On January 16, 2025, the U.S. Food and Drug Administration (FDA) approved the combination of sotorasib and panitumumab for treating adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC). This approval applies to patients who have undergone prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as determined by an FDA-approved diagnostic test.
The FDA also approved the therascreen KRAS RGQ PCR Kit as a companion diagnostic tool. This device identifies patients whose tumors harbor KRAS G12C mutations, allowing clinicians to determine eligibility for the sotorasib and panitumumab combination therapy.
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This approval is based on the findings from the CodeBreaK 300 study, a randomized, open-label, controlled trial involving 160 patients with KRAS G12C-mutated mCRC. All participants had previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Tumor tissue samples were analyzed prospectively using the therascreen KRAS RGQ PCR Kit to identify KRAS G12C mutations.
Patients were randomized in a 1:1:1 ratio into three groups: those receiving sotorasib 960 mg orally once daily combined with panitumumab 6 mg/kg IV every two weeks; those receiving sotorasib 240 mg orally once daily combined with panitumumab 6 mg/kg IV every two weeks; and those receiving standard of care (SOC), consisting of either trifluridine/tipiracil or regorafenib.
The trial’s primary endpoint was progression-free survival (PFS), evaluated using RECIST v1.1 criteria by blinded independent central review. Additional efficacy measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR). Median PFS in the sotorasib 960 mg and panitumumab group was 5.6 months (95% CI: 4.2, 6.3) compared to 2 months (95% CI: 1.9, 3.9) in the SOC group, with a hazard ratio of 0.48 (95% CI: 0.3, 0.78) and a two-sided p-value of 0.005. The ORR was 26% (95% CI: 15, 40) in the sotorasib 960 mg and panitumumab group compared to 0% (95% CI: 0, 7) in the SOC group. The median duration of response was 4.4 months.
The lower-dose sotorasib (240 mg) group did not demonstrate statistically significant results for PFS compared to the SOC group. Additionally, the study was not powered to achieve statistical significance for overall survival (OS), and the final OS analysis was inconclusive. The most common adverse reactions observed with the sotorasib 960 mg and panitumumab combination included rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain.
The FDA’s approval of the sotorasib and panitumumab combination marks a new advancement in the treatment of KRAS G12C-mutated metastatic colorectal cancer. With this targeted therapy, patients who have previously undergone standard chemotherapy regimens now have a new option with improved progression-free survival outcomes. The availability of the therascreen KRAS RGQ PCR Kit as a companion diagnostic ensures precise identification of eligible patients, underscoring the importance of personalized medicine in oncology.
References:
M. G. Fakih et al., “Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C,” New England Journal of Medicine, vol. 389, no. 23, pp. 2125–2139, Oct. 2023, doi: 10.1056/nejmoa2308795.
“FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer,” U.S. Food And Drug Administration, Jan. 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer
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