Etrumadenant-Based Chemoimmunotherapy Improves Survival in Metastatic Colorectal Cancer
Key Clinical Summary:
- Design/Population: Cohort B of the phase 2 ARC-9 trial randomized 112 patients with metastatic colorectal cancer who progressed after oxaliplatin- and irinotecan-based therapy to receive either etrumadenant plus zimberelimab, mFOLFOX-6, and bevacizumab or regorafenib.
- Key Outcomes: The combination significantly improved progression-free survival and overall survival. Grade ≥3 adverse events were higher with the combination but treatment discontinuation due to adverse events was lower.
- Clinical Relevance: Etrumadenant-based chemoimmunotherapy demonstrated substantial survival and response benefits over regorafenib in heavily pretreated metastatic colorectal cancer, supporting adenosine pathway inhibition combined with chemotherapy and immunotherapy, pending further validation.
Results from the phase 2 ARC-9 study, demonstrate that etrumadenant plus zimberelimab, mFOLFOX-6, and bevacizumab significantly improves survival compared with regorafenib among heavily pretreated patients with metastatic colorectal cancer (mCRC).
“Etrumadenant is a small-molecule, selective dual antagonist of A2aR and A2bR that prevents extracellular adenosine-mediated immunosuppression,” stated Michael Cecchini, MD, Yale University, New Haven, Connecticut, and coauthors. “Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced [mCRC], for whom treatment options are limited.”
In cohort B of this open-label study, researchers enrolled 112 patients who progressed on or after ≤2 prior lines of treatment with oxaliplatin- and irinotecan-based therapies. Patients were randomized 2:1 to receive either 150 mg of once daily etrumadenant plus 480 mg of zimberelimab once every 4 weeks with mFOLFOX and 5 mg/kg of bevacizumab once every 2 weeks (n = 75) or dose-escalated regorafenib (n = 37) in 28-day cycles until disease progression or unacceptable toxicity. Upon disease progression, patients were permitted to crossover into the etrumadenant arm after a 5-day washout period (n = 21). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), duration of response, disease control rate, overall survival (OS), and safety.
At a median follow-up of 20.4 months, median PFS was 6.2 months in the etrumadenant arm and 2.1 months in the regorafenib arm (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.17 to 0.43; P < .0001). At 12 months, 16% of patients in the etrumadenant arm and 3% of patients in the regorafenib arm were alive and progression free.
Median OS was 19.7 months in the etrumadenant arm and 9.5 months in the regorafenib arm (HR, 0.37; 95% CI, 0.22 to 0.63; P = .0003), with 12 months OS rates of 64% and 34% and 18 month OS rates of 53% and 14%, respectively. When adjusted for crossover, the OS HR was 0.13 in the in the etrumadenant arm. Confirmed ORR was 17% in the etrumadenant arm and 3% in the regorafenib arm. Median duration of response was 11.5 months in the etrumadenant arm and not evaluable in the regorafenib arm due to only 1 response. Disease control rates were 63% and 8%, respectively.
Any-grade treatment-emergent adverse events were reported in 99% of patients in the etrumadenant arm and 87% of patients in the regorafenib arm. Grade ≥3 treatment-emergent adverse events were reported in 82% and 49% of patients, respectively. Treatment-emergent adverse events led to discontinuation of at least 1 study drug in 60% of patients in the etrumadenant arm, primarily due to oxaliplatin (53%). Treatment-emergent adverse events led to discontinuation of all study treatments in 5% of patients in the etrumadenant arm. Treatment-emergent adverse events were more commonly attributed to mFOLFOX6 compared to etrumadenant, zimberelimab, and bevacizumab. No treatment-emergent adverse events led to death in either treatment arm.
Grade ≥3 immune-related adverse events were reported in 16% of patients in the etrumadenant arm and 6% of patients in the regorafenib arm. Grade 3 immune-related adverse events were reported in 3 patients and 1 patient experienced grade 4 hemolytic anemia. No grade ≥3 immune-related adverse events were reported in the regorafenib arm.
“[Etrumadenant plus zimberelimab, mFOLFOX-6, and bevacizumab] significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile,” concluded Dr Cecchini et al. “Further investigation is warranted, given the clinically meaningful improvements in [PFS] and [OS].”
Source:
Cecchini M, Han SW, Lee S, et al. The randomized phase 2 ARC-9 study of etrumadenant-based therapy vs regorafenib in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. Published online: March 23, 2026. doi:10.1158/1078-0432.ccr-25-3727
