Despite standard 1L chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP), up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) relapse or develop refractory disease. High-risk features include an International Prognostic Index (IPI) score of 3 to 5, an IPI of 1 to 2 with bulky disease (approximately 7 cm), or elevated lactate dehydrogenase (>1.3×ULN). Golcadomide (Golca) is a novel, oral CELMoD with preferential lymphoid tissue distribution and enhanced activity in lymphoma models, inducing degradation of Ikaros and Aiolos to drive both tumor cell death and immune modulation. Encouraging activity has been observed with Golca plus R-CHOP, including a ≥90% minimal residual disease (MRD) negativity rate and durable progression-free survival (PFS). This phase 1B study evaluates Golca combined with Pola-R-CHP (NCT04884035).

Adults with newly diagnosed aggressive B-cell lymphoma, an ECOG Performance Status of ≤2, and measurable disease were enrolled. Patients received Golca plus Pola-R-CHP for 6 21-day cycles. Dose escalation evaluated Golca 0.2 mg and 0.4 mg (days 1-7), followed by dose expansion with 1:1 randomization to each dose. The primary endpoint was safety; secondary endpoints included response and durability. Patients had an IPI of 0 to 5 (dose escalation) or 2 to 5 (dose expansion).

As of September 15, 2025, 57 patients were treated (0.2 mg, n=28; 0.4 mg, n=29). Median age was 63 years; 86% had high-risk disease; and 84% had DLBCL not otherwise specified. Among evaluable patients, 47% had a germinal center B-cell (GCB) subtype and 39% had a non-GCB subtype. Most patients (83%) completed treatment. Grade 3/4 treatment-emergent adverse events were primarily hematologic and predictable, with neutropenia representing an on-target effect (grade 3/4 neutropenia occurred in 89% of patients receiving Golca 0.2 mg and 83% receiving 0.4 mg), and grade 3/4 anemia occurred in 43% and 35% of patients, respectively. Events were manageable, the addition of Golca did not compromise chemotherapy delivery, and up to 99% dose intensity was maintained.

At a median follow-up of 15.5 months, efficacy outcomes were favorable. End-of-treatment complete metabolic response (CMR) rates were 69% with Golca 0.2 mg and 89% with Golca 0.4 mg, with high rates also seen in high-risk populations (65% at 0.2 mg and 88% at 0.4 mg), and irrespective of cell-of-origin. Twelve-month duration of response was approximately 92% and 96%, and PFS was approximately 88% and 96% with Golca 0.2 and 0.4 mg, respectively; 12-month overall survival was approximately 92% and 100%. MRD analysis using circulating tumor DNA (ctDNA) and PhasED-Seq showed high rates of negativity at end of treatment—65% at 0.2 mg and 83% at 0.4 mg among evaluable patients. ctDNA levels declined by end of treatment with both Golca doses, with a greater reduction at 0.4 mg. MRD negativity was higher with Golca 0.4 mg plus Pola-R-CHP (83% vs 65% with the 0.2-mg dose) and correlated with the CMR.

Golca combined with Pola-R-CHP demonstrated a manageable and predictable safety profile without compromising chemotherapy dose intensity. The 0.4-mg dose showed high and durable response rates, deep remissions (including MRD negativity), and promising 12-month PFS and OS, with results consistent across overall and high-risk populations. These findings support the potential of Golca to improve frontline outcomes in high-risk, aggressive B-cell lymphoma and further validate its evaluation in ongoing phase 3 studies.

Source: Hoffmann MS, et al. Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD, + Pola-RCHP in patients (pts) with newly diagnosed aggressive B-cell lymphoma (a-BCL): safety and 12-month (mo) efficacy results. Presented at: ASCO Annual Meeting. May 29-June 2, 2026; Chicago, IL. Abstract 7011.