ASCO 2025: metastatic colorectal cancer—focus on precision oncology

Summary Precision oncology has changed first-line therapy in metastatic colorectal cancer (mCRC) considerably. During ASCO 2025, relevant practice-changing data were reported for distinct molecular subgroups. Key trials addressed novel approaches in upfront therapy of BRAF V600E mutated (BREAKWATER) and dMMR/MSI‑h mCRC. In comparison with standard of care (SOC), BRAF V600E inhibition demonstrated a doubling of overall survival (OS). An update of the CheckMate 8HW trial confirmed the plateauing of OS curves after longer follow-up, suggesting the potential for cure with dual immune blockade in MSI‑h mCRC. Targeting the KRAS G12C mutation is also a promising strategy; data were presented for sotorasib plus panitumumab plus FOLFIRI in pretreated patients. Although the numbers are small, the results on objective response rate (ORR), progression-free survival (PFS), and OS are clinically meaningful. Consequently, KRAS G12C inhibition is now evaluated in a first-line setting (CodeBreaK 301). Additionally, phase 1/2 data for next-generation KRAS G12C inhibitors were presented. Immune therapy as part of therapeutic strategies in pMMR/MSS tumors remains a topic of special interest. The results of an interim analysis from early phase 1/2 dose finding and dose expansion trials were reported. The aim of this review is to summarize clinically relevant abstracts, focusing on practice-changing trials, and to provide insights into new therapeutic strategies.