Sotorasib at 960 mg Plus Panitumumab Emerges as SOC in KRAS G12C+ mCRC

Favorable efficacy data and manageable safety data support 960 mg of sotorasib, when combined with panitumumab, as the optimal dose in patients with colorectal cancer.

A dose of sotorasib (Lumakras) at 960 mg plus panitumumab (Vectibix) elicited survival and response rates that, though not statistically significant, when paired with safety, support the dosage as a standard of care in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (CRC), according to results from an analysis of the phase 3 CodeBreaK 300 trial (NCT05198934) published in the Journal of Clinical Oncology.

At data cutoff, with a median follow-up of 13.6 months, 24 deaths occurred in the 960 mg sotorasib/panitumumab arm, 28 deaths occurred in the 240 mg sotorasib/panitumumab arm, and 30 deaths occurred in the investigator’s choice of therapy arm. The median overall survival (OS) was not reached (95% CI, 8.61-not estimable [NE]) with 960 mg sotorasib/panitumumab, 11.9 months (95% CI, 7.52-NE) with 240 mg sotorasib/panitumumab, and 10.3 months (95% CI, 7.00-NE) with investigator’s choice.

The favorable OS trend for sotorasib 960 mg-panitumumab was also observed in prespecified key subgroups, though study authors noted that the small sample sizes led to wide confidence intervals.

For OS, the estimated hazard ratio (HR) was 0.70 (95% CI, 0.41-1.18; P = .20) with 960 mg sotorasib/panitumumab and 0.83 (95% CI, 0.49-1.39; P = .50) with 240 mg sotorasib/panitumumab. An ad hoc sensitivity analysis that adjusted for the confounding effects of initiating subsequent therapies of interest showed stratified HRs of 0.65 (95% CI, 0.28-1.37) with 960 mg sotorasib/panitumumab and 0.84 (95% CI, 0.44-1.58) with 240 mg sotorasib/panitumumab.

The updated objective response rates (ORRs) were 30.2% (95% CI, 18.3%-44.3%), 7.5% (95% CI, 2.1%-18.2%), and 1.9% (95% CI, 0.0%-9.9%), respectively; since statistical significance was not achieved for OS, ORR per blinded independent central review wasn’t formally reviewed. The median duration of response was 10.1 months (95% CI, 3.9-NE) in the 960 mg sotorasib/panitumumab.

“Considering all the reported improved outcomes, this study supports a consistent treatment benefit of 960 mg sotorasib/panitumumab as a new standard-of-care treatment for patients with KRAS G12C-mutated chemorefractory [metastatic] CRC,” wrote lead study author Marwan Fakih, MD, in Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center in Duarte, CA, and fellow authors.

CodeBreaK 300 was a randomized, open-label trial that evaluated the efficacy and safety of sotorasib plus panitumumab vs investigator’s choice of therapy in patients with previously treated metastatic CRC harboring a KRAS G12C mutation. A total of 160 patients were randomly assigned, in a 1:1:1 ratio, to receive 960 mg of sotorasib plus panitumumab (n = 53), 240 mg of sotorasib plus panitumumab (n = 53), or investigator’s choice (n =54; [trifluridine/tipiracil (Lonsurf), n = 37; regorafenib (Stivarga), n = 14]).

Eligible patients were 18 years or older with pathologically documented metastatic CRC with a KRAS G12C mutation who received at least 1 prior therapy for metastatic disease.² Additionally, patients had an ECOG performance status of 2 or less, measurable disease per RECIST v1.1, and at least 3 months of life expectancy.

Exclusion criteria included active brain metastases, history of hematological malignancies, leptomeningeal disease, and prior treatment with a KRAS G12C inhibitor.

Key secondary end points were OS and ORR; additional secondary end points were time to response, duration of response, disease control, and safety.

Grade 3 or higher treatment-related adverse events (TRAEs) were observed in 45.3% of the 960 mg sotorasib/panitumumab group, 34.0% of the 240 mg sotorasib/panitumumab group, and 45.1% of the investigator’s choice group; grade 3 or higher treatment-related hepatoxicity events occurred in 1.9%, 0%, and 2.0%, respectively. The most common TRAEs with 960 mg sotorasib/panitumumab were dermatitis acneiform (17.0%), hypomagnesemia (7.5%), and rash (5.7%).

Previously, the treatment combination was approved in the indicated patient population after primary analysis from the trial showed that the primary end point, progression-free survival, was met.^3,4

References

1. Pietrantonio F, Salvatore L, Esaki T, et al. Overall survival analysis of the phase III CodeBreaK 300 study of sotorasib plus panitumumab versus investigator’s choice in chemorefractory KRAS G12C colorectal cancer. J Clin Oncol. doi:10.1200/JCO-24-02026
2. Sotorasib and panitumumab versus investigator's choice for participants with kirsten rat aarcoma (KRAS) p.G12C mutation (CodeBreak300). ClinicalTrials.gov. Updated April 15, 2025. Accessed April 25, 2025. https://tinyurl.com/mtf4e3am
3. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed April 25, 2025. https://shorturl.at/1WviB
4. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C [published correction appears in N Engl J Med. 2025 Feb 13;392(7):728. doi: 10.1056/NEJMx240006.]. N Engl J Med. 2023;389(23):2125-2139. doi:10.1056/NEJMoa2308795