Subject terms
tumor, tumors, RAS-mutant unresectable, CRC
METASTATIC COLORECTAL CANCER, SECONDARY, TUMORS, TUMOR
Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2–96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9–8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial–mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab–tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: Treatment with anti-PDL1 and anti-CTLA4 in combination with mFOLFOX6 chemotherapy for patients with treatment-naive microsatellite stable metastatic colorectal cancer is safe, shows encouraging progression-free survival and induces a tumor-specific immune response.