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The FDA granted accelerated approval to adagrasib (Krazati) for KRAS G12C-mutated colorectal cancer (CRC), which accounts for 3-5% of CRCs.

The stipulates use of adagrasib in combination with cetuximab (Erbitux) in patients with KRAS G12C-positive CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Support for the approval came from the phase I/II KRYSTAL-1 trial. The study included patients with unresectable/metastatic CRC. The primary endpoint was objective response rate, and the data showed that 32 of 94 patients responded to the combination of adagrasib and cetuximab. An additional 48 patients had stable disease, resulting in a disease control rate of 85.1%. With a median follow-up of 11.9 months, the median overall survival was 15.9 months.

In a subgroup of 83 patients with paired tissue and blood samples, 27 of 29 responses occurred in patients with KRAS G12C mutations.

The safety profile of the combination was consistent with the individual drugs known safety. The most common adverse reactions (≥20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, cough, dizziness, constipation, and peripheral neuropathy.

The response rate was consistent with results of the trial that paired the KRAS inhibitor sotorasib (Lumakras) and the EGFR inhibitor panitumumab (Vectibix) and showed an ORR of 30%. The National Comprehensive Cancer Network recommends a KRAS inhibitor plus an EGFR inhibitor as an option for refractory CRC and KRAS G12C mutation.

Enrollment has ended in a global phase III randomized controlled trial comparing adagrasib and cetuximab with chemotherapy as second-line treatment for KRAS-mutant CRC.

Both adagrasib and sotorasib have approved indications for KRAS-positive non-small cell lung cancer.

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