Leronlimab in combination with trifluridine/tipiracil (TAS-102) plus bevacizumab for patients with refractory metastatic colorectal cancer (mCRC): The phase 2 CLOVER study.

e15525 Background: C-C chemokine receptor 5 (CCR5) is implicated in tumor progression, immune modulation, and metastatic behavior in colorectal cancer. Leronlimab (LRM) is a humanized monoclonal antibody targeting CCR5 already showing promising activity in patients with metastatic triple-negative breast cancer. The open-label phase-2 CLOVER (CCR5-targeting leronlimab with Oral chemotherapy and VEGF-inhibitor Enriched Regimen) trial evaluates the efficacy and safety of LRM in combination with TAS-102 plus bevacizumab (BEV). Methods: CLOVER (NCT06699836) plans to enroll up to 60 patients with refractory mCRC eligible for TAS-102 plus BEV and with CCR5-positive tumors by IHC. LRM will be administered weekly at 350 mg (cohort 1) or 700 mg (cohort 2) subcutaneously, with TAS-102 plus BEV at standard doses. Cohort 2 will be initiated if no LRM dose-limiting toxicities (DLTs) are seen in cohort 1. Primary objectives include safety and objective response rate per RECIST v1.1 criteria. Other evaluations include ctDNA kinetics, and PD-L1 expression on circulating tumor cells (CTCs) and cancer associated macrophage-like cells (CAMLs). Results: All pre-screened patients with evaluable archival samples met prespecified criteria for CCR5 expression (Table). As of abstract drafting 23/37 (62.2%) screened patients have been enrolled. No LRM-related DLTs have been observed at 350 mg and 700 mg LRM dosing has commenced. Among six patients with evaluable centrally assessed images all patients thus far have stable disease and remain on study treatment. All patients with available data have shown a numerical reduction in ctDNA by as early as Week 2 (Table) either paralleling or preceding clinical/biomarker improvement (CEA, CA-19-9, liver function tests). Increases in PD-L1 have been observed in CTCs and CAMLs (Table). Conclusions: In the CLOVER trial LRM in combination with TAS-102 plus BEV has been well tolerated with no LRM-related DLTs. Rapid declines in ctDNA have been observed along with stable objective responses, with most patients having baseline liver metastases and RAS-mutant. At the time of abstract submission approximately half of the target number of patients have been enrolled and at the time of presentation the trial is expected to be fully or close to fully enrolled. Observations of increases in PD-L1 on CTCs and/or CAMLs are hypothesis-generating and support investigation of immune checkpoint inhibitor strategies for patients who progress. Clinical trial information: NCT06699836 . Parameter Result CCR5 expression for all pre-screened patients: n/N (%) 64/64 (100%) Age (N=23): median (range) 51 years (31-76 years) Weight (N=23): median (range) 73.8 kg (46.2-112.9) Sex (N=23) Male n=15; female n=8 Change in tumor size: median (range) -10.2% (+12.5 to -28.4%) Change in ctDNA (N=11): median (range) -85% (-9%-99%) PD-L1 increase in CAMLs/CTCs by Week 5 (N=17) 12/17 (70.6%)