Epigenetic and genomic changes have been identified as potential drivers of resistance to the sotorasib combination therapy in KRAS G12C colorectal cancer. Data from the study revealed a diverse range of emergent alteration patterns across the treatment arms, with notable numerical differences in ERBB2 and MET alterations. While statistically insignificant, the rate of ERBB2 alterations was 14.7% in the investigator’s choice arm, 9.1% in the sotorasib at 240 mg plus panitumumab arm, and 6.3% in the sotorasib at 960 mg plus panitumumab arm. Similarly, the rate of MET alterations varied across the arms, highlighting the complex landscape of resistance mechanisms in this setting.
These findings underscore the importance of understanding the underlying molecular changes that contribute to resistance in KRAS G12C CRC patients receiving sotorasib combination therapy. Further exploration of the impact of epigenetic and genomic alterations on treatment outcomes could inform personalized therapeutic strategies and potentially enhance treatment efficacy. As the field of precision medicine continues to evolve, insights into these resistance mechanisms may pave the way for novel targeted therapies or combination approaches to overcome treatment challenges in KRAS-mutated colorectal cancer.
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