The combination of sotorasib and panitumumab significantly improved progression-free survival compared with standard treatment in patients with chemotherapy-refractory metastatic colorectal cancer with KRAS G12C mutations, the phase III CodeBreaK 300 trial has shown. The KRAS G12C inhibitor sotorasib at the standard dose of 960 mg/d plus panitumumab, an inhibitor of the epidermal growth factor receptor (EGFR), led to tumor shrinkage in 81% of patients and a 51% reduction in the risk of disease progression, according to Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, at the European Society for Medical Oncology (ESMO) Congress 2023.1
“This combination is a potential new standard-of-care therapy for patients with previously treated KRAS G12C–mutated metastatic colorectal cancer.”— Filippo Pietrantonio, MD
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“This combination is a potential new standard-of-care therapy for patients with previously treated KRAS G12C–mutated metastatic colorectal cancer,” Dr. Pietrantonio said. The study was simultaneously published in The New EnglandJournal of Medicine.2
KRAS G12C, a driver mutation, occurs in approximately 3% of patients with metastatic colorectal cancer and may be associated with a poor prognosis. In patients who experience disease progression on standard initial therapies, treatment with trifluridine-tipiracil or regorafenib—which were used in the control arm of CodeBreaK 300—have shown limited efficacy, and better late-line therapies are lacking.
About CodeBreaK 300
In the open-label trial, more than 150 patients enrolled from sites in 12 countries were randomly assigned to one of the following three arms:
- Sotorasib at 960 mg once daily (standard dose) plus panitumumab at 6 mg/kg every 2 weeks (n = 53)
- Sotorasib at 240 mg once daily plus panitumumab (n = 53)
- Standard therapy with investigator’s choice of either trifluridine/tipiracil at 35 mg/m2 on days 1–5 and 8–12 every 28 days (n = 37) or regorafenib at 160 mg once daily on days 1–21 every 28 days (n = 14).
Approximately 85% of patients had received two or more prior lines of therapy, but none included a KRAS-targeted agent. Right-sided tumors were more common in the 960-mg sotorasib arm (45%) than the 240-mg sotorasib arm (32%) or the control arm (30%). The primary endpoint was progression-free survival by blinded independent central review.
Improvements With Combination Therapy
At a median follow-up of 7.8 months, patients treated with sotorasib at 960 mg plus panitumumab had a median progression-free survival of 5.6 months vs 2.2 months with standard therapy (hazard ratio [HR] = 0.49; P = .006). With the lower sotorasib dose of 240 mg plus panitumumab, median progression-free survival was 3.9 months (HR = 0.58; P = .03). “Progression-free survival by blinded independent central review favored sotorasib plus panitumumab across key patient subgroups,” Dr. Pietrantonio said.
The objective response rate was 26% with 960 mg of sotorasib plus panitumumab (including one complete response), 6% with 240 mg of sotorasib plus panitumumab, and 0% with standard treatment. Disease control rates were 72%, 68%, and 46%, respectively, and the median duration of response was 4.4 months in the 960-mg sotorasib group. Tumor shrinkage of any level was observed in 81%, 57%, and 20%, respectively. Overall survival results were immature at the time of the analysis.
Safety
Treatment-related grade ≥ 3 adverse events occurred in 36%, 30%, and 43% of patients given 960 mg of sotorasib, 240 mg of sotorasib, and standard care, respectively. Skin-related toxicities (rash and dermatitis acneiform) and hypomagnesemia were the most common adverse events seen with sotorasib plus panitumumab, whereas neutropenia and nausea were the most common adverse events reported with standard therapies. Treatment-related serious adverse events occurred in 6%, 0%, and 8% of patients in the three groups and led to discontinuation of any study drug in 4%, 2%, and 2%, respectively.
“No new safety concerns were observed. These results, along with previous data from non–small cell lung cancer, support sotorasib at 960 mg as the sotorasib dose for use in metastatic colorectal cancer,” Dr. Pietrantonio concluded.
DISCLOSURE: The study was funded by Amgen. Dr. Pietrantonio reported financial relationships with Amgen, Astellas Pharma, Bayer, Bristol Myers Squibb, GSK, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Johnson & Johnson, Takeda, and Servier.
REFERENCES
1. Pietrantonio F, Salvatore L, Esaki T, et al: Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C–mutated metastatic colorectal cancer: CodeBreaK 300 phase III study. ESMO Congress 2023. Abstract LBA10. Presented October 22, 2023.
