Regorafenib plus avelumab in macrophage-low microsatellite-stable colorectal cancer: A prospective study

Background: Microsatellite-stable (MSS) colorectal cancer (CRC) is largely refractory to immune checkpoint blockade. Regorafenib can remodel the tumor microenvironment and may synergize with PD‑L1 blockade. In the phase II REGOMUNE trial (cohort A, NCT03475953), regorafenib plus avelumab showed modest activity in unselected chemorefractory MSS CRC , but an exploratory biomarker analysis suggested that low baseline tumor-associated macrophage (TAM) infiltration was associated with clinical benefit (Cousin et al Clin Cancer Research 2021). We prospectively evaluated TAM-based enrichment in a new dedicated cohort (A′). Methods: REGOMUNE A′ is a multicenter, single‑arm, phase II study enrolling patients with chemorefractory MSS CRC selected for low macrophage infiltration on baseline tumor tissue by centralized multiplex immunofluorescence. Patients received regorafenib 80 mg once daily (3 weeks on/1 week off) plus avelumab 10 mg/kg every 2 weeks. The primary endpoint was the 4‑month progression‑free rate (PFR) by central radiology review. An exploratory pooled analysis compared outcomes in macrophage‑low tumors (cohorts A + A′) versus macrophage‑high tumors (cohort A) among patients with available macrophage quantification. Results: From 2021 to 2024, 851 patients were screened to enroll 32 patients with macrophage‑low MSS CRC; 28 were eligible and assessable for efficacy. The 4‑month PFR was 32.1% (90% CI 17.9-49.4), exceeding the prespecified 20% activity threshold. Best overall response was 2 confirmed partial responses (7.1%); disease control rate was 46.4% (90% CI 30.4-63.0). Median PFS was 1.8 months (95% CI 1.7-4.6; local assessment) and median OS was 14.1 months (95% CI 9.9-21.8) with a median follow‑up of 15.7 months. Treatment‑related grade 3-4 adverse events occurred in 11/32 patients (34.4%); the most common grade ≥3 events were palmar‑plantar erythrodysesthesia (4/32, 12.5%) and hypertension (2/32, 6.3%). Two grade 5 treatment‑related events were reported (6.3%). In the pooled macrophage analysis (n=50 patients enrolled in cohorts A and A' with macrophage data), macrophage‑low tumors had higher 4‑month PFR (31.8% vs 0.0%), longer median PFS (3.5 vs 1.9 months; local assessment), and longer median OS (14.1 vs 4.6 months) than macrophage‑high tumors. Among patients with liver metastases (n=34), macrophage‑low remained associated with improved OS (10.9 vs 4.6 months) and 4‑month PFR (21.4% vs 0.0%). Conclusions: Prospective selection for low TAM infiltration is feasible and enriches for patients deriving benefit from regorafenib plus avelumab in MSS CRC. These pooled data strengthen TAM density as a predictive biomarker for TKI + PD‑L1 combinations and support biomarker‑driven trials with randomized validation in MSS CRC. Trial registration: NCT03475953