A dual-oral combination of the focal adhesion kinase (FAK) inhibitor ifebemtinib and the KRAS G12C inhibitor garsorasib was evaluated in previously treated patients with KRAS G12C–mutated metastatic colorectal cancer (mCRC). Results from the multicenter phase 1b/2 study, which included a randomized phase 2 component, were published in the September 2026 issue of The Lancet Oncology.
The original article, “Ifebemtinib plus garsorasib in previously treated metastatic colorectal cancer with KRAS G12C mutation: a multicentre, randomised, phase 1b/2 trial,” was authored by Zhengbo Song, Liming Zhu, Ying Liu, Rongbo Lin, Xingya Li, Yongzhong Luo, Yuan Yuan, Huaqiu Shi, Yiping Zhang, Baoyuan Zhang, Yinxin Zhu, Zaiqi Wang, and Xiangdong Cheng.
Study Design
Ifebemtinib is an oral FAK inhibitor. Preclinical findings supported its combination with garsorasib, an oral KRAS G12C inhibitor, as a strategy to address adaptive resistance to KRAS G12C inhibition. The phase 1b portion used a 3+3 design to determine the recommended phase 2 dose. Six patients with previously treated KRAS G12C–mutated non-small cell lung cancer received ifebemtinib 100 mg once daily plus garsorasib 600 mg twice daily. No dose-limiting toxicities were observed, establishing this regimen as the recommended phase 2 dose.
For the KRAS G12C–mutated mCRC cohort, phase 2 was conducted in two parts. An initial single-arm study evaluated ifebemtinib plus garsorasib using a Simon two-stage design. After the prespecified activity threshold was reached, the trial proceeded to an open-label randomized study comparing ifebemtinib plus garsorasib with garsorasib monotherapy.
Eligible patients were adults with locally advanced or metastatic colorectal cancer harboring a KRAS G12C mutation, ECOG performance status 0–1, and progression after previous irinotecan- or oxaliplatin-based combination therapy. Previous treatment with a KRAS G12C or FAK inhibitor was not permitted.
The primary phase 2 endpoint was investigator-assessed objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included disease control rate, progression-free survival (PFS), duration of response, overall survival (OS), and safety. The study is registered as NCT06166836 and NCT05379946.
Ifebemtinib and Garsorasib: Mechanisms of Action
Ifebemtinib (IN10018) is a potent, selective oral inhibitor of focal adhesion kinase (FAK), a non-receptor tyrosine kinase involved in signaling pathways that regulate tumor-cell survival, migration, and stromal remodeling. FAK activation has also been implicated in adaptive resistance to KRAS G12C inhibition. Preclinical studies have shown that ifebemtinib can synergize with KRAS G12C blockade by suppressing FAK–YAP signaling, reducing cancer-associated fibrosis, and enhancing T-cell infiltration, providing the rationale for combining FAK inhibition with KRAS inhibition.
Garsorasib (D-1553) is an oral KRAS G12C inhibitor. The combination therefore pairs KRAS G12C inhibition with FAK inhibition, a strategy supported by preclinical evidence showing that FAK inhibition can enhance the activity of KRAS G12C blockade.
Single-Arm Phase 2 Results
Fifteen patients received ifebemtinib plus garsorasib in the single-arm portion. The median age was 53 years, and all participants were Asian. At the June 30, 2025 data cutoff, with a median follow-up of 23.8 months, seven patients had a partial response, six had stable disease, and one had progressive disease. The confirmed ORR was 46.7% (95% CI, 21.3–73.4) in the safety analysis set and 50.0% (95% CI, 23.0–77.0) among response-evaluable patients. Median duration of response was 5.4 months, median PFS was 6.9 months, and median OS was 14.3 months. The observed response rate met the criterion for proceeding to the randomized portion of the study.
Randomized Phase 2 Results
Thirty-six patients were randomly assigned 1:1 to ifebemtinib plus garsorasib or garsorasib alone, with 18 patients in each group. Median follow-up was 10.3 months with the combination and 10.9 months with monotherapy.
The confirmed ORR, the primary endpoint, was:
- 38.9% (95% CI, 17.3–64.3) with ifebemtinib plus garsorasib
- 16.7% (95% CI, 3.6–41.4) with garsorasib alone
The between-group difference was 22.2% (95% CI, –7.7 to 49.1; one-sided p=0.068). Therefore, the improvement in ORR did not reach the prespecified threshold for statistical significance. Disease control was reported in 100% of patients receiving the combination and 77.8% receiving garsorasib alone. Median duration of response was 15.4 months with the combination and was not estimable in the monotherapy group. Median PFS was 7.7 months with ifebemtinib plus garsorasib versus 4.0 months with garsorasib alone (HR 0.48; 95% CI, 0.22–1.04; nominal one-sided p=0.029).
Median OS was not estimable in the combination group and was 7.5 months with garsorasib alone (HR 0.34; 95% CI, 0.11–1.12; nominal one-sided p=0.032). These time-to-event comparisons were descriptive, with nominal p values provided for reference only and without formal statistical hypothesis testing.
Safety
Across the single-arm and randomized cohorts, 33 patients received ifebemtinib plus garsorasib. Treatment-related adverse events occurred in all 15 patients in the single-arm cohort and in 17 of 18 patients receiving the combination in the randomized cohort. Among all 33 patients treated with the combination, the most common treatment-related adverse events were diarrhea and proteinuria, each reported in 64%, followed by nausea in 52%.
Grade 3 treatment-related adverse events occurred in 30% of patients receiving the combination and 28% of those receiving garsorasib monotherapy. The most frequent grade 3 events with the combination were diarrhea in 18%, proteinuria in 6%, and intestinal obstruction in 6%.
No grade 4 treatment-related adverse events or treatment-related deaths were reported. Serious adverse events occurred in 30% of patients receiving the combination and 22% receiving garsorasib alone. One patient in the monotherapy group died from the underlying malignancy within 30 days after completing study treatment; investigators considered the death unrelated to garsorasib. No treatment-emergent adverse event led to study-drug discontinuation. Dose reductions associated with treatment-emergent adverse events occurred in 24% of patients receiving the combination and 6% receiving garsorasib alone.
Exploratory cfDNA Analysis
Baseline circulating cell-free DNA samples were available from 48 patients, with KRAS G12C detected in 35 patients. The investigators reported deeper and more durable clearance of KRAS G12C variant allele frequency with ifebemtinib plus garsorasib compared with garsorasib alone. These analyses were exploratory.
Limitations
The investigators highlighted several limitations. The randomized portion included only 36 patients, reflecting the signal-seeking design and an overly optimistic initial assumption regarding the expected ORR with the experimental regimen. The primary endpoint difference in ORR did not reach statistical significance. In addition, the trial was open-label and did not use masked independent central review, introducing uncertainty into assessment of treatment effect. Finally, the study was conducted exclusively in an Asian population, which may limit the generalizability of the findings to other racial and ethnic populations.
Takeaway
Ifebemtinib plus garsorasib showed encouraging antitumor activity with a manageable safety profile in previously treated KRAS G12C–mutated mCRC. In the randomized phase 2 portion, the combination produced a numerically higher ORR and longer median PFS than garsorasib alone; median OS was not estimable with the combination versus 7.5 months with monotherapy (HR 0.34; 95% CI, 0.11–1.12). However, the primary ORR comparison did not reach statistical significance.
The findings should be interpreted cautiously because of the small randomized cohort, open-label design, absence of masked independent central review, and exclusively Asian study population. Overall, the results provide preliminary support for further evaluation of FAK inhibition as a strategy to enhance KRAS-targeted therapy and warrant a pivotal trial of ifebemtinib plus garsorasib in this population.
