KRYSTAL-1: A pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRASG12C mutation

Adagrasib is an irreversible KRAS G12C inhibitor that is designed to have a 23-hour half-life, dose-dependent pharmacokinetics, and central nervous system penetration. The pooled analysis of Phase I/II (KRYSTAL-1) trial that was presented during the AACR 2024 conference demonstrated that, as of the data cutoff date of June 30, 2023, and a median follow-up of 11.9 months, the ORR achieved by the combination as per blinded independent central review (BICR) was 34.0% and the disease control rate was 85.1%. Moreover, the median duration of response (DOR) was 5.8 months. Further findings showed that the median PFS was 6.9 months and the 6-month PFS rate was 57.7%. The median OS was 15.9 months and the 6-month OS rate was 87.8%.

Regarding safety, all patients experienced any grade treatment-related adverse effects (TRAEs), and most were grade 2 (63.8%). The most frequent TRAEs were nausea (any-grade, 60.6%; grade 3, 2.1%), vomiting (51.5%; 0%), diarrhea (48.9%; 1.1%), dermatitis acneiform (47.9%; 2.1%), fatigue (42.6%; 1.1%), dry skin (34.0%; 0%), hypomagnesemia (28.7%; 2.1%; grade 4, 1.1%), headache (26.6%; 3.2%), and rash (22.3%; 2.1%).

The National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology currently recommend adagrasib plus cetuximab or panitumumab (Vectibix) for use in patients with previously treated KRAS G12C–mutant CRC.

Most importantly, in February 2024, the US FDA accepted a supplemental new drug application for priority review regarding the approval of adagrasib plus cetuximab for this population, based on the KRYSTAL-1 findings. The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

KOL insight

“Adagrasib and cetuximab demonstrated clinically meaningful activity…in these patients, and the safety profile was consistent with what was previously known.” –Expert Opinion.

Conclusion

Adagrasib and cetuximab combination exhibited promising effectiveness and a tolerable safety profile in patients previously treated for KRAS G12C–mCRC. These results advocate for adagrasib and cetuximab as a prospective new standard of care (SOC) for individuals with previously treated metastatic KRAS G12C [–mutant] colorectal cancer, potentially influencing regulatory considerations for a revised SOC.