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LUX-Head & Neck 3 clinical trial

Afatinib vs Methotrexate as Second-line Treatment in Asian Patients with Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck On or 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 cancer (HNSCC) following first-line platinum-based therapy.

Trial NCT01856478


  • Asian patients with histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which had recurred/metastasised and were not amenable to salvage surgery or radiotherapy
  • Documented progressive disease following a cisplatin- and/or carboplatin- and/or nedaplatin-based regimen
  • Eastern Cooperative Oncology Group performance status 0–1


Overall, 340 patients were randomised 2:1 to receive afatinib or methotrexate

Afatinib 40 mg Oral once daily
Methotrexate 40 mg/m² IV once weekly


Primary outcome measure:

Progression-free survival (PFS) assessed by independent central review


Secondary outcome measures:

Overall survival (OS)

Objective response rate (ORR)

  • Health-related quality of life


PFS by independent review:

In the overall population, median PFS was significantly longer with afatinib than methotrexate (2.9 vs 2.6 months).

Hazard ratio = 0.63 95% CI: 0.48–0.82 p=0.0005
LUX-Head & Neck 3: progression-free survival (PFS) in the overall population

HR, hazard ratio; PFS, progression-free survival.

In the afatinib and methotrexate arm, PFS rate at 12 weeks was 58% vs 41% and at 24 weeks was 21% vs 9%.

Pre-planned subgroup analysis of PFS:

The PFS benefit of afatinib over methotrexate by independent review was consistently demonstrated across most major pre-specified subgroups.


The study was not powered to detect an OS benefit; there was no significant difference in OS with afatinib versus methotrexate (median OS: 6.9 [95% CI: 6.3‒8.4] vs 6.4 [95% CI: 5.2‒8.2] months; HR=0.88 [95% CI: 0.68‒1.13]; p=0.32).

Response rate:

ORR was 28% with afatinib vs 13% with methotrexate (odds ratio [OR]: 2.76 [95% CI: 1.47‒5.18]; p=0.0016), and disease control rate was 67% and 40%, respectively.

Patient-reported quality of life outcomes:

Afatinib significantly improved global health status and swallowing symptoms compared with methotrexate; afatinib was also associated with a numerical improvement in pain symptoms, which did not reach significance.


The safety profile of afatinib was as expected from previous clinical experience and consistent with the LUX-Head & Neck 1 trial.

Grade ≥3 adverse events (AEs) were reported in 50% of patients in the afatinib arm and 45% of patients in the methotrexate arm. The most common Grade ≥3 treatment-related AEs (group terms) were:

  • Rash/acne (afatinib 4% vs methotrexate 0%)
  • Diarrhoea (afatinib 4% vs methotrexate 0%)
  • Fatigue (afatinib 1% vs methotrexate 5%)
  • Anaemia (afatinib <1% vs methotrexate 5%)
  • Leukopenia (afatinib 0% vs methotrexate 5%)

Treatment-related AEs led to dose reductions in 22% of patients in the afatinib arm and 29% of patients in the methotrexate arm, and to discontinuations in 11% of patients in the afatinib arm and 17% of patients in the methotrexate arm. Treatment-related serious AEs occurred in 8% of patients in the afatinib arm and 15% of patients in the methotrexate arm. Treatment-related fatal AEs occurred in <1% of patients in the afatinib arm and 4% of patients in the methotrexate arm.


The LUX-Head & Neck 3 trial results are consistent with the global LUX-Head & Neck 1 trial; afatinib significantly improved PFS vs methotrexate, with a manageable safety profile. In the subgroup analyses, afatinib was associated with particular benefit in patients with p16-negative disease and in those who had not responded to previous chemotherapy. In conclusion, the results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for patients with recurrent or metastatic HNSCC.

Although the LUX-Head & Neck 3 data are particularly relevant to patients in Asian countries, they could also have a wider global importance as the need for second-line treatment options remains high.

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1 (Accessed: April 2019).


Guo, Y et al. Poster presented at ASCO 2019 (Poster 6024).

*Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list, please click here. Registration conditions differ internationally; please refer to locally approved prescribing information. Afatinib is being investigated in head and neck squamous cell carcinoma (HNSCC) and is not approved for this use. The efficacy and safety of afatinib in HNSCC has not been established.

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Page last updated: June 2019