Frontline Golcadomide/R-CHOP Shows Potent Antitumor Activity in Aggressive B-Cell Lymphoma

Jason R. Westin, MD

Golcadomide at a 0.4-mg dose combined with rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) delivered high, durable metabolic response rates with a tolerable profile in patients with previously untreated aggressive B-cell lymphoma (a-BCL), according to preliminary findings from the phase 1b CC-220-DLBCL-001 trial (NCT044484035) that were presented during the 2024 SOHO Annual Meeting.¹

At a median follow-up of 12.6 months (range, 0.7-22.4) in the overall study population, results showed that the combination led to an 82% objective response rate (ORR) when golcadomide was given at the 0.2-mg dose (DL-1; n = 33) vs 88% when it was given at a 0.4-mg dose (DL1; n = 33). The DL-1 ORR comprised a 64% complete metabolic response (CMR) rate and an 18% partial metabolic response (PMR) rate; there was a 3% stable disease (SD) rate and 15% of patients had progressive disease (PD). Within the DL1 ORR, the CMR was 88%; the PD rate was 6% and data were missing for 6% of patients.

Lead study author Jason R. Westin, MD, director of the Lymphoma Clinical Research Program and section chief of the Aggressive Lymphoma research team, in the Department of Lymphoma and Myeloma, of The University of Texas MD Anderson Cancer Center in Houston, said in an oral presentation of the data that the DL1 dose, given on days 1 to 7, resulted in 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 [with a] good dose intensity,” Westin explained. “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.”

Approximately 60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured of their disease with frontline chemoimmunotherapy. However, Westin noted that up to 40% will either have primary refractory disease or will relapse after their initial response to therapy. Those who have a high International Prognostic Impact (IPI) score are more likely to experience disease progression or death. Prior data have demonstrated that a high-risk DLBCL subset includes those who have an IPI score of 1 to 2, along with very high lactate dehydrogenase levels (≥1.3 x upper limit of normal) or bulky disease (single lesion of ≥7 cm maximum diameter).²

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Golcadomide is a first-in-class oral CELMoD agent that degrades target proteins with a design to produce dual immunomodulatory and cell-killing antitumor activity. The agent directly binds to the CRL4CRBN E3 ubiquitin ligase substrate receptor cereblon and induces selective recruitment and ubiquitination of Ikaros and Aiolos, which are key regulators of lymphoid development and differentiation. Westin added that golcadomide is more efficient than lenalidomide (Revlimid) at driving conformation.

Golcadomide previously showed high rates of end-of-treatment CMR and undetectable minimal residual disease (uMRD) in those with treatment-naive disease, but longer follow-up is needed, according to Westin.³

In the ongoing, open-label, multicenter, dose-escalation/-expansion, phase 1b CC-220-DLBCL-001 trial, investigators assessed the preliminary efficacy and safety of frontline golcadomide combined with R-CHOP in patients with a-BCL. In the data presented at the 2024 SOHO Annual Meeting, Westin reported both safety and 1-year efficacy data from the dose-escalation and -expansion phases.

To be eligible for enrollment, patients had to be at least 18 years old with previously untreated a-BCL, have a measurable lesion of at least 1.5 cm on CT/MRI, an ECOG performance status of 0 to 2, and have an IPI score of 0 to 5 (dose escalation; part 1) or 2 to 5 (dose expansion; part 2).

In part 1, golcadomide was combined with R-CHOP, which was administered every 21 days. Golcadomide was administered at the following dose levels: 0.2 mg on days 1 to 7 (DL-1), 0.4 mg on days 1 to 7 (DL1), and 0.4 mg on days 1 to 10 (DL2). In part 2, patients were randomized 1:1 to receive golcadomide at DL-1 plus R-CHOP or golcadomide at DL1 plus R-CHOP. Patients were treated for 6 cycles until disease progression, unacceptable toxicity, study withdrawal, or physician discretion.

The primary end point in part 1 of the trial is establishing the maximum tolerated dose and recommended phase 2 dose (RP2D); in part 2, the primary end point is safety and tolerability at the RP2D, which was determined to be DL1. Secondary outcome measures included best ORR, CMR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory end points include assessment of pharmacokinetic and pharmacodynamic biomarkers.

The safety and efficacy data cutoff dates were October 10, 2023, and March 26, 2024, respectively.

Regarding baseline characteristics in the DL-1 (n = 35) and DL1 dose cohorts (n = 37), the median age was 62.0 years (interquartile range [IQr], 52.0-69.0) and 63.0 years (IQR, 53.0-69.0), respectively, and 34% and 54% of patients were female. At enrollment, patients’ IPI scores were low and low-intermediate risk (0-2; 37% vs 30%), low-intermediate (1-2) with high-risk disease (23% vs 11%), high-intermediate risk (3; 46% vs 43%), and high-risk (4-5; 17% vs 27%). Eighty-six percent and 81% of patients, respectively, had high-risk disease. The cell of origin was germinal B-cell (GCB; 51% vs 49%), activated B-cell–like (ABC)/non-GCB (34% vs 32%), or other (14% vs 19%). Most patients had DLBCL not otherwise specified (NOS; 80% vs 87%), followed by grade 3b follicular lymphoma (11% vs 3%), double-hit lymphoma (6% vs 8%), Epstein-Barr virus–positive DLBCL NOS (3% vs 0%), and ALK-positive large B-cell lymphoma (LBCL; 0% vs 3%).

Additional efficacy data showed that, in high-risk patients, the 0.2-mg dose (n = 28) led to an 82% ORR, comprising a 64% CMR rate and an 18% PMR rate; 18% of patients had SD. At the DL1 level (n = 28), the ORR was 89%, consisting entirely of CMRs; 7% and 4% of patients had PD and missing data, respectively.

Of patients in the GCB subset who were treated with golcadomide at the 0.2-mg dose (n = 17), the ORR was 71%, comprising a 53% CMR and an 18% PMR; 29% of patients had PD. At DL1 (n = 17), the ORR was 94% and consisted of all CMRs; the PD rate was 6%. In the ABC/non-GCB cohort of patients who received golcadomide at 0.2 mg (n = 11), the ORR was 91% and consisted of a 73% CMR rate and an 18% PMR rate; 9% of patients had SD. For those who received treatment at DL1 (n = 11), the ORR was 82% and comprised all CMRs; 18% of patients had missing data.

Overall, the end-of-treatment uMRD rates, assessed through phased variant enrichment and detection sequencing, were 73% at DL-1 vs 90% at DL1. In patients whose IPI scores were between 3 and 5, these rates were 65% and 91%, respectively; in all high-risk patients, these rates were 74% and 93%, respectively.

Treatment response was evaluated in the safety population at the DL1 dose (n = 37) and in high-risk patients at DL1 (n = 31). In the former group, the median DOR was not reached (NR); the 12-month DOR, 12-month PFS, and 12-month OS rates were 97%, 85%, and 91%, respectively. In the high-risk subset, the median DOR was also NR; the 12-month DOR, 12-month PFS, and 12-month OS rates were 96%, 86%, and 93%, respectively.

Regarding safety, grade 3/4 treatment-emergent adverse effects (TEAEs) were reported in 91% and 92% of patients at the DL-1 and DL1 dose levels, respectively. Blood and lymphatic disorders occurred in 91% and 89% of patients, respectively, consisting of neutropenia (86% vs 89%), thrombocytopenia (20% vs 59%), anemia (20% vs 41%), and febrile neutropenia (20% vs 24%). Incidence of infections and infestations were similar, occurring in 20% of patients at DL-1 and 19% at DL1; pneumonia was reported in 9% and 8% of patients, respectively. Nervous system disorders were experienced in 6% and 8% of patients; syncope was observed in 3% and 5% of patients. Gastrointestinal disorders occurred in 9% and 14% of patients and comprised diarrhea (6% vs 8%) and vomiting (0% vs 8%). Embolic and thrombotic events were reported in 14% of patients at DL-1 and 8% of those at DL1.

At DL-1, the median relative dose intensity with golcadomide, cyclophosphamide, doxorubicin, and vincristine were 98%, 98%, 99%, and 93%; in the DL1 cohort, these rates were 97%, 99%, 99%, and 99%, respectively.

Westin also reported that the neutrophil nadir and recovery occurred in a “predictable fashion,” as 3% of patients had an absolute neutrophil count of less than 1000 by the start of their next cycle of treatment. “Very few patients had a delayed recovery of neutrophil count prior to the next cycle, so although it is a known toxicity of golcadomide, it is one that didn’t lead to a lot of infections and is able to recover prior to the next cycle of therapy,” he added.

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.

REFERENCES:

1. Westin JR, Hoffman MS, Vassilakopoulos TP, et al. ABCL-503: golcadomide (GOLCA; CC-99282), a potential first-in-class oral CELMoD™ agent, with R-CHOP, as first-line (1L) therapy in aggressive B-cell lymphoma (a-BCL): safety and efficacy in an open-label, multicenter, phase 1b trial. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, TX. ABCL-503.

2. Maurer MJ, Khurana A, Farooq U, et al. The presence of bulky disease and/or very high LDH defines a high-risk subset of IPI 1-2 for eligibility in clinical trials of newly diagnosed aggressive B-cell lymphoma. Blood. 2023;142(suppl 1):4512. doi:10.1182/blood-2023-187350

3. Hoffman MS, Munoz JL, Westin J, et al. Golcadomide (GOLCA; CC-99282), a novel CELMoD agent, plus R-CHOP in patients (pts) with previously untreated aggressive B-cell lymphoma (a-BCL): safety and efficacy results from phase 1b dose expansion.Blood. 2023;4459. doi:10.1182/blood-2023-174242