 cognitive disorder, n=1; Gr 1/2 somnolence, n=1) in Arm 2. Febrile neutropenia (FN) occurred in 11% of pts in Arm 1 and 8% of pts in Arm 2. AEs leading to treatment discontinuation occurred in 17% of pts (neutropenia, n=3; anemia, disseminated intravascular coagulation, and thrombocytopenia, n=1 each) in Arm 1 and none in Arm 2. DLTs were reported in 3 pts in Arm 1 (Golca 0.2mg, Gr 3 FN and herpes zoster; Golca 0.1mg, Gr 3 rash) and one patient in Arm 2 (Golca 0.4mg, Gr 3 FN). In efficacy-evaluable pts (Arm 1, n=27 [14 FL; 13 DLBCL/trFL]; Arm 2, n=10 [8 FL; 2 DLBCL/trFL]), responses were observed at all Golca doses in both arms. In Arm 1, the ORR and CRR were 70% and 44%, respectively. In pts with FL, the ORR and CRR were 79% and 43%, and in DLBCL/trFL, 62% and 46%, respectively. At the 0.4mg dose of Golca (n=7), 4/4 pts with FL had a CR, 2/3 pts with DLBCL/trFL had a partial response (PR). In Arm 2, the ORR and CRR were 90% and 70%, respectively. In 8 pts with FL, the ORR was 88% (7/8), CRR was 75% (6/8). Of the 2 pts with DLBCL/trFL, one had a CR, one a PR. Median time to first response was 2.6 months (range: 2–4) in Arm 1 and 1.9 months (range: 1–3) in Arm 2. Ikaros degradation in peripheral T cells was observed at 0.2 and 0.4mg doses of Golca. Conclusions: Early data suggest Mosun/Glofit+Golca is an active regimen with a manageable safety profile consistent with the risks of individual agents. No new safety signals were observed; CRS events were low grade. Neutropenia was the most common overlapping toxicity and was manageable with prophylactic and therapeutic G-CSF. ICANS as a preferred term was low grade and occurred in one patient. This novel combination therapy showed activity in heavily pretreated pts with B-NHL and warrants further investigation.