JNJ-74699157 / J&J - LARVOL DELTA

[VIRTUAL] Clinical Data for KRAS G12C Inhibitors (IASLC-WCLC 2020) - "Currently the phase 3 CodeBreak 200 trial of sotorasib in combination with docetaxel is recruiting patients with locally advanced and unresectable or metastatic NSCLC with KRAS G12C who are previously treated with 1 prior therapy...The agent was also administered in combination with either pembrolizumab, afatinib, or cetuximab in various expansion cohorts...Treatment with adagrasib in KRYTAL-1 led to TRAEs of any grade in 85% of the population, as well as grade 3/4 TRAEs in 30% and grade 5 TRAEs in 2%. Upcoming trials exploring KRAS inhibition would be phase 1 studies of JNJ-74699157 and GDC-6036 as treatment of patients with KRAS G12C mutations."

Clinical data • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation. (PubMed, Oncologist) - P1 | "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."

Journal • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1; N=140; Not yet recruiting; Sponsor: Janssen Research & Development, LLC

Clinical • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1; N=140; Recruiting; Sponsor: Janssen Research & Development, LLC; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1; N=10; Completed; Sponsor: Janssen Research & Development, LLC; Active, not recruiting ➔ Completed; Trial completion date: Mar 2021 ➔ Jul 2020; Trial primary completion date: Mar 2021 ➔ Jul 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1; N=10; Active, not recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Jul 2023 ➔ Mar 2021; Trial primary completion date: Jul 2023 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1; N=10; Active, not recruiting; Sponsor: Janssen Research & Development, LLC; Recruiting ➔ Active, not recruiting; N=140 ➔ 10

Clinical • Enrollment change • Enrollment closed • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS

KRAS G12C-mutant non-small-cell lung cancer: biology, developmental therapeutics, and molecular testing. (PubMed, J Mol Diagn) - "These agents include sotorasib (AMG 510), adagrasib (MRTX 849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for expression of PD-L1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRAS protein."

IO biomarker • Journal • Review • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • HER-2 • KRAS • MET • NTRK • PD-L1 • ROS1

KRAS: From undruggable to a druggable Cancer Target. (PubMed, Cancer Treat Rev) - "Recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target K-RAS G12C. Additionally, various other approaches including, SHP2, SOS1 and eIF4 inhibition, have been utilized to abrogate tumor growth in K-RAS mutant cells, resulting in a renewed interest in this pathway. In this review article, we provide an overview on the role of K-RAS in tumorigenesis, past approaches to inhibiting Kras, and current and future prospects for targeting Kras."

Journal • Review • Oncology

KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? (PubMed, Cancer Treat Rev) - "Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRAS at the cysteine at residue 12, keeping KRAS in its inactive GDP-bound state and inhibiting KRAS-dependent signaling...In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps."

IO Biomarker • Journal • Review