ESMO 2014: Afatinib vs Methotrexate in Second-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Primary efficacy results of a phase III LUX-Head and Neck 1trial

Primary efficacy data from the LUX-Head and Neck, phase III trial of second-line treatment with afatinib vs methotrexate showed improvement in the study’s primary endpoint progression-free survival (PFS) and delayed deterioration of patient-reported outcomes with a manageable safety profile in patients with  head and neck squamous cell carcinoma (HNSCC) after failure of platinum-based therapy. The results were presented durring the Proffered Paper session on Head and Neck Cancer at ESMO Congress 2014 Congress in Madrid, Spain by Prof. Jean-Pascal Machiels of the Medical Oncology Department, Cliniques Universitaires St. Luc, Brussels, Belgium.

Patients with recurrent/metastatic HNSCC who progress after first-line platinum-based therapy have a dismal prognosis with median overall survival (OS) of approximately 3–6 months.

Epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of HNSCC and is associated with poor prognosis. Afatinib, an orally available, irreversible ErbB family blocker, showed promising anti-tumour activity in a phase II trial in patients with recurrent/metastatic HNSCC.

Afatinib vs methotrexate in second-line treatment

In this phase III trial, patients with recurrent/metastatic HNSCC after progression on/after platinum-based therapy were randomised 2:1 to oral treatment with afatinib (322 patients) or intravenous methorexate (161 patients). They were stratified by ECOG performance status (0 vs 1) and prior use of anti-EGFR antibody therapy in the recurrent/metastatic setting.

The primary endpoint was PFS; secondary endpoints included OS, objective response rate (ORR), patient reported outcomes and safety.

The study used RECIST 1.1 criteria and the primary analysis was based on independent radiology review. It was required 364 independent events to detect hazard ratio (HR) of 0.70 (increase in median PFS from 2.1 to 3.0 months) at 90% power with one-sided type-I error of α=0.025. For OS analysis it was required 343 deaths to detect HR of 0.73 (increase in median OS from 6.5 to 8.9 months) at 80% power with one-sided type-I error of α=0.025.

The study recruitment in 19 countries around the world started in January 2012 and finished in December 2013 with a median follow-up of 6.7 months. Patient characteristics were well balanced in both groups.

Afatinib improved at a statistically significant level the primary study endpoint of PFS (median 2.6 vs 1.7 months; p = 0.03). The PFS was more favourable with afatinib in subgroup analysis as well. Howevver, afatinib did not improve OS in comparison with methorexate (median 6.8 vs 6.0 months).

Disease control rate was higher with afatinib vs methotrexate (49.1% vs 38.5%; p=0.035); the ORR was 10.2% vs 5.6% (p=0.10).

Tumour shrinkage from baseline was observed in 34.8% afatinib-treated patients compared with 22.4% of methotrexate-treated patients.

Assessed by European Organisation for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 and Head and Neck cancer-specific module (QLQ-H&N35) for pain and swallowing, afatinib showed delay in deterioration of global health status, pain and swallowing (all p ≤ 0.03), and provided improvement in pain.

The most frequent grade 3/4 drug-related adverse events were rash/acne (9.7%) and diarrhoea (9.4%) with afatinib, and leukopaenia (15.6%) and stomatitis (8.1%) with methotrexate.


Prof. Machiels concluded that afatinib significantly improved PFS vs methotrexate. Tumour shrinkage was greater, response rate higher and DCR significantly higher compared to methotrexate. Patient-reported outcomes favoured afatinib over methotrexate. Fewer treatment-related dose reductions, discontinuations and fatal events were recorded with afatinib compared with methotrexate.

Afatinib is the first oral tyrosine kinase inhibitor to demonstrate efficacy and improved patient-reported outcomes in a phase III trial in this setting. Investigations with adjuvant afatinib in locally-advanced HNSCC following chemoradiotherapy are ongoing.

At the beginning of the session, the participants were alerted to the fact that the last approved therapy in Head & Neck cancer was cetixumab, 10 years ago, and that there is a desperate need for progress. Cetixumab is the only approved targeted therapy but there are no predictive biomarkers.

LUX-1 trial is the second positive study for recurrent/metastatic Head and Neck cancer since the EXTREME study. Afitinib showed to be an active agent in this disease and the first oral targeted agent to show benefit, quality of life and functional outcome improvements.

Discussing the study results, Dr Seiwert  said that the difference of 0.9 months in PFS is of unclear clinical benefit and uncertain to lead to the drug approval. However, he suggested that there are two potential ways to lead to progress in this setting, one being more passive, waiting for the results of the LUX-2 study results and the second one, active search of predictive biomarkers to identify population with larger effect size.

The subgroup analysis showed that the most benefit seemed to be found in the patients who did not receive prior EGFR therapies (suggesting a degree of cross-resistance) and in patients with p16 positive status (HPV negative disease) but this finding should be cautiously interpreted.


LBA29_PR: Afatinib versus methotrexate (MTX) as second-line treatment for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based therapy: primary efficacy results of LUX-Head & Neck 1

The study sponsor was Boehringer Ingelheim.