And just like that, adagrasib + cetuximab is no longer FDA approved for KRAS G12C colorectal cancer. The accelerated approval was officially withdrawn September 1 after KRYSTAL-10 failed to confirm benefit. We talked about KRYSTAL-10 when it was presented earlier this year. The phase III randomized 461 patients in 2L to adagrasib + cetuximab vs chemotherapy ± VEGF inhibition. It missed both primary endpoints: ▪️PFS: 7.5 vs 8.1 months, HR 0.89
▪️OS: 21.6 vs 21.7 months, HR 0.83 Hard to argue with a negative phase III trial. But I still like the idea of a chemo free option. Response rate was 47% vs 16%. That could matter for some patients (like those who you need just a little more shrinkage to enable crative intent therapy). KRYSTAL-10 asked whether adagrasib + cetuximab was better than chemotherapy in 2L. It wasn’t. That doesn’t mean the concept of KRAS G12C + EGFR blockade was wrong. And it doesn’t mean there aren’t patients for which this isnt valuable. Anyone celebrating this should look themselves in the mirror; this is a tool that has just been removed from our arsenal. However, the FDA did exactly what the system is designed to do; pull back if the Ph III doesnt pan out after accelerated approval. @OncoAlert @TheGutOncLab @Onco_Nexus

#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