- The ongoing KRYSTAL-1 trial is evaluating the use of adagrasib as monotherapy or in combination with cetuximab in patients with previously treated metastatic colorectal cancer with a KRAS G12C mutation
- Adagrasib monotherapy resulted in an objective response rate of 19%, median response duration of 4.3 months, median progression-free survival of 5.6 months, and median overall survival of 19.8 months
- When cetuximab was added to adagrasib the response rate increased to 46%, the duration of response was 7.6 months, progression-free survival was 6.9 months and overall survival was 13.4 months
- Neither regimen resulted in any new safety concerns, and the combination of adagrasib and cetuximab did not produce synergistic toxic effects
- These results demonstrate the activity of combined KRAS and EGFR inhibition in patients with previously treated colorectal cancer
The KRAS G12C mutation occurs in 3% to 4% of patients with colorectal cancer (CRC) and confers an even worse prognosis than other KRAS mutations. Adagrasib, a KRAS G12C inhibitor, has shown promise in CRC, but resistance may be related to EGFR reactivation.
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Samuel J. Klempner, MD, a medical oncologist at the Mass General Cancer Center, and colleagues have provided clinical evidence that adagrasib is active against advanced CRC with mutated KRAS G12C both as monotherapy and in combination with cetuximab, an EGFR inhibitor. They report initial results from an open-label, randomized trial in The New England Journal of Medicine.
The ongoing KRYSTAL-1 trial is sponsored by Mirati Therapeutics. It is enrolling adults with advanced, unresectable, or metastatic CRC with the KRAS G12C mutation and ECOG performance status of 0 or 1.
The initial report concerns two cohorts:
- 44 patients who received adagrasib monotherapy (median follow-up, 20.1 months; median duration of treatment, 5.9 months)
- 32 patients who received adagrasib plus cetuximab (17.5 and 7.3 months)
The results of monotherapy were:
- Objective response rate (ORR)—19%
- Median duration of response—4.3 months
- Median time to response—1.5 months
- Median progression-free survival (PFS)—5.6 months
- Median overall survival (OS)—19.8 months
The results of combination therapy were:
- Duration of response—7.6 months
- Time to response—1.4 months
- PFS—6.9 months
- OS—13.4 months
Neither regimen resulted in any new safety concerns. The combination of adagrasib and cetuximab did not produce synergistic toxic effects, and treatment-related adverse events were consistent with those previously reported for each treatment alone.
A phase 3 trial, KRYSTAL-10, is comparing adagrasib plus cetuximab to standard chemotherapy as second-line treatment for patients with CRC and mutated KRAS G12C.
The FDA approved adagrasib in 2022 for locally advanced or metastatic non–small-cell lung cancer with mutated KRAS G12C.
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