Dr Fakih on the Importance of Genetic Testing in KRAS G12C–Mutant mCRC

"Every patient with mCRC should undergo next-generation sequencing up front at the time of diagnosis. It is always important to understand what one’s options are as a patient; as a provider, [we need to know] how to sequence [therapies] and be prepared for that sequencing."

Marwan G. Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research, the associate director of Clinical Sciences, the medical director of the Briskin Center for Clinical Research, the division chief of GI Medical Oncology, and the co-director of the Gastrointestinal Cancer Program at City of Hope, discusses the importance of genetic testing for patients with colorectal cancer (CRC) harboring KRAS G12C mutations.

KRAS G12C mutations are present in approximately 4% of patients with microsatellite-stable, metastatic CRC (mCRC), and treatment options for this population have historically been limited following progression on standard chemotherapy, Fakih begins. Given the importance of identifying targetable alterations, all patients with mCRC should undergo next-generation sequencing at diagnosis to guide therapeutic decision-making and optimize treatment sequencing, Fakih asserts. Additionally, clinical trials evaluating targeted agents in the frontline setting remain an important consideration, he notes.

The combination of sotorasib (Lumakras) and panitumumab (Vectibix) hasdemonstrated efficacy and is associated with a tolerable safety profile when administered alongside FOLFIRI (folinic acid, fluorouracil, and irinotecan) as frontline therapy for patients with mCRC harboring KRAS G12C mutations, Fakih states. On January 16, 2025, the FDA approved sotorasib plus panitumumab for the treatment of adult patients with KRAS G12C–mutated mCRC, as determined by an FDA-approved test, who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This decision was supported by data from the phase 3 CodeBreak300 study (NCT05198934).

Findings from the phase 1b CodeBreaK 101 trial (NCT04185883), presented at the 2024 ESMO Congress, have also showed response rates with this regimen in patients with advanced solid tumors, Fakih reports. These results provided the rationale for the phase 3 CodeBreaK 301 trial (NCT06252649), which is evaluating FOLFIRI plus panitumumab and sotorasib compared with FOLFIRI with or without bevacizumab (Avastin) he says. Given these emerging data, it is critical to assess targetable alterations early in each patients’ disease course and incorporate precision oncology strategies into clinical decision-making, Fakih concludes.