ASCO24: Etrumadenant improves survival in refractory colorectal cancer

Arcus Biosciences' etrumadenant, an oral adenosine receptor antagonist, has shown encouraging results in a Phase II study for metastatic colorectal cancer (mCRC), potentially revitalizing its clinical prospects. This development comes after the drug's earlier challenges, including its deprioritization in prostate cancer and the suspension of its lung cancer program due to insufficient clinical benefit.

The promising data from the ARC-9 study was disclosed ahead of the American Society of Clinical Oncology (ASCO) conference. The study investigated the combination of etrumadenant, the experimental anti-PD-1 antibody zimberelimab, and standard chemotherapy in mCRC patients who had previously progressed on oxaliplatin- and irinotecan-based treatments. Cohort B of the ARC-9 study included 112 patients who were randomized to receive either the etrumadenant combination therapy or Bayer's Stivarga (regorafenib) alongside standard chemotherapy.

With a median follow-up period of 20.4 months, the etrumadenant combination showed a significant improvement in progression-free survival (PFS) and overall survival (OS) compared to Stivarga. Specifically, the median PFS for the etrumadenant group was 6.2 months, in contrast to 2.1 months for the Stivarga group, representing a 73% improvement. Additionally, the median OS for the etrumadenant group was 19.7 months compared to 9.5 months for the Stivarga group, indicating a 63% improvement.

However, the safety profile revealed that Grade ≥3 treatment-emergent adverse events (TEAEs) were more frequent in the etrumadenant arm, occurring in over 82% of patients versus nearly 49% in the Stivarga group. Despite this, the rate of TEAEs leading to treatment discontinuation was lower for etrumadenant at 5.4%, compared to approximately 17% for Stivarga.

Arcus Biosciences' CEO, Terry Rosen, highlighted the significance of the ARC-9 findings during a recent company earnings call, emphasizing the validation of the adenosine pathway as a crucial therapeutic target in oncology. Rosen also pointed to related studies, including ARC-8 (which evaluated Arcus' CD73 inhibitor quemliclustat in first-line pancreatic cancer) and MORPHEUS-PDAC (which assessed etrumadenant with chemotherapy in first-line pancreatic cancer). He noted that these studies collectively provide compelling evidence that mitigating the immunosuppressive effects of adenosine, in combination with chemotherapy, may enhance survival outcomes compared to chemotherapy alone.

The ARC-9 study's positive results suggest that etrumadenant could become a valuable treatment option for mCRC patients, potentially offering a new lease on life for those who have exhausted other treatment regimens. The data supports further investigation into the adenosine pathway as a promising avenue for cancer therapy, with the potential to improve outcomes for a broader range of cancer patients.

In summary, the ARC-9 trial has breathed new hope into the clinical development of etrumadenant, demonstrating significant benefits in both progression-free and overall survival for mCRC patients. While safety concerns remain, the overall efficacy of the drug combination presents a compelling case for its continued exploration in oncology.