Combining sotorasib and panitumumab improved progression-free survival for patients with KRAS G12C mutation in metastatic colorectal cancer, based on the phase 3 CodeBreaK 300 trial.
Sotorasib (Lumakras) across multiple dose levels in combination with panitumumab (Vectibix) led to an improvement in progression-free survival (PFS) vs standard of care (SOC) among patients with chemorefractory metastatic colorectal cancer (mCRC) harboring a KRAS G12C mutation.1
Findings come from the primary analysis of the phase 3 CodeBreaK 300 trial (NCT05198934) which were recently published in the New England Journal of Medicine.1,2 At the data cutoff date of June 19, 2023, with a median follow-up of 7.8 months (range, 0.1-13.9), patients treated with either 960 mg or 240 mg of sotorasib with panitumumab and SOC achieved a median PFS of 5.6 months (95% CI, 4.2-6.3), 3.9 months (95% CI, 3.7-5.8), and 2.2 months (95% CI, 1.9-3.9), respectively.
The hazard ratio (HR) for disease progression or death in the 960-mg sotorasib/panitumumab arm vs the SOC arm was 0.49 (95% CI, 0.30-0.80; P = .006). The HR for disease progression or death in the 240-mg sotorasib/panitumumab arm vs the SOC arm was 0.58 (95% CI, 0.36-0.93; P = .03).
“This is the first phase 3 clinical trial to show a benefit over standard of care in patients with the KRAS G12C mutation whose cancer progressed after receiving standard chemotherapy. The efficacy results from our study are promising in this population with unmet needs and should set a new standard of care for metastatic colorectal cancer patients with KRAS G12C mutation who progressed following prior standard treatments,” said Marwan Fakih, MD, professor in the Department of Medical Oncology & Therapeutics Research and the Judy & Bernard Briskin Distinguished Director of Clinical Research at City of Hope, in a press release.
The multicenter, open-label, randomized, phase 3 CodeBreaK 300 trial randomized patients with chemorefractory KRAS G12C-positive, metastatic CRC who were naïve to prior KRASG12C inhibitors in a 1:1:1 fashion where they were treated with 960 mg of the KRAS G12C inhibitor sotorasib once a day plus panitumumab (n = 53), 240 mg of sotorasib once daily plus panitumumab (n = 53), or investigator’s choice of standard trifluridine/tipiracil (TAS-102; n = 37) or regorafenib (n = 14).
The primary end point of the study was PFS as assessed by blinded independent central review according to the RECIST v1.1., and key secondary end points included overall survival and objective response.
Additional data showed that the objective response rates were 26.4% (95% CI, 15.3-40.3), 5.7% (95% CI, 1.2-15.7), and 0% (95% CI, 0.0-6.6) in the 960 mg sotorasib/panitumumab, 240 mg sotorasib/panitumumab, and SOC arms, respectively. Overall survival data are still maturing.
For safety, grade 3 or greater treatment-related adverse events (AEs) were seen in 35.8%, 30.2%, and 43.1% of patients, across the 3 arms, respectively. With sotorasib plus panitumumab, the most common AEs were skin-related toxicities and hypomagnesemia.
“While this study sets a new standard following progression on standard chemotherapy, additional studies will interrogate the value of this regimen when combined with standard chemotherapy in earlier treatment settings in patients with metastatic KRAS G12C mutated colorectal cancer,” said Fakih in a press release.1 “In addition, ongoing biomarker work will help better define mechanisms of resistance to this targeted combination and how to overcome such challenges.”