Basavanhally, Tara

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 (≥102.5-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 (>102.5 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.

Introduction Golcadomide (GOLCA, CC-99282) is an orally available cereblon E3 ligase modulator (CELMoD ®) that potently degrades target proteins Ikaros and Aiolos, enhancing antiproliferative, apoptotic, and immunomodulatory activity and preferentially distributing to lymphoid organs. In a phase 1 study, GOLCA monotherapy previously demonstrated a manageable safety profile with promising clinical activity in relapsed/refractory non-Hodgkin lymphoma (Michot Blood 2021). In the ongoing CC-220-DLBCL-001 study (NCT04884035), GOLCA dose finding is underway in patients with previously untreated aggressive B-cell lymphoma (BCL), in combination with R-CHOP in 21-day (D) cycles (C), at a variety of GOLCA dose levels (DLs) and schedules: DL-1 = 0.2 mg D1-7, DL1 = 0.4 mg D1-7, and DL2 = 0.4 mg D1-10. Here, we report Ikaros degradation, immune modulation, circulating tumor DNA (ctDNA) assessment, and baseline tumor genomics. Methods Peripheral blood was collected to analyze Ikaros and Aiolos levels in T cells by flow cytometry (C1D1, C1D7, and C2D1). Immune phenotyping of T and natural killer (NK) cells was performed by flow cytometry (C1D1, C1D15, C2D1, and C3D1). ctDNA levels were analyzed by the PhasED-Seq assay (timepoints C1D1, C2D1, C3D1, and end of treatment [EOT]; Kurtz Nat Biotechnol 2021); somatic variants were filtered by performing PhasED-seq on buffy coats. Pretreatment biopsies were analyzed by whole genome sequencing and whole transcriptome sequencing. DL1 (0.4 mg D1-7) and DL2 (0.4 mg D1-10) data were pooled. Results Ikaros levels in T cells at 5 hours after the first dose had a 1.1% median increase with 0.2 mg and 44% median decrease with 0.4 mg; by C1D7 pretreatment, Ikaros substantially decreased with both DLs (median: 0.2 mg, 87% decrease; 0.4 mg, 83% decrease). Ikaros differences between 0.2 mg and 0.4 mg were not substantial. By C2D1, Ikaros levels recovered to baseline. Based on preclinical benchmarks, steady-state Ikaros degradation in T cells suggested that direct tumor cell killing by GOLCA was achieved. Changes in T and NK cell phenotypes in peripheral blood included activation, increased proliferation, increased T effector memory and regulatory cell levels, and decrease in naive T cells. Changes were seen by C1D15 and maintained at C2D1 and C3D1. Overall, immune changes between 0.2 mg and 0.4 mg dose levels were not substantially different. Phased variant data from ctDNA and buffy coats were evaluable for 34 patients (0.2 mg, n =15; 0.4 mg, n = 19). Baseline ctDNA levels were similar between the 0.2 mg and 0.4 mg cohorts and, consistent with prior studies, correlated with International Prognostic Index and cell of origin. Previously reported landmarks such as early molecular response (EMR; ≥ 2 log decrease) at C2D1 and major molecular response (MMR; ≥ 2.5 log decrease) at C3D1 were assessed (Kurtz J Clin Oncol 2018) . A high fraction of patients designated high risk by pretreatment ctDNA (≥ 2.5 log haploid genome equivalents [HGE]/mL; Kurtz J Clin Oncol 2018) were clinical responders. Patients who achieved minimal residual disease (MRD) negativity on treatment generally remained MRD negative at subsequent timepoints. At C2D1, the EMR and MRD negativity rates for 0.2 mg were 73% (11/15) and 20% (3/15), respectively; for 0.4 mg these rates were 83% (15/18) and 44% (8/18). At C3D1, the MMR and MRD negativity rates for 0.2 mg were 83% (10/12) and 42% (5/12), respectively; for 0.4 mg these were 83% (10/12) and 58% (7/12). Although ctDNA differences between 0.2 mg and 0.4 mg were not substantial, numerically greater ctDNA changes were seen with 0.4 mg GOLCA + R-CHOP vs 0.2 mg GOLCA + R-CHOP and vs R-CHOP and R-CHOP-like regimens from other cohorts ( Figure). Insufficient samples were available to draw conclusions about EOT, but additional ctDNA data will be presented. Whole genome and transcriptome sequencing data from GOLCA + R-CHOP-treated patients will be shown. Conclusions Pharmacodynamic biomarkers and ctDNA levels indicate that both tumor-intrinsic and immune-modulating mechanisms of action of GOLCA remain relevant in combination with R-CHOP in previously untreated aggressive BCL. ctDNA data during treatment are consistent with the efficacy noted on clinical restaging. Translational data demonstrate the potency of GOLCA and will support future frontline clinical trial designs in patients with untreated aggressive BCL. Study support: Celgene, a Bristol-Myers Squibb Company