Longer Follow-up of Golcadomide (GOLCA), a Cereblon E3 Ligase Modulator (CELMoD™) Agent ± Rituximab (RTX), in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction

GOLCA is a potential first-in-class CELMoD agent for the treatment of lymphoma. GOLCA targets the proteins Ikaros and Aiolos (Ik/Ai) to produce dual immunomodulatory and anti-tumor activity, with preferential distribution to lymphoid organs. Compared to other immunomodulatory (IMiD) agents like lenalidomide, GOLCA has 10- to 100-fold enhanced antiproliferative and apoptotic activity in preclinical models of DLBCL due to greater efficiency at driving the closed active conformation of cereblon.

Pts with DLBCL frequently relapse after initial treatment with current treatment options. GOLCA was well-tolerated and effective in pts with R/R DLBCL in a 2-part, multicenter, first-in-human study with dose escalation of GOLCA monotherapy in Part A and expansion with GOLCA ± RTX in Part B (CC-99282-NHL-001; Chavez et al, ASH 2023, #4496). Here, we report long-term follow up results for GOLCA + RTX in pts with R/R DLBCL from Part B, and from the biomarker analysis population.

Methods

Pts with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible pts after ≥ 1 line of therapy were included. Following dose exploration in Part A, GOLCA was dosed at 0.2 or 0.4 mg + RTX (14 days on/14 days off schedule) in Part B Cohort C. Total duration of treatment was up to 2 years; subsequent monitoring of efficacy and safety was up to 1 year. Pharmacodynamic (PD) changes in immune-populations and Ik/Ai degradation were monitored by flow cytometry, ctDNA was analyzed by CAPP-Seq and baseline (BL) biopsies were profiled by RNA-Seq.

Results

As of May 31, 2024, 77 pts with R/R DLBCL were enrolled for GOLCA + RTX therapy. Median age was 66 years (range, 20–86) with a median of 4 prior lines of systemic anti-cancer therapy (range, 1–11); 52% had received prior chimeric antigen receptor (CAR) T cell therapy and 27% prior bispecific antibody (BiAb) therapy; 35% had achieved an objective response to their last treatment.

Twenty-three (30%) pts were ongoing, 1 completed 2 years of treatment, and 53 (69%) had discontinued treatment, mostly due to progressive disease (n = 45, 58%).

Neutropenia and anemia were the most common any grade (G) treatment emergent adverse events (TEAEs) (61% and 38% of pts, respectively). G3–4 neutropenia occurred in 18/39 (46%) pts treated at 0.2 mg vs 27/38 (71%) at 0.4 mg. Febrile neutropenia occurred in 2 (5%) pts at 0.2 mg vs 5 (13%) at 0.4 mg. G-CSF was used in 39/47 pts with neutropenia, and 4/7 pts with febrile neutropenia. One pt discontinued treatment due to G4 thrombocytopenia.G5 TEAEs occurred (1 Covid-19 infection, 1 pneumonia, 1 septic shock); only pneumonia was considered related to study treatment.

In the efficacy evaluable population (n = 65), overall response rate (ORR) and complete response (CR) were 33% and 21% at 0.2 mg (n = 33) vs 59% and 44% at 0.4 mg (n = 32). At a median follow up of 7 months (range, 3–25), median duration of response was 5.5 months (range, 1.5–23.3), including a durable response > 12 months in 5 pts. The median time to response (n = 30) was 1.7 months (range, 1.6–2.6). Reduction from BL of > 1.5 log10 mutant molecules per mL in ctDNA, observed as early as cycle 1 day 15, correlated with response to GOLCA treatment.

Degradation of Ik/Ai in peripheral T cells was dose-dependent, being faster at ≥ 0.4mg. Maximum degradation (> 90%) achieved at steady state was similar between 0.2 and 0.4 mg irrespective of RTX combination. Increased T-cell activation in peripheral blood was potentiated by combination with RTX. In all pts with DLBCL and RNA-Seq data, including GOLCA mono and + RTX in Part A and Part B, ORR was comparable between ABC (45% for 14/31) and GCB (40% for 8/20) subgroups. Similar results were observed in tumor microenvironment gene expression signature positive vs negative groups.

Conclusions

GOLCA + RTX showed a manageable safety profile with no new safety signals. Neutropenia was the most common TEAE and managed with G-CSF administration and/or dose interruption. PD data were consistent with strong GOLCA anti-tumor activity and showed differentiated activity from prior Ik/Ai targeting agents. Responses were independent of cell of origin and tumor microenvironment status. These data support GOLCA + RTX as a convenient, well-tolerated, promising regimen in pts with R/R DLBCL, including those with prior CAR T cell and BiAb therapies. This study continues to enrol in Part B with other combination partners.