The first clinical evaluation of the chemotherapy-free combination of ifebemtinib and garsorasib showed encouraging antitumor activity in patients with previously treated KRAS G12C–mutated metastatic colorectal cancer, although the improvement in objective response rate over garsorasib alone did not reach statistical significance. The findings from the phase Ib/II trial, led by Song et al, were published in The Lancet Oncology.
KRAS G12C mutations occur in approximately 3% to 4% of metastatic colorectal cancers and are associated with poor prognosis. KRAS G12C inhibitor monotherapy has produced relatively modest response rates and short progression-free survival in previously treated disease. Combining these agents with anti-EGFR antibodies has improved outcomes, but these regimens require intravenous treatment and are commonly associated with skin toxicities.
Ifebemtinib is an oral inhibitor of focal adhesion kinase (FAK), which has been implicated in resistance to KRAS G12C inhibition. Preclinical studies suggest that FAK inhibition could enhance the activity of KRAS-targeted therapy.
Study Details
The multicenter, open-label phase Ib/II trial evaluated ifebemtinib plus the oral KRAS G12C inhibitor garsorasib in patients with KRAS G12C–mutated solid tumors. Phase Ib established the recommended phase II dose as ifebemtinib at 100 mg once daily plus garsorasib at 600 mg twice daily. Phase II then evaluated the combination in patients with previously treated KRAS G12C–mutated metastatic colorectal cancer.
Eligible patients had locally advanced or metastatic colorectal cancer harboring a KRAS G12C mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous irinotecan- or oxaliplatin-based combination therapy.
Phase II began with a single-arm evaluation of ifebemtinib plus garsorasib in 15 patients. Seven patients had partial responses, meeting the prespecified threshold to proceed to the randomized portion. An additional 36 patients were then randomly assigned 1:1 to ifebemtinib plus garsorasib or garsorasib alone. The primary endpoint was investigator-assessed objective response rate.
Key Findings
In the initial single-arm cohort, the confirmed objective response rate was 46.7%. Median progression-free survival was 6.9 months, and median overall survival was 14.3 months.
In the randomized portion, the confirmed objective response rate was 38.9% with ifebemtinib plus garsorasib vs 16.7% with garsorasib alone, although the difference did not reach statistical significance (P = .068). Disease control rates were 100% and 77.8%, respectively.
Median progression-free survival was 7.7 months with the combination vs 4 months with garsorasib alone (HR = 0.48). Median overall survival had not been reached with combination therapy and was 7.5 months with garsorasib alone (HR = 0.34). These time-to-event comparisons were descriptive and were not subject to formal statistical hypothesis testing.
The combination was associated with more grade 3 treatment-related adverse events in the randomized portion, occurring in 33% of patients vs 28% with garsorasib alone. Across all 33 patients who received the combination during phase II, the most common treatment-related adverse events were diarrhea and proteinuria, each occurring in 64%, followed by nausea in 52%. No grade 4 treatment-related adverse events or treatment-related deaths were reported.
The investigators noted that the all-oral regimen could offer an alternative to KRAS G12C inhibitor combinations with anti-EGFR antibodies, which require intravenous administration and are commonly associated with dermatologic toxicities. However, they cautioned against cross-trial comparisons and said larger comparative trials are needed to establish the role of the combination.
The authors also emphasized several limitations, including the small randomized cohort, the lack of statistical significance for the primary endpoint, the open-label design, and the lack of masked independent central review. Because all patients were Asian and the study was conducted exclusively in China, the findings may not be generalizable to other populations.
“These findings support further investigation of FAK inhibition as a strategy to enhance KRAS-targeted therapies and warrant a pivotal trial of this combination regimen in this patient population,” the investigators concluded.
Xiangdong Cheng, MD, of Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, China, is the corresponding author of the article.
DISCLOSURE: The study was funded by InxMed, InventisBio, the National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project. For full disclosures of the study authors, visit thelancet.com/oncology.
