The Randomized Phase II ARC-9 Study of Etrumadenant-Based Therapy versus Regorafenib in Patients with Previously Treated Metastatic Colorectal Cancer

PURPOSE: Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited. PATIENTS AND METHODS: The phase II ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti-PD-1 mAb), FOLFOX, and bevacizumab (EZFB) versus regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens. RESULTS: From September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n = 75) or regorafenib (n = 37). As of November 13, 2023, the median survival follow-up was 20.4 months. The primary endpoint of progression-free survival (PFS) was improved with EZFB (6.2 months) versus regorafenib [2.1 months; hazard ratio (HR), 0.27; 95% confidence interval (CI), 0.17-0.43; nominal P < 0.0001], as was the secondary endpoint of overall survival (OS; EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37; 95% CI, 0.22-0.63; nominal P = 0.0003). The confirmed overall response rate was 17% (90% CI, 10.6%-26.1%) with EZFB and 3% (90% CI, 0.1%-12.2%) with regorafenib. Treatment-emergent adverse events (TEAE), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm and in 87%, 49%, and 17% of the regorafenib arm, respectively. CONCLUSIONS: EZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in PFS and OS.