ARC-9: etrumadenant plus chemo-immunotherapie versus regorafenib bij uitgezaaid colorectaal carcinoom

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 2 ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti-PD-1 monoclonal antibody), FOLFOX, and bevacizumab (EZFB) vs 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, median survival follow-up was 20.4 months. The primary endpoint of progression-free survival was improved with EZFB (6.2 months) vs regorafenib (2.1 months; HR, 0.27 [95%CI: 0.17, 0.43]; nominal P<.0001), as was the secondary endpoint of overall survival (EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37 [95% CI: 0.22, 0.63]; nominal P = .0003). 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 (TEAEs), 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. CONCLUSION: 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 progression-free survival and overall survival.