Updated results from KRYSTAL-1, a multicohort phase I/II study, evaluating adagrasib—an investigational, highly selective, and potent oral small-molecule inhibitor of KRAS G12C—with or without cetuximab in patients with advanced colorectal cancer harboring a KRAS G12C mutation were presented by Samuel J. Klempner, MD, and colleagues at the European Society for Medical Oncology (ESMO) 2022 Congress (Abstract LBA24).
Samuel J. Klempner, MD
The prognosis for patients with colorectal cancer has historically been poor in later lines of therapy, with response rates of approximately 1% to 2% and median progression-free survival rates of approximately 2 months in patients with late-line colorectal cancer; patients with KRAS G12C–mutated colorectal cancer tend to have even worse outcomes than the broader colorectal cancer patient population.
Study Details
In this analysis, 44 patients received adagrasib monotherapy (600 mg twice daily) and 32 patients received the combination of adagrasib (600 mg twice daily) with full-dose cetuximab, with a follow-up of 20.1 months and 17.5 months, respectively.
Among the evaluable patients in the adagrasib monotherapy cohort (n = 43), the investigator-assessed confirmed objective response rate was 19% (8 of 43 patients) and the disease control rate was 86% (37 of 43 patients). The median duration of response was 4.3 months (95% confidence interval [CI] = 2.3–8.3 months) and the median progression-free survival was 5.6 months (95% CI = 4.1–8.3 months).
Of the evaluable patients in the adagrasib-plus-cetuximab combination cohort (n = 28), the investigator-assessed confirmed objective response rate was 46% (13 of 28 patients) and the disease control rate was 100% (28 of 28 patients). The median duration of response was 7.6 months (95% CI = 5.7 months–not evaluable) and median progression-free survival was 6.9 months (95% CI = 5.4–8.1 months).
In the overall subset of patients with KRAS G12C–mutated colorectal cancer evaluated in this study, adagrasib was found to be well tolerated as a monotherapy and in combination with cetuximab. The majority of observed treatment-related adverse events were grade 1 or 2 (59%); no grade 5 treatment-related adverse events were observed.
“These data illustrate the importance of durable KRAS inhibition in colorectal cancer and the added benefit that dual EGFR/KRAS blockade may provide for some patients in their regimen, as evidenced by the more sustained responses from the adagrasib and cetuximab combination,” commented Dr. Klempner, of the Massachusetts General Cancer Center. “Overall, it’s encouraging to see the emergence of KRAS inhibitors like adagrasib providing more targeted, efficacious, and safe treatment options for colorectal cancer and other solid tumors with KRAS mutations.”
Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org.
