Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, ± rituximab (R) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Phase 1/2 study extended follow-up Results

Abstract

Abstract Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.