Golcadomide (GOLCA) Plus R-CHOP Has High Minimal Residual Disease (MRD) Negativity across High-Risk, Untreated Aggressive B-Cell Lymphoma (a-BCL)

Introduction:

GOLCA is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent for non-Hodgkin lymphoma, purposefully designed to target Ikaros/Aiolos and have favorable pharmacokinetics, resulting in apoptotic and immunomodulatory activity with preferential distribution to lymphoid organs. CC-220-DLBCL-001 (NCT04884035) is an ongoing phase 1b, open-label, multicenter, dose-escalation/expansion trial to assess safety and preliminary 1L GOLCA + R-CHOP efficacy in a-BCL. Although longer follow-up is needed to assess durability of response, MRD negativity (MRD-) is an emerging endpoint in a-BCL. Achieving MRD- on and at end of treatment (EOT) can potentially predict clinical benefit. This study aimed to analyze circulating tumor DNA (ctDNA) kinetics of GOLCA + R-CHOP across the trial population and in defined patient (pt) segments-cell of origin (COO), high baseline ctDNA, and high-risk genomics-and to correlate MRD- with imaging and clinical outcomes.

Methods:

Eligible pts were ≥ 18 years of age with ECOG performance status ≤2, IPI 0-5 in Part 1 and 2-5 in Part 2, and untreated a-BCL with measurable disease. Pts were treated with GOLCA + R-CHOP for 6 x 21-day (D) cycles (C) or until disease progression/unacceptable toxicity/study withdrawal. Dose escalation phase GOLCA dose levels (DLs) were 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), or 0.4 mg D1-10 (DL2). During dose expansion, pts were randomized 1:1 to R-CHOP + GOLCA DL-1 or DL1. The primary endpoint was safety of GOLCA at DL1; efficacy was a secondary endpoint, ctDNA was an exploratory endpoint.

ctDNA was analyzed using the PhasED-Seq assay (<10^-6 sensitivity) at baseline, C2D1, C3D1, and EOT. MRD- was defined as the absence of detectable ctDNA on-treatment. Pretreatment biopsies were sequenced by whole genome sequencing (WGS) and whole transcriptome sequencing (WTS).

Results:

At data cutoff (June 3, 2024), the median follow-up was 14.3 months. One-year progression-free survival (PFS) was 85.3% at 0.4 mg and 77.3% at 0.2 mg. Rates of MRD- increased over time but were consistently higher at 0.4 vs 0.2 mg, with values of 44% (14/32) vs 29% (8/28) at C2D1; 63% (17/27) vs 54% (15/28) at C3D1, and 90% (26/29) vs 73% (19/26) at EOT, respectively. Interim MRD- at C3D1 strongly predicted EOT MRD-; all 0.4 mg pts and all but two 0.2 mg pts who were MRD- at C3D1 remained MRD- at EOT.

In contrast, fold-changes from baseline ctDNA were similar between 0.4 mg and 0.2 mg. The early molecular response rate (≥10²-fold drop from baseline at C2D1) was 81.2% (26/32) at 0.4 mg and 82.1% (23/28) at 0.2 mg. The major molecular response rate (≥10^2.5-fold drop from baseline at C3D1) was 88.9% (24/27) at 0.4 mg and 85.7% (24/28) at 0.2 mg.

Across genetically defined pt segments, EOT MRD- at 0.4 mg was prevalent for both COO subtypes measured by the Hans algorithm: 94% (17/18) among germinal center B-cell (GCB) and 75% (6/8) among non-GCB pts. Of the 29 pts with baseline genomics, 13 were genomically high risk: p53 mutant (VAF >0.5), DZsig and/or A7 subtype. In these pts, EOT MRD- was 80% (4/5) at 0.4 mg but only 20% (1/5) at 0.2 mg.

In high baseline ctDNA (>10^2.5 hGE/mL) pts who were high-risk for R-CHOP failure, EOT MRD- at 0.4 mg was 86.7% (13/15) vs 57.1% (8/14) at 0.2 mg. There was an association between high baseline ctDNA and lower PFS at 0.2 mg (HR, 4.56 [95% CI, 0.53-39.12]), but interestingly the association decreased at 0.4 mg (HR, 2.10 [95% CI, 0.19-23.5]).

Combining both arms, MRD- at both C3D1 and EOT trends with improved PFS (C3D1: HR, 0.73 [95% CI, 0.2114-2.523]; EOT: HR, 0.53 [95% CI, 0.1103-2.592]); longer follow-up may be required to demonstrate significance.

Conclusions:

Interim and EOT levels of MRD- were higher at 0.4 mg vs 0.2 mg GOLCA, with a one-year PFS of 85.3% vs 77.3%, respectively. Although pt numbers were small, the data suggest that 0.4 mg is efficacious in high-risk ctDNA and high-genomic risk pts, independent of COO, and support the 0.4 mg GOLCA + R-CHOP regimen in the randomized phase 3 trial GOLSEEK-1. Interim MRD- may play a role in future adaptive trial designs.

Amzallag:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Basavanhally:Bristol Myers Squibb: Current Employment. Westin:Pfizer: Consultancy; Genentech, Inc.: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Nurix: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie/GenMab: Consultancy. Hoffmann:Bristol Myers Squibb: Other: Travel; Genentech: Consultancy, Research Funding; ADC, Janssen, Pharmacyclics, BeiGene, Novartis, Astra-Zeneca, Abbvie, Kite, TG: Consultancy, Honoraria. Munoz:Pfizer: Consultancy; Targeted Oncology: Honoraria; Curio: Honoraria; OncView: Honoraria; Genzyme: Consultancy; Genentech/Roche: Consultancy, Research Funding; Fosunkite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; Janssen: Consultancy, Research Funding; Aurobindo: Consultancy; Verastem: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; MEI: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Alexion: Consultancy; BeiGene: Consultancy; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis,: Consultancy; Karyopharm: Consultancy; Kyowa: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Alexion: Consultancy; Eli Lilly: Consultancy; Bayer: Consultancy, Research Funding; Merck: Research Funding; Portola: Research Funding; Genmab: Consultancy; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria; Bayer: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding. Nowakowski:Karyopharm Therapeutics: Consultancy; Segen: Consultancy; MEI Pharma: Consultancy; Genentech: Consultancy; Selvita Inc: Consultancy; TG Therapeutics Inc: Consultancy; Fate Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie Inc.: Consultancy; Celgene Corporation: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; Ryvu Therapeutics: Consultancy; Kymera Therapeutics: Consultancy; Blueprint Medicines Corporation: Consultancy; ADC Therapeutics: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; Zai Laboratory: Consultancy; MorphoSys AG: Consultancy, Research Funding; Incyte Corporation: Consultancy; F. Hoffmann-La Roche Limited: Consultancy; Debiopharm: Consultancy; Curis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Boucaud:Bristol Myers Squibb: Current Employment. Stokes:BMS: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sudhindra:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Gandhi:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kaplan:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.