LUX-Head & Neck 1: A Phase III Trial of Afatinib vs Methotrexate for the Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma After Platinum-Based Chemotherapy

A randomised, open-label, Phase III study to evaluate the efficacy and safety of oral afatinib vs intravenous (IV) methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (SqCC) who have progressed after platinum-based therapy.

Trial CTgov-Identifier: NCT01345682


SqCC of the oral cavity, oropharynx, hypopharynx or larynx, that was recurrent and/or metastatic and not amenable for salvage surgery or radiotherapy

Progressive disease after first-line cisplatin or carboplatin (≥2 cycles) for recurrent and/or metastatic disease

No prior treatment with epidermal growth factor receptor (EGFR) inhibitors Eastern Cooperative Oncology Group performance status of 0–1

N = 483

Randomisation 2:1

  • Afatinib 40 mg
    Oral once daily

  • Methotrexate 40 mg/m2
    IV once weekly


Primary outcome measures:
Progression free survival (PFS), assessed by  independent central review

Key secondary outcome measure:
Overall survival (OS)

Secondary outcome measures: 
Objective response (OR) 
Disease control rate (DCR)
Tumour shrinkage
Health-related quality of life (HRQoL)


LUX-Head & Neck 1 met its primary endpoint of PFS and showed that patients taking afatinib after failure of previous platinum-based chemotherapy experienced a significant delay in tumour growth of 2.6 vs 1.7 months with methotrexate (MTX). This translated into a 20% reduction in risk of disease progression.

PFS figure1


OS was not significantly different between afatinib and methotrexate

OS figure2


DCR was achieved in 49.1% of patients on afatinib vs 38.5% of patients on methotrexate.

DCR figure3


Compared with methotrexate, afatinib was associated with delayed time to deterioration of global health status (3.3 vs 2.7 months, p=0.027), pain (3.0 vs 2.3 months, p=0.022) and swallowing (3.8 vs 2.1 months, p=0.004).


Adverse events (AEs) of Grade ≥3 occurred in 67% of patients in the afatinib group compared with 63% in the methotrexate group. The most frequent AEs were rash/acne (Grade 3/4=10%) and diarrhoea (Grade 3/4=9%) with afatinib and stomatitis (Grade 3/4=8%) and neutropenia (11%) with methotrexate.

Subgroup analysis according to age:

Analysis according to the pre-specified subgroups of patients aged ≥65 years and

Subgroup analysis according to characteristics linked to HPV negativity:

Post-hoc analyses found that subgroups of patients that had baseline characteristics potentially linked to human papillomavirus (HPV) negativity (i.e. p16-negative disease, primary disease in the larynx, and smoking history ≥10 pack-years) exhibited a greater benefit in PFS with afatinib than with methotrexate.


Afatinib was associated with significant improvements in PFS and had a manageable safety profile.


Machiels J-P, Haddad RI, Fayette J, et al. LUX-Head & Neck 1: Afatinib versus methotrexate as second-line treatment for patients (pts) with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based therapy. Lancet Oncol 2015;16(5):583–594.

Clement PM, Gauler T, Machiels JP, et al. Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial. Ann Oncol 2016;27:1585–1593. (Accessed: April 2017).