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FDA approves sotorasib with panitumumab for KRAS G12C-mutated metastatic colorectal cancer

On January 16, 2025, the U.S. Food and Drug Administration (FDA) granted approval to the combination of sotorasib, a KRAS inhibitor, and panitumumab, an anti-EGFR antibody, for adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC) who have progressed on or after standard systemic therapy.1 KRAS G12C mutations, occurring in approximately 3-5% of colorectal cancer cases, represent a critical driver of tumor progression and resistance mechanisms.2

This approval is based on findings from the Phase III, randomized, open-label, CodeBreaK 300 trial (NCT05198934), which recruited 160 patients with KRAS G12C–mutated mCRC who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Patients were prospectively identified in tumor tissue samples using the QIAGEN therascreen KRAS RGQ PCR kit, and were randomly assigned 1:1:1 to receive panitumumab at 6 mg/kg intravenously every two weeks with sotorasib at either 960mg orally once daily or 240mg orally once daily, or investigator’s choice of standard of care (SOC).3

The primary endpoint, progression-free survival (PFS), was met, where both arms receiving sotorasib with panitumumab had a superior PFS compared with standard of care. At a median follow-up of 7.8 months, patients receiving 960 mg and 240 mg of sotorasib with panitumumab had a PFS of 5.6 months (95% CI, 4.2-6.3) and 3.9 months (95% CI, 3.7-5.8) respectively, whereas the SOC had a PFS of 2.2 months (95% CI, 1.9-3.9). Grade 3 or higher treatment-related adverse effects in ≥5% of patients in the experimental arm included dermatitis acneiform, hypomagnesemia, and diarrhea.3

We recently spoke with Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, who commented on the significance of sotorasib with panitumumab in mCRC, stating that:

“It’s good to have different options and to have the possibility to treat patients with several options across treatment lines, also in the later line setting. This is pretty quite new and we are happy to have these new options for our patients with oncogenic driven disease.”

This latest approval marks a pivotal step forward in addressing a historically challenging subset of patients with colorectal cancer, characterized by limited treatment options and poor prognosis.

References:

  1. Center for Drug Evaluation and Research. FDA approves sotorasib with Panitumumab for colorectal cancer [Internet]. FDA; [cited 2025 Jan 21]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer?utm_medium=twitter&utm_source=social
  2. Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, et al. Sotorasib Plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. New England Journal of Medicine. 2023 Dec 7;389(23):2125–39. doi:10.1056/nejmoa2308795
  3. Pietrantonio F, Salvatore L, Esaki T, Modest DP, Paez D, Taieb J, et al. LBA10 Sotorasib plus panitumumab versus standard-of-care for Chemorefractory Kras G12c-mutated metastatic colorectal cancer (MCRC): Codebreak 300 phase III study. Annals of Oncology. 2023 Oct;34. doi:10.1016/j.annonc.2023.10.016