Opinion
Video
Potential for Precision: Exploring Targeted Therapies in mCRC Care
Panelists discuss how the importance of having pharmacists embedded in oncology clinics has transformed metastatic colorectal cancer care by enabling real-time decision-making and dose adjustments, while highlighting that these are exciting times with multiple new oral treatment options that patients often prefer over infusions, though managing adherence and side effects remains challenging, and emphasizing that current targeted therapy opportunities include rare but actionable NTRK fusions, HER2 amplifications (3% of cases with multiple treatment options), and KRAS G12C mutations (3% of cases), with future promise in pan-RAS inhibitors, expanded immunotherapy beyond MSI-high tumors, and combination therapies, though dermatologic toxicity from targeted agents like RAS inhibitors will likely be the rate-limiting factor requiring better assessment tools and multidisciplinary management including dermatology support.
The current landscape of targeted therapies in refractory metastatic colorectal cancer includes several established actionable targets, though some remain relatively rare. NTRK fusions, while uncommon, represent highly actionable targets that warrant celebration when identified due to their excellent therapeutic response. More common actionable targets include HER2 amplifications (approximately 3% of cases) with multiple treatment options including trastuzumab plus pertuzumab (FDA-approved), tucatinib plus trastuzumab (NCCN guideline-supported), and trastuzumab deruxtecan as an antibody-drug conjugate. KRAS G12C mutations, also occurring in about 3% of patients, can be targeted with sotorasib, though the data shows a hazard ratio of 0.7 without definitive overall survival benefit from the relatively small study that wasn't powered for survival endpoints.
Future targeted therapy development focuses on expanding RAS inhibitor applications beyond G12C mutations, with particular excitement around pan-RAS and other RAS-specific inhibitors across multiple cancer types. The ongoing challenge involves extending immunotherapy efficacy beyond the microsatellite instability-high population, with early promising data from studies combining novel agents with PD-L1 inhibitors. However, the success of targeted therapies depends critically on comprehensive genomic testing at diagnosis to identify actionable mutations and guide appropriate treatment sequencing. The potential for synergistic combination therapies mirrors approaches seen in other solid tumors, though balancing tolerability with enhanced depth and durability of response remains a key consideration.
A significant challenge with emerging targeted therapies, particularly RAS inhibitors, involves managing severe dermatologic toxicity that often becomes the rate-limiting factor for treatment continuation. Skin toxicity represents a major quality of life issue that can lead to treatment discontinuation despite clinical benefit, requiring multidisciplinary management involving dermatologists and comprehensive supportive care measures including doxycycline and topical corticosteroids. The disconnect between provider and patient perceptions of skin toxicity severity highlights the importance of patient-centered assessment tools that can quickly evaluate how dermatologic side effects impact multiple functional and social domains. This challenge has likely contributed to slower adoption of EGFR inhibitors in frontline treatment compared to international practice patterns, emphasizing the need for better supportive care strategies and patient assessment tools to optimize the therapeutic window of these promising targeted agents.
Newsletter
Stay informed on drug updates, treatment guidelines, and pharmacy practice trends—subscribe to Pharmacy Times for weekly clinical insights.
