The combination of golcadomide and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has shown promising antitumor activity and a manageable safety profile in patients with previously untreated aggressive B-cell lymphoma (a-BCL). Preliminary results from the phase 1b CC-220-DLBCL-001 trial, presented at the 2024 SOHO Annual Meeting, indicate high metabolic response rates and durable remissions with this novel combination.
At a median follow-up of 12.6 months, the combination of golcadomide at a 0.4-mg dose (DL1) plus R-CHOP resulted in an 88% objective response rate (ORR), with an 88% complete metabolic response (CMR) rate. The 0.2-mg dose (DL-1) achieved an 82% ORR, including a 64% CMR rate. These results suggest a potential benefit of golcadomide in improving outcomes for patients with a-BCL.
High CMR Rate Regardless of Cell of Origin
According to Dr. Jason R. Westin, Director of the Lymphoma Clinical Research Program at The University of Texas MD Anderson Cancer Center, the 0.4-mg dose of golcadomide, administered on days 1 to 7, led to a high end-of-treatment CMR rate that was independent of cell of origin. "Golcadomide plus R-CHOP demonstrates a toxicity profile that I think looks similar to R-CHOP, and golcadomide was able to be delivered at a relatively good dose intensity as was R-CHOP," Dr. Westin noted. The 0.4-mg dose showed a high durable CMR rate regardless of cell of origin, with promising 12-month progression-free survival in both the overall and high-risk groups.
Addressing Unmet Needs in DLBCL
While approximately 60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with frontline chemoimmunotherapy, a significant proportion experiences primary refractory disease or relapse. Patients with a high International Prognostic Impact (IPI) score are particularly vulnerable. Golcadomide, a first-in-class oral CELMoD agent, aims to address this unmet need by inducing selective recruitment and ubiquitination of Ikaros and Aiolos, key regulators of lymphoid development and differentiation.
Trial Design and Patient Population
The ongoing, open-label, multicenter, dose-escalation/-expansion, phase 1b CC-220-DLBCL-001 trial evaluated the safety and efficacy of frontline golcadomide combined with R-CHOP in patients with a-BCL. The trial included patients aged 18 years or older with previously untreated a-BCL, measurable lesions, an ECOG performance status of 0 to 2, and an IPI score of 0 to 5 (dose escalation) or 2 to 5 (dose expansion).
Patients received golcadomide at varying dose levels (0.2 mg or 0.4 mg on days 1 to 7, or 0.4 mg on days 1 to 10) in combination with R-CHOP every 21 days for 6 cycles. The primary endpoint was establishing the maximum tolerated dose and recommended phase 2 dose (RP2D), determined to be 0.4 mg. Secondary endpoints included ORR, CMR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Efficacy and Safety Outcomes
In high-risk patients, the 0.2-mg dose led to an 82% ORR (64% CMR, 18% PMR), while the 0.4-mg dose resulted in an 89% ORR consisting entirely of CMRs. Overall, the end-of-treatment undetectable minimal residual disease (uMRD) rates were 73% at the 0.2-mg dose and 90% at the 0.4-mg dose. In high-risk patients, these rates were 74% and 93%, respectively.
At the 0.4-mg dose, the median DOR was not reached. The 12-month DOR, PFS, and OS rates were 97%, 85%, and 91%, respectively. In the high-risk subset, the corresponding rates were 96%, 86%, and 93%.
Grade 3/4 treatment-emergent adverse effects (TEAEs) were reported in 91% and 92% of patients at the 0.2-mg and 0.4-mg dose levels, respectively. Common TEAEs included neutropenia, thrombocytopenia, anemia, and febrile neutropenia. Embolic and thrombotic events were reported in 14% of patients at the 0.2-mg dose and 8% at the 0.4-mg dose.
Ongoing Phase 3 Trial
Dr. Westin concluded that these phase 1b data support the ongoing, randomized phase 3 GOLSEEK-1 trial (NCT06356129), which is evaluating golcadomide plus R-CHOP compared with R-CHOP alone as a frontline treatment for patients with high-risk LBCL.
