Biomarkers Indicate Survival Benefit With Afatinib in HNSCC

Kathy Boltz, PhD
Published: Saturday, Feb 20, 2016

Ezra Cohen, MD

Ezra Cohen, MD

Both progression-free and overall survival (OS) with second-line afatinib (Gilotrif) in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are associated with several biomarkers, according to an analysis of the phase III LUX-Head and Neck 1 (LHN1) study, which compared afatinib with methotrexate.

“Remarkably, when we looked at progression-free survival [PFS], we identified a subset that appeared to benefit from afatinib therapy. These included patients with p16-negative disease, EGFR-amplified disease, HER3 low, and PTEN high,” first author Ezra Cohen, MD, University of California San Diego, said when presenting the results at the 2016 Multidisciplinary Head and Neck Cancer Symposium. “All of these groups appear to have favorable PFS when being treated with afatinib versus methotrexate.”

The LHN1 study randomized patients with recurrent and/or metastatic HNSCC who had progressed on first-line platinum-based chemotherapy in a 2:1 ratio to the irreversible ErbB family blocker afatinib (starting dose, 40 mg orally once daily; n = 316) or methotrexate (starting dose, 40 mg/m2 IV once weekly; n = 158). In the overall study population, afatinib significantly improved PFS (median, 2.6 vs 1.7 months; HR, 0.80; P = .030) and patient-reported outcomes.

Samples for biomarker analysis were obtained from 268 patients, and Cohen said that these samples were felt to be representative of the entire study. The analysis presented at the symposium focused on the association of prespecified biomarkers (p16, EGFR amplification, PTEN, and HER3 expression) with clinical outcomes in the trial.

Cohen explained that p16 is the standard methodology used by multiple labs and multiple publications around the world. A total of 15% (35/234) of patients were positive for p16 (H-score ≥210) and 85% (199/234) were negative for p16.

Patients were nearly evenly split between EGFR amplified (49%; 101/206) and EGFR not amplified (51%; 105/206 patients) and between HER2-low (H-score ≤50; 51%; 91/179 patients) and HER3-high (H-score >50; 49%; 88/179 patients). Most patients (74%; 137/186 patients) were PTEN-low (H-score ≤150), and 26% (49/186 patients) were PTEN-high (H-score >150).

Afatinib improved PFS over methotrexate for patients who were p16-negative (n = 199; HR, 0.70; 95% CI, 0.50-0.97), EGFR amplified (n = 112; HR, 0.53; 95% CI, 0.33-0.85), HER3-low (n = 119; HR, 0.57; 95% CI, 0.37-0.88) and PTEN-high (n = 63; HR, 0.55, 95% CI, 0.29-1.05). Likewise, OS was improved over methotrexate for patients who were EGFR amplified (HR, 0.76; 95% CI, 0.48-1.19) and for patients who were PTEN-high (HR, 0.67; 95% CI, 0.38-1.17).

Among patients who were EGFR monoclonal antibody-naïve, median PFS was 4.0 months with afatinib (n = 51) versus 2.4 months with methotrexate (n = 21; HR, 0.55; 95% CI, 0.31-0.98) and median OS was 8.0 months versus 10.3 months (HR, 1.67; 95% CI, 0.92-3.02). Among patients who were EGFR amplified, median PFS was 2.7 months with afatinib (n = 62) versus 1.5 months with methotrexate (n = 26; HR, 0.47; 95% CI, 0.28-0.80) and median OS was 6.8 versus 4.7 months (HR, 0.77; 95% CI, 0.47-1.26).

For patients who were EGFR monoclonal antibody-naïve (n = 72), objective response rate (ORR) by central review was 27.5% with afatinib versus 4.8% with methotrexate. For patients who were EGFR amplified (n= 88), ORR was 17.7% with afatinib versus 0% with methotrexate.

Overall, afatinib had more pronounced antitumor effects, in terms of PFS and ORR, in patients with p16-negative tumors, tumors with EGFR amplification, and tumors with low HER3 expression or high PTEN expression. This last group of tumors may reflect low activity of the PIK3CA pathway.

Among patients with p16-negative disease, a greater proportion had clinical benefit with afatinib versus methotrexate who also had EGFR amplification or who were therapy-naïve to EGFR monoclonal antibodies (45% reduced risk of progression or death) versus patients who had been pretreated with EGFR monoclonal antibodies (14% reduced risk of progression or death). Cohen said that p16 is a clinically relevant biomarker, since its status is routinely analyzed in HNSCC.


Tumor biomarker association with clinical outcomes in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients treated with afatinib vs methotrexate: LUX-Head & Neck 1 (LHN1). Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ. Abstract 10.

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