Dr Weinberg on the Importance of Biomarker Status for Third-Line Treatment Selection in mCRC

"It is important to repeat molecular testing often, especially in this era of liquid biopsies where we can get results back quite quickly. But, for the most part, much of the biomarker selection [should have] already taken place by the time we hit the third line.”

Benjamin A. Weinberg, MD, FACP, an associate professor of medicine in the Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center at Georgetown University, discussed how key molecular markers and tumor characteristics, such as tumor sidedness, guide the selection and sequencing of therapies for patients with metastatic colorectal cancer (mCRC).

Although molecular profiling is essential throughout the disease course, the most effective biomarker-driven strategies should ideally be implemented in the first-line setting to optimize patient outcomes, Weinberg began. He added that biomarkers, including RAS or BRAF mutations, HER2 amplification, and microsatellite instability (MSI) status, now largely dictate the standard of care in mCRC. For example, patients with MSI-high or mismatch repair deficient (dMMR) tumors should receive immunotherapy upfront. Furthermore, for patients with RAS/BRAF wild-type disease, the location of the primary tumor is a decisive factor; those with left-sided primary tumors should typically receive EGFR-targeted therapy combined with chemotherapy as their initial treatment.

In the later-line setting, HER2 amplification remains a significant therapeutic target. Weinberg recommended confirming HER2 status via tissue testing for immunohistochemistry (IHC) 3+ expression. Established later-line regimens include the combination of tucatinib (Tukysa) and trastuzumab (Herceptin). Additionally, fam-trastuzumab deruxtecan-nxki (Enhertu) represents a viable treatment option.

Weinberg also emphasized the importance of repeat molecular testing, noting that the rapid turnaround of liquid biopsies makes frequent reassessment feasible. This is especially relevant for patients with disease harboring BRAF mutations who may not have received targeted therapy in earlier lines; such patients should be considered for encorafenib (Braftovi) in combination with an EGFR antibody in the third line or beyond. He concluded that although the majority of biomarker-based decisions are made early, ongoing molecular surveillance is crucial to ensuring that patients do not miss opportunities for targeted interventions as their disease evolves.