Sotorasib Combo Approval May Address Novel Therapy Need in KRAS G12C+ CRC

In a conversation with CancerNetwork^®, Marwan G. Fakih, MD, spoke about the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix), and how it may affect the treatment paradigm for patients with KRAS G12C-mutant metastatic colorectal cancer (CRC).¹

Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California.

According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring KRAS G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga).

Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; P = .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm.

Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic KRAS G12C-mutant CRC.² Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents.

References

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB
2. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326