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Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation
Judy Wang1, Patricia Martin-Romano2, Philippe Cassier3
1Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA.
Background:
Patients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation.
Methods:
Eligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method.
Results:
Ten patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non-small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3-4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%).
Conclusion:
Based on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development.
Clinicaltrials.Gov Identifier:
NCT04006301.
Insights
A phase I trial of JNJ-74699157, a KRAS G12C inhibitor, showed dose-limiting toxicities and no significant clinical benefit in advanced cancers. Further development was halted due to safety concerns.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- KRAS-mutant cancers present limited therapeutic options.
- JNJ-74699157 is an oral, selective, covalent inhibitor targeting the KRAS G12C isoform.
- This study investigated JNJ-74699157 in patients with advanced KRAS G12C-mutated cancers.
Purpose of the Study:
- To evaluate the safety and preliminary efficacy of JNJ-74699157.
- To determine dose-limiting toxicities and maximum tolerated dose.
- To assess the response of advanced cancers with KRAS G12C mutations to JNJ-74699157.
Main Methods:
- Phase I clinical trial design.
- Modified continual reassessment method for dose escalation.
- Daily oral administration of JNJ-74699157 in 21-day cycles.
Main Results:
- Ten patients with non-small cell lung cancer, colorectal cancer, and unknown primary site carcinoma were enrolled.
- Dose-limiting toxicities, specifically increased blood creatinine phosphokinase (CPK), were observed at 100 mg and 200 mg dose levels.
- The best observed response was stable disease in 40% of patients, with no significant clinical benefit.
Conclusions:
- Dose-limiting skeletal muscle toxicities and lack of efficacy at the 100 mg dose led to the cessation of further enrollment.
- The safety profile of JNJ-74699157 was deemed unfavorable for continued clinical development.
- JNJ-74699157 is not recommended for further investigation in KRAS G12C-mutated cancers based on this phase I study.
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