Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation

Judy Wang, Patricia Martin-Romano, Philippe Cassier, Melissa Johnson, Eric Haura, Laurie Lenox, Yue Guo, Nibedita Bandyopadhyay, Michael Russell, Elizabeth Shearin, Josh Lauring, Laetitia Dahan, Judy Wang, Patricia Martin-Romano, Philippe Cassier, Melissa Johnson, Eric Haura, Laurie Lenox, Yue Guo, Nibedita Bandyopadhyay, Michael Russell, Elizabeth Shearin, Josh Lauring, Laetitia Dahan

Abstract

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.

Keywords: KRAS G12C mutation; JNJ-74699157; advanced solid tumors; pharmacokinetics; safety.

© The Author(s) 2022. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
Overall anti-tumor activity of JNJ-74699157 based on best overall response (per RECIST v1.1) and duration of treatment. Abbreviations: CRC, colorectal adenocarcinoma; NSCLC, non–small cell lung cancer; PD, progressive disease; SD, stable disease.
Figure 2.
Figure 2.
Plasma concentration–time profiles of JNJ-74699157 (a) and M1 (b) at Cycle 1 Day 1 (Cohort 1) and Cycle 2 Day 1 (Cohort 2) after administration of 100 mg dose once daily (Pharmacokinetics data analysis Set). Abbreviations: h, hours; qd, once daily.

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Source: PubMed

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