Gilead and Arcus: Etrumadenant Plus Zimberelimab Cuts Death Risk in Third-line Metastatic Colorectal Cancer

Gilead Sciences, Inc. and Arcus Biosciences, Inc. have released new findings from Cohort B of the ARC-9 study, a Phase 1b/2 clinical trial. The study examines the safety and efficacy of a combination treatment involving etrumadenant, an A2a/b adenosine receptor antagonist, along with zimberelimab, an anti-PD-1 monoclonal antibody, FOLFOX chemotherapy, and bevacizumab (EZFB) for third-line metastatic colorectal cancer (mCRC). These results will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting by Dr. Zev A. Wainberg, a leading researcher at the University of California Los Angeles.

The ARC-9 study is the first randomized Phase 2 trial to demonstrate that a combination of an adenosine receptor inhibitor with anti-PD-1, anti-VEGF, and chemotherapy can significantly enhance clinical outcomes for patients with metastatic colorectal cancer who have already undergone at least two previous treatment regimens. Dr. Wainberg noted, "The median overall survival of 19.7 months reported in third-line mCRC is the longest observed and suggests the potential of an etrumadenant-based treatment approach for colorectal cancer."

Cohort B of the ARC-9 trial included 112 patients who were randomized into two groups to receive either the EZFB regimen or regorafenib. The median follow-up period was 20.4 months at the data cut-off on November 13, 2023. Patients in the EZFB group showed consistently better outcomes in terms of both overall survival (OS) and progression-free survival (PFS) compared to those receiving regorafenib, across all analyzed sub-groups, including those with liver metastases.

Key efficacy results from the trial are summarized as follows:

- Median OS was 19.7 months for the EZFB group (n=75) compared to 9.5 months for the regorafenib group (n=37), with a hazard ratio (HR) of 0.37 (95% CI 0.22-0.63, p=0.0003).
- Median PFS was 6.2 months for the EZFB group versus 2.1 months for the regorafenib group, with an HR of 0.27 (95% CI 0.17-0.43, p<0.0001).
- Confirmed objective response rate (ORR) was 17.3% for the EZFB group compared to 2.7% for the regorafenib group.
- Median duration of response (DOR) was 11.5 months for the EZFB group, with no comparable evaluable duration for the regorafenib group due to only one patient responding.

The safety profile of the EZFB regimen was consistent with known profiles of the individual components, and no unexpected toxicities were observed. Notably, a higher percentage of patients on regorafenib (17%) experienced treatment-emergent adverse events (TEAEs) leading to discontinuation compared to those on the EZFB regimen (5%). Additionally, fewer patients experienced Grade ≥3 TEAEs attributed to etrumadenant or zimberelimab compared to regorafenib (23.0% vs. 25.7%).

Etrumadenant and zimberelimab remain investigational and have not received regulatory approval for any use, and their safety and efficacy for treating colorectal cancer are yet to be established.

The ARC-9 study continues to evaluate the combination of etrumadenant, zimberelimab, FOLFOX, and bevacizumab in various cohorts of mCRC patients, focusing on progression-free survival as the primary endpoint and overall survival as a key secondary endpoint. Cohort B specifically enrolled patients who had previously progressed on oxaliplatin- and irinotecan-based chemotherapy regimens with anti-VEGF or anti-EGFR therapies.

Etrumadenant is designed to combat adenosine-mediated immunosuppression within the tumor microenvironment, potentially restoring antitumor immune responses. Zimberelimab aims to inhibit PD-1, thereby reinvigorating T-cell antitumor activity. Both are being tested in various combinations to evaluate their potential against different cancer types.