The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC

• Type of Material: Article
• Authors: Joanne B. Weidhaas, University of California, Los Angeles; Chen Hu, Johns Hopkins University; Ritsuko Komaki, MD Anderson Cancer Center; Gregory A. Masters, Helen F. Graham Cancer Center; George R. Blumenschein, MD Anderson Cancer Center; Joe Y. Chang, MD Anderson Cancer Center; Bo Lu, Thomas Jefferson University; Adam P. Dicker, Thomas Jefferson University; Jeffrey A. Bogart, Upstate Medical University; Yolanda I. Garces, Mayo Clinic, Rochester; Samir Narayan, St. Joseph Mercy Cancer Center; Clifford G. Robinson, Washington University, St. Louis; Vivek S. Kavadi, Texas Oncology Cancer Center, Sugar Land; Joel S. Greenberger, University of Pittsburgh; Christopher D. Koprowski, Helen F. Graham Cancer Center; James Welsh, MD Anderson Cancer Center; Elizabeth M. Fore, Medical College of Wisconsin; Robert M. MacRae, The Ottawa Hospital; Rebecca Paulus, NRG Oncology Statistics and Data management Center; Jeffrey Bradley, Emory University
• Language: English
• Date: 2023-10-11
• Publisher: American Association for Cancer Research
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1158/2767-9764.CRC-23-0084
• Title of Journal or Parent Work: Cancer Research Communications
• Volume: 3
• Issue: 10
• Start Page: 2074
• End Page: 2081
• Grant/Funding Information: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC), U24CA196067 (NRG Specimen Bank) from the NCI and Eli Lilly. J.B. Weidhaas was supported with a grant from the NCI (R01 CA238998).
• Keywords: chemotherapy; KRAS-variant patients; lung cancer; radiotherapy
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Purpose: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non–small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. Experimental Design: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran—Mantel–Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. Results: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients—while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13–10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11–0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11–2.28, P = 0.012). Conclusions/Discussion: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. Significance: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.