#ESMOGI2026# Surprising news for mCRC out of ESMOGI. KRYSTAL-10: Adagrasib + cetuximab misses its primary endpoint in 2L KRAS G12C mCRC. After the accelerated approval and encouraging activity from KRYSTAL-1, many expected dual KRAS/EGFR inhibition to outperform chemotherapy in the second line. That didn't happen. Quick hits: • Primary endpoint (PFS): Negative • mPFS 7.5 vs 8.1 months • HR 0.89 (95% CI 0.71-1.13) • Response rate dramatically improved • ORR 47% vs 16% • CR 7% vs <1% • No improvement in OS at the final analysis despite the higher response rate. So what happened? This is a reminder that response rate ≠ durable disease control. Nearly half of patients responded, but those responses did not translate into longer PFS or OS compared with modern chemotherapy. Targeted therapy works, but mCRC can overcome via resistance mechanisms (such as via massive KRAS upregulation). Will be interesting to see how novel degraders come into the mix here... Remember, this is a first gen KRASi, the future is still bright here. What does this mean for clinic tomorrow? Honestly, I still love a chemo-free option that is at least on par with chemotherapy. This isn't the end of KRAS G12C in CRC. Far from it. The focus now shifts to moving targeted therapy earlier, where combinations with chemotherapy may produce deeper, more durable responses before resistant clones emerge. Multiple frontline studies are already underway. @TheGutOncLab @OncoAlert @Onco_Nexus @myESMO