Advancing Precision Care in Unresectable Metastatic Colorectal Cancer – Immunotherapy in the First-Line Setting

This opening segment frames the discussion around recent advances in metastatic CRC (mCRC), with an emphasis on biomarker-driven treatment and first-line immunotherapy strategies for patients with deficient mismatch repair (dMMR)/microsatellite instability–high (MSI-H) disease. Moderator Aparna Parikh, MD, sets the stage by highlighting the rapid evolution of the treatment landscape after decades of limited progress beyond cytotoxic chemotherapy and anti-VEGF therapy.

The panelists engage in a focused discussion on first-line systemic therapy. The panelists undertake a detailed review of immunotherapy data in dMMR/MSI-H mCRC, contextualizing recent regulatory approvals and key trials. They discuss the impact of dual immune checkpoint blockade with nivolumab plus ipilimumab, referencing the CheckMate 8HW study, which compared the combination with nivolumab monotherapy in immunotherapy-naïve patients. Although not a purely frontline study, the data were described as practice-affirming, demonstrating improved progression-free survival and response rates with manageable toxicity, supporting guideline incorporation and FDA approval.

The discussion then turns to emerging and controversial data from the COMMIT study, which evaluated atezolizumab alone versus atezolizumab combined with FOLFOX and bevacizumab in the frontline dMMR/MSI-H population. The panel expresses disappointment with atezolizumab monotherapy outcomes and concerns regarding increased toxicity with the chemotherapy-containing arm, questioning its clinical relevance given the durability and tolerability seen with nivolumab-based approaches.

Faculty conclude by emphasizing how profoundly durable responses to dual immunotherapy are reshaping clinical practice, including reconsideration of surgery and local therapies in patients achieving long-term disease control, and raising questions about when such patients might be considered functionally cured.