HER2 and HER3 in HPV⁺ and HPV⁻ HNSCC—Response

We appreciate the perspective of Drs. Machiels, Galot and Schmitz of our article, which was published earlier this year in Clinical Cancer Research, prior to the publication of the LUX-Head and Neck 1 trial results. The open-label randomized phase III study did not demonstrate increased response rates to afatinib in individuals with HPV-positive HNSCC and/or prior exposure to cetuximab. Baseline tumor HER2 or HER3 expression and/or dimer formation was not included in the clinical manuscript, so the assessment of these parameters as potential predictive biomarkers to afatinib is still pending. In addition, it is possible that prior exposure to an EGFR mAb may not equal “resistance,” underscoring the importance of developing clear definitions of clinical cetuximab resistance.

We agree that close coordination between preclinical modeling and clinical trials is required to support bidirectional translation, with the ultimate goal of improving responses to anticancer therapies. Our interrogation of human tumors as well as the TCGA results demonstrated increased HER2 and HER3 expression in HPV-positive HNSCC. We agree that more research is needed, ideally in relevant preclinical models including PDXs, to determine the appropriate predictive biomarker(s) for HER2/HER3–targeted therapies.

HNSCC cells engineered to express EGFRvIII were used in our study as a model of cetuximab resistance. In fact, we demonstrated that afatinib was more effective than cetuximab in both HPV-positive cells as well as HPV-negative models rendering cetuximab resistant by virtue of EGFRvIII. In the absence of EGFRvIII expression studies in the baseline tumors from the LUX-Head and Neck 1 trial, and a direct comparison with cetuximab, the role of this EGFR variant in response to afatinib remains unknown.

We thank Drs. Machiels, Galot, and Schmitz for their interest in our study and agree that clinical results should drive further preclinical mechanistic studies.

See the original Letter to the Editor, p. 1825

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.