Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation
Open accessAbstract
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
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JNJ-74699157 phase I trial (NCT04006301) was completed in July 2020 with no results posted.
“Subsequently, JNJ-74699157 conducted a clinical phase I trial (NCT04006301) enrolling patients with KRASG12C positive advanced solid tumor, which was completed in July 2020 with no results posted.66”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [66]
Naquotinib is an orally available, irreversible, mutant-selective EGFRL858R/T790M inhibitor.
“Naquotinib (ASP8273) (66) is an orally available, irreversible and mutant-selective EGFRL858R/T790M inhibitor that has shown potential as an antitumor agent.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [66]
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Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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The Next Generation of KRAS Targeting: Reasons for Excitement and Concern
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- Authors
- Wang, J., Martin-Romano, P., Cassier, P., Johnson, M., Haura, E., Lenox, L., Guo, Y., Bandyopadhyay, N., Russell, M., Shearin, E., Lauring, J., & Dahan, L.
- Affiliations
- Florida Cancer Specialists/Sarah Cannon Research Institute , Sarasota, FL , USA
- Institut Gustave Roussy , Villejuif , France
- Centre Léon Bérard (FR)
- Sarah Cannon (US)
- Moffitt Cancer Center (US)
- Janssen Research & Development , Spring House, PA , USA
- Janssen Research & Development (United States) (US)
- Centre Hospitalier Universitaire La Timone, Marseille , France
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-24
- Volume
- 27
- Issue
- 7
- Pages
- 536-e553
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC9255981
- OpenAlex
- W4211014206
- Cited by
- 60
- References
- 8
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 12 · 2023: 16 · 2022: 6
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Oncologist (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Janssen Research & Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C mutation, KRAS inhibitors, covalent KRAS inhibitor, advanced solid tumors, dose-limiting toxicity, creatine kinase elevation, skeletal muscle toxicity, non-small cell lung cancer, colorectal cancer, oral anticancer drugs
- MeSH terms
- Adolescent, Adult, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras)
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