Dr. Klempner on the Significance of KRYSTAL-1 Data in KRAS G12C–Mutant CRC

Sam Klempner, MD, faculty member, Oncology, Massachusetts General Hospital, Medicine, Harvard Medical School, discusses the incidence of KRAS G12C mutations in patients with metastatic colorectal cancer (CRC), the viability of the target in this disease, the efficacy of adagrasib (MRTX849) in combination with cetuximab (Erbitux) in this patient population, and the importance of genetic testing.

KRAS G12C mutations occur with varying prevalence across different types of solid tumors, including gastrointestinal cancers like CRC, Klempner says. Data from retrospective studies have indicated that approximately 3% to 4% of patients with CRC harbor these mutations. These mutations appear to be associated with an inferior prognosis—even compared with other KRAS mutations, Klempner adds. Moreover, those with KRAS G12C mutations typically derive a shorter duration of benefit from standard frontline chemotherapy options, according to Klempner.

The phase 1b/2 KRYSTAL-1 trial (NCT03785249) evaluated the safety, tolerability, and clinical activity of adagrasib monotherapy and in combination with cetuximab in patients with KRAS G12C–mutated tumors, including CRC. Data presented at the 2022 ESMO Congress showed that the activity displayed by adagrasib plus cetuximab confirmed preclinical observations of combining a KRAS G12C inhibitor with an EGFR inhibitor, Klempner says. With a longer follow-up of 17.5 months, the combination elicited a confirmed objective response rate of 46%, with a disease control rate of 100% in 28 evaluable patients with KRAS G12C–mutated CRC.

Ninety-three percent of patients experienced a decrease in tumor volume, according to Klempner. Moreover, many patients achieved deep responses, with more than a 50% decrease in the tumor volume, Klempner adds. Patients treated with the combination also experienced durable responses, with a median duration of response of 7.6 months. The median time to response with the doublet was rapid, at 1.4 months, Klempner adds. At data cutoff, 5 patients were still receiving treatment with the combination, Klempner says. Treatment-related adverse effects were observed in all 32 patients (100%).

The most frequent toxicities were nausea (63%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), and dry skin (41%). The combination was tolerable and had a manageable safety profile.

These data suggest that KRAS G12C mutations represent a viable target in CRC, Klempner adds. The relatively high rates of responses achieved with the doublet, and the durability of those responses, suggest that the regimen may be more beneficial for this subgroup of patients with CRC compared with other options available in the late-line setting, such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf), Klempner says.

The potential viability of targeting KRAS G12C mutations underscores the importance of performing genetic testing in all patients with CRC, Klempner adds. Moreover, if these kinds of mutations are detected, all efforts should be made to identify clinical trials that may be appropriate for this patient subset, Klempner concludes.