The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC. Cancer Res Commun 2023 Oct 11;3(10):2074-2081
Date
09/20/2023Pubmed ID
37728512Pubmed Central ID
PMC10566451DOI
10.1158/2767-9764.CRC-23-0084Abstract
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.
Author List
Weidhaas JB, Hu C, Komaki R, Masters GA, Blumenschein GR, Chang JY, Lu B, Dicker AP, Bogart JA, Garces YI, Narayan S, Robinson CG, Kavadi VS, Greenberger JS, Koprowski CD, Welsh J, Gore EM, MacRae RM, Paulus R, Bradley JDAuthor
Elizabeth M. Gore MD Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy Protocols
Biomarkers
Carcinoma, Non-Small-Cell Lung
Cetuximab
Humans
Lung Neoplasms
Proto-Oncogene Proteins p21(ras)
