Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial

Summary

Background

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy.

Methods

In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m² per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682.

Findings

Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1–9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0–2·7] for the afatinib group vs 1·7 months [1·5–2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65–0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients.

Interpretation

Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC.

Funding

Boehringer Ingelheim.

Introduction

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) who progress after platinum-based therapy have a dismal prognosis and no well-defined standard treatment.1, 2 In a retrospective analysis¹ of outcomes in patients with HNSCC who were refractory to platinum-based therapy, median survival was roughly 1·8 months with best supportive care. Methotrexate, taxanes, and cetuximab (a monoclonal antibody targeting EGFR) are used alone or in combination (eg, with paclitaxel and cetuximab) as second-line therapy after platinum failure, despite the lack of randomised trials demonstrating improvement in outcomes or disease-related symptoms.3, 4 Cetuximab monotherapy is approved for second-line treatment in this population,⁵ but only in the USA; it is also often used in earlier treatment lines.6, 7 In prospective studies of second-line methotrexate or cetuximab after platinum therapy in patients with recurrent or metastatic HNSCC, median survival ranged between 3 months and 6 months.2, 8, 9

Research in context

Evidence before this study

We did a systematic review of the scientific literature published up to Sept 30, 2014, using PubMed and of trials presented as abstracts at major oncology meetings (ie, annual meetings of the American Society of Clinical Oncology and the European Society for Medical Oncology). Using the search terms “phase 2” or “phase 3” and “recurrent” or “metastatic HNSCC”, we reviewed articles and presentations reporting phase 2 and 3 trials investigating anticancer agents (chemotherapy or targeted therapies) in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) who progressed on or after platinum therapy. This review of the published literature and congress presentations showed an unmet medical need for patients in this setting, with no well-defined standard of care and few efficacious treatment options.

Added value of this study

This study demonstrates that the irreversible ERBB-family blocker afatinib has clinical efficacy in second-line recurrent or metastatic HNSCC, with a significant improvement in progression-free survival and patient-reported outcomes compared with chemotherapy after platinum failure. Interestingly, we noted a more pronounced benefit for progression-free survival in patients with baseline characteristics potentially linked to human papillomavirus (HPV) negativity. To our knowledge, no studies, including this trial, have shown an improvement in overall survival in this difficult-to-treat population.

Implications of all the available evidence

In light of the unmet medical need, these data provide important new insights into the treatment of patients with recurrent or metastatic HNSCC progressing on or after platinum therapy and support further investigations with irreversible ERBB family blockers in HNSCC, particularly in patients with HPV-negative disease.

The ERBB receptor family network, comprising EGFR (HER1, ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4), plays an important part in tumorigenesis.¹⁰ About 80–90% of patients with HNSCC overexpress EGFR, and this overexpression negatively affects prognosis.⁴ Crosstalk among ERBB receptors could decrease the clinical efficacy of EGFR-targeted therapies and promote treatment resistance.¹¹ One strategy to improve efficacy and overcome resistance is to inhibit several ERBB receptors simultaneously.

Afatinib, an irreversible ERBB-family blocker,12, 13 showed efficacy in a phase 2 study of patients with recurrent or metastatic HNSCC after failure of platinum-based therapy.¹⁴ Here, we report results of a phase 3 trial comparing the efficacy and safety of afatinib with that of methotrexate in patients with recurrent or metastatic HNSCC who had progressed on or after first-line platinum-based chemotherapy. We chose methotrexate as the comparator group in this study because this single-agent chemotherapy is used globally in recurrent or metastatic HNSCC15, 16 and was a comparator for studies of other targeted agents in HNSCC.8, 9