Sotorasib Plus Panitumumab Provides Effective Targeted Therapy Option in KRAS G12C+ mCRC

Given the lower response rates historically seen with available therapies for patients with KRAS G12C–mutated metastatic colorectal cancer (mCRC) after progression on standard-of-care (SOC) chemotherapy, the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix)provides a much-needed, highly effective, targeted treatment option, according to Marwan G. Fakih, MD.

On January 16, 2025, the FDA approved sotorasib in combination with panitumumab for the treatment of adult patients with KRAS G12C–mutated mCRC, as determined by an FDA-approved test, who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.1

This decision was supported by data from the phase 3 CodeBreak300 study (NCT05198934). Finding showed that 960 mg of sotorasib administered daily alongside panitumumab (n = 53) led to a median progression-free survival (PFS) of 5.6 months (95% CI, 4.2-6.3) vs 2 months (95% CI, 1.9-3.9) with investigator’s choice of trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga; n = 54; HR, 0.48; 95% CI, 0.3-0.78; 2-sided P = .005). Moreover, sotorasib at 960 mg plus panitumumab generated an objective response rate (ORR) of 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in the SOC arm.

“Approximately 4% of patients with mCRC have KRAS G12C mutations. The treatment [options] for those patients—similar to other patients with KRAS mutations—are quite limited after progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-[based chemotherapy] and bevacizumab [Avastin],” said Fakih. “The advent of a targeted therapy for [patients with mCRC harboring] KRAS G12C mutations with the combination of sotorasib and panitumumab, which has an updated ORR of [approximately] 30%, provides hope for these patients.”

In an interview with OncLive®, Fakih highlighted the significance of the FDA approval of sotorasib plus panitumumab in KRAS G12C–mutated mCRC, discussed key findings from CodeBreak300 that supported the approval, and emphasized the importance of genetic screening for patients with CRC to guide treatment selection and sequencing.

Fakih serves as a professor in the Department of Medical Oncology & Therapeutics Research; associate director of 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 in Duarte, California.

OncLive: What is the significance of the FDA approval of sotorasib plus panitumumab for KRAS G12C–mutated mCRC?

Fakih: It’s great to see that the FDA has approved sotorasib and panitumumab in combination for the treatment of patients with KRAS G12C–mutated mCRC. This approval provides patients access to this effective combination.

The percentage of patients with [advanced mCRC displaying] KRAS G12C mutations is certainly small; however, the treatment of those patients is relevant. We have the option of trifluridine/tipiracil [with or without] bevacizumab in that patient population [following progression on SOC chemotherapy regimens], as well as other TKIs, but the response rates are low with those approved agents. A bigger response can better palliate symptoms, and the median PFS has also been quite notable with the combination [of sotorasib plus panitumumab]. This supports the FDA’s decision to approve this combination.

What were the design and objectives of the CodeBreak300 study?

CodeBreak300 was a randomized, phase 3 clinical trial that tried to answer 2 main questions. First, does the combination of sotorasib and panitumumab improve upon the outcomes [experienced with] SOC? At that time, SOC was trifluridine/tipiracil or regorafenib. Second, is there a better dose of sotorasib [we should use]? What is the impact of a lower dose of sotorasib plus panitumumab? There were 2 doses of sotorasib evaluated: 240 mg and 960 mg daily. The third arm was the control arm.

What key efficacy and safety findings from CodeBreak300 supported this regulatory decision?

Although the study was not powered to compare the 2 doses of sotorasib—240 mg and 960 mg—as a primary end point, at the end of the day, the 960-mg dose was associated with the higher ORR of 30% [95% CI, 18.3%-44.3%] vs 8% [95% CI, 2.1%-18.2%] in the 240-mg arm on the updated analysis.2 We all agree that this was a meaningful difference in ORR. In addition, the PFS differences were also in favor of the higher dose. The take-home message is that sotorasib should be used at 960 mg in combination with panitumumab.

The other take-home message is that the combination is safe. There were no new safety signals with this combination, and it was very well tolerated. We saw the skin rashes that we would expect with panitumumab, but sotorasib itself has very minimal adverse effects, and most of those were grade 1 or 2. [These are] encouraging data supporting the safety and efficacy of this combination in patients with mCRC with KRAS G12C [mutations].

Why is genetic screening crucial for patients with CRC?

Every patient with mCRC should undergo next-generation sequencing up-front at the time of diagnosis. It is always important to understand what one’s options are as a patient; as a provider, [we need to know] how to sequence [therapies] and be prepared for that sequencing.There are also clinical trials available for first-line therapy.

It is of note that sotorasib plus panitumumab was combined safely with FOLFIRI in the frontline for mCRC [in the phase 1b CodeBreak 101 trial (NCT04185883)] with very encouraging response rates, which were presented at the 2024 ESMO Congress. Those data supported the launch of the randomized phase 3 [CodeBreaK 301] trial [NCT06252649] evaluating the combination of FOLFIRI plus panitumumab and sotorasib compared with SOC systemic chemotherapy. My advice is to look for what's targetable and make the decisions accordingly.

References

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer
2. Fakih M, Salvatore L, Esaki T, et al. Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRAS G12C-mutated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(suppl 17):LBA3510. doi:10.1200/JCO.2024.42.17_suppl.LBA3510