Dominik Modest, MD, presented these new results of the phase 3 CodeBreaK 300 trial at the 2024 ASCO Gastrointestinal Cancers Symposium.
The KRAS G12C mutation occurs in 3%-4% of metastatic colorectal cancer cases, according to Dr. Modest and the other authors of a paper published in the New England Journal of Medicine describing the primary outcome of the trial. The study included 160 patients who were randomized to once daily sotorasib (960 mg) plus panitumumab (Soto960), once daily sotorasib (240 mg) plus panitumumab (Soto240), or investigator’s choice of trifluridine–tipiracil or regorafenib.
The December 2023 paper described improvements in median progression-free survival, progression or death, and objective response (OR). The authors described statistically significant improvements in disease progression or death in the Soto960 group (hazard ratio [HR], 0.49; P = .006) and the Soto240 group (HR, 0.58; P = .03). The objective response rate was highest in the Soto960 group (26.4%; 95% CI, 15.3%-40.3%), followed by the Soto240 group (5.7%; 95% CI, 1.2%-15.7%), and the control group (0%; 95% CI, 0.0%-6.6%). Grade 3 or higher treatment-related adverse events were generally similar at 35.8% (Soto960), 30.2% (Soto240), and 43.1% (control) in each group. The most common adverse events associated with sotorasib-panitumumab were skin-related toxicity and hypomagnesemia.
The new analysis showed that both doses of sotorasib also improved patient-reported outcomes from baseline to week 8, Dr. Modest, professor of medicine at Charité University of Medicine in Berlin, said at the meeting.
Compared with the chemotherapy group, there were statistically significant differences in least square mean change from baseline to week 8 for: pain at its worst in the Soto240 group (Brief Pain Inventory [BPI], –1.18; 95% CI, –2.05 to –0.32) and the Soto960 group (BPI, –1.49; 95% CI, –2.36 to –0.61); and physical functioning, as measured by the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire, in the Soto240 (7.95; 95% CI, 2.39-13.51) and Soto960 (6.73; 95% CI, 1.05-12.41) groups. Nearly all other measures trended toward favoring the sotorasib/panitumumab groups, but did not reach statistical significance. A similar pattern was seen in time to deterioration measures. Among adverse events, diarrhea trended toward being more frequent in the intervention arms.
At week 9, 63% of patients in Soto960 and 84% in Soto240 reported improvement in the Patient Global Impression of Change score (PGI-C), versus 37% in the chemotherapy arm. At week 17, the percentages were 77%, 59%, and 21%, respectively.
“The clinical benefits and the better quality of life outcomes associated with sotorasib at the high dose of 960 milligrams plus panitumumab establishes this combination as a potential new standard [therapy] for patients with chemorefractory KRAS G12C mutant colorectal cancer, and I think it’s quite reassuring that even if you compare two active drugs versus one active drug, this does not necessarily translate into impaired quality of life assessments by the patients,” Dr. Modest said during his presentation.
CodeBreaK 300 may point the way to other dual therapies involving kinase inhibitors, according to Rona Yaeger, MD, who wrote an accompanying editorial to the NEJM paper. Dr. Yaeger noted that clinical and preclinical studies had shown that targeted oncogenes like KRAS G12C and BRAF V600E alone would be insufficient in colorectal cancer.
When combined with KRAS G12C inhibitors, EGFR inhibitors prevent EGFR from participating in negative feedback loops that can otherwise lead to drug resistance. “Whether targeting [receptor tyrosine kinases like EGFR] in epithelial tumors other than those associated with colorectal cancers would improve the incidence of response to KRAS G12C inhibitors remains unknown,” wrote Dr. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. There is an ongoing clinical trial evaluating KRAS G12C inhibitors combined with EGFR antibodies in both lung and pancreatic cancer.
She noted that colorectal tumors have high levels of receptor tyrosine kinases, and argued that this will require higher doses of KRAS G12C inhibitors or novel drugs with higher activity. This is supported by the higher frequency of response and longer PFS at the higher dose in CodeBreaK 300, but could present a challenge: “Lowering the drug dose to manage toxic effects may limit the efficacy of the drug against some cancers,” she wrote.
Dr. Yaeger highlighted the KRYSTAL-10 phase 3 randomized trial, which is assessing the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab versus chemotherapy in advanced solid tumors with the KRAS G12C mutation.
“The CodeBreaK 300 trial is an exciting first step for targeting KRAS in colorectal cancer,” Dr. Yaeger wrote.
Dr. Modest has financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Incyte, Lily, Merck Serono, Merck Sharp & Dohme, Onkowissen, Pierre Fabre, Roche, and SERVIER. Dr. Yaeger has financial relationships with Amgen, Boehringer Ingelheim, Daiichi Sankyo, Mirati, Pfizer, and Zai Lab.
