FDA Approves Sotorasib Plus Panitumumab for KRAS G12C-Mutated Metastatic CRC

The FDA has approved sotorasib (Lumakras; Amgen) plus panitumumab (Vectibix; Amgen) for use in patients with colorectal cancer (CRC) that is metastatic and has a KRAS G12C mutation, as determined by an FDA-approved test.¹ Patients must have also received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The treatment was shown to increase progression-free survival (PFS) in these patients.

Sotorasib is traditionally used as treatment with locally advanced or metastatic non–small cell lung cancer with a KRAS G12C mutation, whereas panitumumab has been used to treat metastatic CRC since its initial FDA approval in 2006, working primarily as an estimated glomerular filtration inhibitor. The combination of these treatments was tested in the CodeBreaK 300 trial (NCT05198934), which was a global phase 3 trial and whose results were presented at the European Society for Medical Oncology 2023 Congress and published in the New England Journal of Medicine.²

The approval was based on results from CodeBreaK 300, a phase 3, multicenter, open-label, randomized trial that enrolled 160 patients who had not had previous treatment with a KRAS G12C inhibitor. These patients were separated into 3 groups to receive either sotarasib at a 960 mg dose once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg daily plus panitumumab (53 patients), or trifluridine-tipiracil or regorafenib (54 patients). The PFS of each patient was the primary end point. Overall survival and objective response were the secondary end points. The study used blinded independent central review to determine the efficacy.

“In metastatic colorectal cancer, KRAS mutations are historically associated with worse mortality rates and inferior outcomes compared to non-mutated tumors, and standard treatment options have shown minimal benefit,” Marwan G. Fakih, MD, primary study investigator and codirector of the Gastrointestinal Cancer Program, City of Hope, said in a statement. “Designed for dual blockade of KRAS G12C and EGFR pathways, the combination of sotorasib plus panitumumab provides a needed new treatment option to better overcome cancer’s escape mechanisms. The CodeBreaK 300 study showed superior progression-free survival compared to the investigated standard of care and represents a clinically meaningful benefit for patients with KRAS G12C-mutated metastatic colorectal cancer.”

Sotorasib plus panitumumab can be used to treat patients with KRAS G12C–mutated metastatic colorectal cancer. | Image credit: Rasi - stock.adobe.com

The study had a median follow-up time of 7.8 (range, 0.1-13.9) months. Within that timeframe, the group taking 960 mg of sotorasib plus panitumumab had a PFS of 5.6 (95% CI, 4.2-6.3) months, the group taking 240 mg of sotorasib plus panitumumab had a PFS of 3.9 (95% CI, 3.7-5.8) months, and the standard care group had a PFS of 2.2 (95% CI, 1.9-3.9) months.

Compared with the standard care group, disease progression or death had a HR of 0.49 (95% CI, 0.30-0.80) in the 960-mg group and 0.58 (95% CI, 0.36-0.93) in the 240-mg group. Objective response was highest in the 960-mg group at 26.4% (95% CI, 15.3%-40.3%), followed by the 240-mg group at 5.7% (95% CI, 1.2%-15.7%); the standard care group had a 0% response rate (95% CI, 0.0%-6.6%).

Tumor shrinkage was also observed in 81% of patients in the 960-mg group, 57% of those in the 240-mg group, and 20% of those on standard care. Disease control rate had improvement in the 960-mg group (72%; 95% CI, 57.7%-83.2%) and the 240-mg group (68%; 95% CI, 53.7%-80.1%) compared with standard care (46%; 95% CI, 32.6%%-60.4). No data on overall survival were collected, as they were immature.

Adverse events were reported in the patients, with the most common being dermatitis acneiform, hypomagnesmia, rash, and diarrhea. These affected 11%, 6%, 6%, and 4% of the 960-group, respectively, and 4%, 8%, 2%, and 6% of the 240-mg group.³ Treatment related adverse events that were grade 3 or higher occurred in 43.1% of patients who received standard care compared with 35.8% of patients who received 960 mg and 30.2% who received 240 mg.

The approval of this treatment could mark a new standard of care for patients with KRAS G12C–mutated metastatic CRC, as the treatment was able to provide longer PFS and improve disease control rate, and could potentially reduce the size of patients’ tumors. Future data on overall survival will be beneficial for prescribing the treatment to patients after the approval.

References

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer

2. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;389(23):2125-2139. doi:10.1056/NEJMoa2308795

3. Amgen presents new Lumarkras (sotorasib) plus Vectibix (panitumumab) data in patients with KRAS G12C-mutated metastatic colorectal cancer. News release. PR Newswire. October 22, 2023. Accessed October 16, 2024. https://www.prnewswire.com/news-releases/amgen-presents-new-lumakras-sotorasib-plus-vectibix-panitumumab-data-in-patients-with-kras-g12c-mutated-metastatic-colorectal-cancer-301963791.html