The KRAS-Variant and Cetuximab in HPV-Positive Oropharyngeal Cancer: Results from the NRG/RTOG 1016 Trial.

PURPOSE: NRG/RTOG 1016 was a phase III noninferiority trial comparing IMRT + cisplatin versus IMRT + cetuximab for human papillomavirus-positive oropharyngeal squamous cell cancer (HPV+ OPSCC). A germline mutation (the KRAS-variant) previously identified patients with improved outcomes to radiation + cetuximab + cisplatin; thus, we investigated whether there may be similar benefits for IMRT + cetuximab.

PATIENTS AND

METHODS

562 patients were tested, with 16% positive for the KRAS-variant. Clinical endpoints were per NRG/RTOG 1016, and hazard ratios (HR) were estimated by Cox models. Negative binomial regression modeled treatment-related acute and late grade 3 to 5 adverse events (AE). All models included KRAS, assigned treatment, their interaction, and other prognostic variables tested at two-sided 0.05.

RESULTS

There was no association between the KRAS-variant and clinical outcomes. There were higher local-regional failure rates (LRF) in nonvariant 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 to 4 acute mucositis was higher in nonvariant 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 nonvariant 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).

CONCLUSIONS

Possible lower LRF and less acute toxicity with cetuximab versus cisplatin for KRAS-variant patients seem to be offset by potentially increased late toxicity. Further evaluation of this class of biomarkers is warranted.

SIGNIFICANCE: Germline microRNA-disrupting biomarkers are functional biomarkers being studied to help guide treatment personalization in cancer. The work in this study is a hypothesis-generating evaluation of the KRAS-variant as a potential biomarker to help predict outcomes and toxicity in patients with head and neck cancer treated with radiation and cetuximab. Findings from this work suggest that these biomarkers may have the potential to differentiate patients at risk of acute versus late toxicity, supporting further study of these biomarkers in radiation studies.