FDA Approves Sotorasib with Panitumumab for KRAS G12C-Mutant Colorectal Cancer
On January 16, 2025, the U.S. Food and Drug Administration (FDA) announced the approval of a new treatment regimen for adult patients with metastatic colorectal cancer (mCRC) harboring the KRAS G12C mutation. This approval pertains to the combination of two drugs: sotorasib, marketed as Lumakras by Amgen Inc., and panitumumab, known as Vectibix, also by Amgen Inc. The treatment is targeted at patients who have previously received a regimen of chemotherapy that includes fluoropyrimidine, oxaliplatin, and irinotecan. The determination of KRAS G12C mutation status is facilitated by an FDA-approved diagnostic test.
In conjunction with the drug approval, the FDA also sanctioned the therascreen KRAS RGQ PCR Kit from QIAGEN GmbH. This companion diagnostic tool is designed to detect the presence of KRAS G12C mutations in colorectal cancer patients, thus identifying those who are potential candidates for the Lumakras and Vectibix treatment combination.
The efficacy and safety of this new treatment were primarily evaluated in a clinical trial known as CodeBreaK 300 (NCT05198934). This trial involved patients with KRAS G12C-mutated mCRC who had already undergone the specified chemotherapy treatments. Over 160 patients participated in the study, with their mutation status confirmed through the QIAGEN diagnostic kit. Participants were randomly assigned to one of three groups: the first received 960 mg of sotorasib orally once per day along with 6 mg/kg of panitumumab administered intravenously every two weeks; the second group received a lower dose of sotorasib (240 mg) with the same panitumumab regimen; and the third group received standard of care (SOC), either trifluridine/tipiracil or regorafenib, as chosen by the investigators.
The main measure of effectiveness was progression-free survival (PFS), reviewed by an independent central body using RECIST v1.1 criteria. Secondary measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR). The trial, however, was not statistically powered to evaluate OS. Results demonstrated a median PFS of 5.6 months for the high-dose sotorasib/panitumumab group, compared to 2 months for the SOC group, with a hazard ratio of 0.48 and a statistically significant p-value of 0.005. Notably, the ORR stood at 26% in the high-dose combination group versus 0% in the SOC group, while the median DOR was 4.4 months.
The trial's results for the lower sotorasib dose did not show a statistically significant PFS improvement compared to standard care. Common adverse effects associated with the high-dose sotorasib/panitumumab treatment included rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain. Laboratory tests frequently revealed Grade 3-4 abnormalities, such as lowered magnesium, potassium, corrected calcium, and increased potassium levels.
For this treatment regimen, the advised dose for sotorasib is 960 mg taken orally every day, and for panitumumab, 6 mg/kg via IV infusion every two weeks. Treatment continues until either the disease progresses, unacceptable side effects occur, or the use of sotorasib is discontinued. Sotorasib should be administered before the initial panitumumab infusion.
The FDA utilized the Real-Time Oncology Review (RTOR) pilot program to expedite this review process, allowing for data submission ahead of the full clinical application. Additionally, the application benefitted from the Assessment Aid, a voluntary submission by the applicant that aids the FDA's evaluation process. This application was also granted orphan drug designation, aligning with the FDA's expedited programs for serious conditions.
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