Biomarkers Predict HNSCC Patients Likely To Benefit From Afatinib Over Methotrexate

Analysis of the phase III LUX-Head & Neck 1 trial identifies biomarkers that predict better progression-free survival with afatinib than methotrexate

medwireNews: Researchers have identified tumour biomarkers that distinguish subgroups of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who are likely to benefit from second-line treatment with afatinib over methotrexate.

These biomarkers reflect human papillomavirus status (p16) and ErbB- and PI3K-pathway regulation, Ezra Cohen, from the University of California San Diego in the USA, and colleagues report in the Annals of Oncology.

The prespecified tumour biomarkers of interest in the LUX-Head & Neck 1 trial were p16, HER2, HER3, c-MET, PTEN and EGFR, but due to only a small sample of patients having high HER2 expression, outcomes based on this biomarker were not assessed.

Among 326 patients with HNSCC and disease progression despite at least two cycles of platinum chemotherapy participating in the phase III randomised study, 85% were p16-negative. These patients were found to derive significantly more benefit from afatinib 40 mg/day than methotrexate 40 mg/m2 per week in terms of progression-free survival (PFS), at a median of 2.7 versus 1.6 months and a hazard ratio (HR) of 0.70, particularly if they were cetuximab-naïve.

The same was true for the 52% of patients with EGFR amplification, defined as high-polyploidy (≥50% of cells with ≥4 copies) or focal amplification (≥1 cell with ≥8 copies), for whom the median PFS was 2.8 months with the irreversible ErbB family blocker versus 1.5 months with methotrexate, giving a HR of 0.53.

When the researchers analysed the two biomarkers combined, the difference in PFS improvement with afatinib over methotrexate was a significant 2.7 versus 1.5 months (HR=0.47) and there was a trend towards improved overall survival, at 6.8 versus 4.7 months (HR=0.77). By contrast, there was no improvement in PFS or overall survival with afatinib in patients who were p16-negative and lacked EGFR amplification.

The other two biomarkers associated with afatinib benefit were HER3, a potent activator of the PI3K-pathway, and PTEN, a negative regulator of the pathway; although the benefit was only significant for HER3. Low expression of HER3 (H-score ≤50), seen in 55% of patients, was associated with a PFS of 2.8 months with afatinib, compared with 1.8 months with methotrexate (HR=0.57), while for the 29% of participants with high PTEN expression (H-score >150), the corresponding durations were 1.6 and 1.4 months (HR=0.55).

“PTEN-high and HER3-low possibly reflect low intrinsic PI3K-pathway activity suggesting that constitutive PI3K-pathway activation may antagonize the activity of afatinib”, say the researchers.

They believe: “Further analysis of identified subgroups may help guide the optimal future application of these agents.

“Future studies are warranted to define assessment methodologies for these biomarkers, including relevance of the cut-offs, and provide more robust analyses of biomarker association with clinical outcomes.”


Cohen EEW, Licitra LF, Burtness B, et al. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol; Advance online publication 14 July 2017. DOI:

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