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The KRAS-variant and cetuximab in HPV-positive oropharyngeal cancer - results from the NRG/RTOG 1016 trial.

The KRAS-variant and cetuximab in HPV-positive oropharyngeal cancer - results from the NRG/RTOG 1016 trial. Cancer research communications Weidhaas, J. B., Harris, J., Gillison, M. L., Blakaj, D., Krempl, G. A., Higgins, K., Phan, J., Dunlap, N. E., Mahamood, S. T., Dorth, J., Caudell, J. J., Desai, A. B., Galloway, T. J., Pennington, J. D., Currey, A., Lathrop, J., Torres-Saavedra, P. A., Hayes, D. N., Yom, S. S., Le, Q. T. 2026

Abstract

NRG/RTOG 1016 was a phase III non-inferiority trial comparing IMRT + cisplatin versus IMRT + cetuximab for HPV-positive oropharyngeal cancer (OPC) patients. A germline mutation (the KRAS-variant) previously identified patients with improved outcomes to radiation + cetuximab + cisplatin, thus we investigated if there may be similar benefits for IMRT + cetuximab.562 patients were tested and 16% positive for the KRAS-variant. Clinical endpoints were per RTOG 1016, and hazard ratios (HRs) were estimated by Cox models. Negative binomial regression modeled treatment-related acute and late grade 3-5 adverse events. All models included KRAS, assigned treatment, their interaction, and other prognostic variables tested at two-sided 0.05.There was no association between the KRAS-variant and clinical outcomes. There were higher local regional failure rates (LRF) in non-variant patients treated with cetuximab (HR=1.83 (1.19, 2.82)) versus KRAS-variant patients (HR (95% CI) = 0.90 (0.34, 2.41)). Grade 3-4 acute mucositis was higher in non-variant patients treated with cetuximab (OR = 1.41 (95% CI 0.98, 2.03)) and lower in KRAS-variant patients (OR = 0.60 (95% CI 0.25, 1.41)). However, the mean late toxicity ratio was lower in non-variant patients (0.55 [95% CI 0.35, 0.87]) versus KRAS-variant patients (1.62 [95% CI 0.57, 4.62]). KRAS by treatment interaction for acute and late AEs was not significant (p=0.0717 and 0.0659, respectively).Possible lower LRF and less acute toxicity with cetuximab versus cisplatin for KRAS-variant patients appear to be offset by potentially increased late toxicity. Further evaluation of this class of biomarkers is warranted.

View details for DOI 10.1158/2767-9764.CRC-25-0551

View details for PubMedID 41790036