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

Authors

Joanne Weidhaas
Chen Hu
Ritsuko Komaki
Gregory Masters
George Blumenschein
Joe Chang
Bo Lu
Adam Dicker, Thomas Jefferson UniversityFollow
Jeffrey Bogart
Yolanda Garces
Samir Narayan
Clifford Robinson
Vivek Kavadi
Joel S Greenberger
Christopher Koprowski
James Welsh
Elizabeth Gore
Robert MacRae
Rebecca Paulus
Jeffrey Bradley

Document Type

Article

Publication Date

10-11-2023

Comments

This article is the author's final published version in Cancer Research Communications, Volume 3, Issue 10, October 2023, Pages 2074 - 2081.

The published version is available at https://doi.org/10.1158/2767-9764.CRC-23-0084.

Copyright © 2023 The Authors

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

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.

Recommended Citation

Weidhaas, Joanne; Hu, Chen; Komaki, Ritsuko; Masters, Gregory; Blumenschein, George; Chang, Joe; Lu, Bo; Dicker, Adam; Bogart, Jeffrey; Garces, Yolanda; Narayan, Samir; Robinson, Clifford; Kavadi, Vivek; Greenberger, Joel S; Koprowski, Christopher; Welsh, James; Gore, Elizabeth; MacRae, Robert; Paulus, Rebecca; and Bradley, Jeffrey, "The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC" (2023). Department of Radiation Oncology Faculty Papers. Paper 196.
https://jdc.jefferson.edu/radoncfp/196

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

37728512

Language

English