Unanswered Questions in First- and Second-Line mCRC Care

In “Unanswered Questions in First- and Second-Line mCRC Care,” the panel explores several areas of uncertainty that remain despite rapid progress in biomarker-driven treatment. Dr. Kazmi begins with MSI-high and dMMR disease, where questions remain about the optimal duration of immunotherapy. While clinical trials have often treated patients for up to two years, it is unclear whether every patient requires that length of therapy or whether selected patients could stop earlier, particularly in the setting of potentially resectable disease.

He also raises questions about right-sided tumors and anti-EGFR therapy. In a highly selected population without apparent resistance alterations on tissue or blood-based testing, the role of anti-EGFR therapy in the first- or second-line setting remains uncertain.

The conversation then turns to targeted therapy. As BRAF-directed treatment has moved earlier in the disease course, similar questions are emerging for KRAS G12C, newer KRAS inhibitors, HER2-directed therapies, and other molecularly selected strategies. Moving these therapies earlier may improve outcomes, but it also creates uncertainty about what should follow after progression. When asked which area could most change his practice, Dr. Kazmi highlights newer KRAS-targeted therapies beyond KRAS G12C as an important area of future development. The episode reflects a treatment landscape where having more options has created new questions about duration, sequencing, resistance, and patient selection.

Our next episode, “Third-Line Treatment and Optimal Dosing in mCRC,” shifts the discussion to later-line care and strategies for balancing treatment efficacy, tolerability, and convenience.