Multinational phase 2 trial of etrumadenant-based therapy versus regorafenib for previously treated metastatic colorectal cancer

Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated metastatic colorectal cancer (mCRC). Cohort B of the multinational randomized phase 2 ARC-9 study evaluated the combination of etrumadenant (A2a and A2b receptor antagonist) with zimberelimab (anti-PD-1 monoclonal antibody), FOLFOX, and bevacizumab (EZFB) versus regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens. Patients were randomized 2:1 to EZFB (n=75) or regorafenib (n=37). At data cutoff, median survival follow-up was 20.4 months. The primary endpoint of progression-free survival was improved with EZFB versus regorafenib (median 6.2 versus 2.1 months; HR 0.27; nominal p<0.0001), as was the secondary endpoint of overall survival (median 19.1 versus 9.5 months; HR 0.37; nominal p= 0.0003). Treatment-emergent adverse events, grade ≥ 3 TEAEs, and TEAEs leading to discontinuation were reported for 99%, 82%, and 5% of the EZFB patients and 87%, 49%, and 17% of the regorafenib patients, respectively. The authors conclude that EZFB significantly improved survival outcomes compared with regorafenib in patients with third-line mCRC, with a manageable safety profile.