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

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Copyright © 2023 The Authors


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.

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Supplementary Data Table 1.docx (17 kB)
Endpoints evaluated in RTOG 0617

Supplementary Data Table 2.docx (17 kB)
Representativeness of Study Participants

Supplementary Data Table 3.docx (18 kB)
KRAS Analysis Inclusion Status

Supplementary Data Table 4.docx (25 kB)
Pretreatment Characteristics by KRAS Analysis Inclusion Status

Supplementary Data Table 5.docx (17 kB)
Best Observed Response by KRAS Analysis Inclusion Status

Supplementary Data Table 6.docx (17 kB)
Worst Overall Treatment-Related Adverse Event by KRAS Analysis Inclusion Status

Supplementary Data Table 7.docx (24 kB)
Pretreatment Characteristics by KRAS-variant or non-variant status

Supplementary Data Table 8.docx (18 kB)
Overall Survival

Supplementary Data Table 9.docx (21 kB)
Overall Survival for non-variant and KRAS-Variant Patients by RT Level Assignment

Supplementary Data Table 10.docx (18 kB)
Overall Survival within non-variant Patients Cetuximab Assignment

Supplementary Data Table 11.docx (18 kB)
Local Failure within KRAS Variant Patients by As-Treated Cetuximab

Supplementary Data Table 12.docx (19 kB)
Worst Treatment-Related Toxicity By KRAS Genotype

Supplementary Data Table 13.docx (17 kB)
Worst Treatment-Related Toxicity Logistic Regression Model of KRAS and As-Treated RT Interaction

Supplementary Data Table 14.docx (18 kB)
Worst Treatment-Related Toxicity within Non-variant Patients By Cetuximab Assignment

Supplementary Data Table 15.docx (17 kB)
Worst Treatment-Related Toxicity within KRAS-Variant Patients By Cetuximab

Supplementary Data Table 16.docx (18 kB)

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