NCT01856478

LUX-Head&Neck 3: Afatinib (BIBW2992) Versus Methotrexate for the Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Cancer After Platinum Based Chemotherapy

Completed Phase 3 Results posted Last updated 12 January 2026

What this trial tests

Phase 3 trial testing Methotrexate in Head and Neck Neoplasms in 340 participants. Completed in 2 October 2024.

Timeline

7 June 2013

Primary endpoint
22 August 2018

2 October 2024

Quick facts

Lead sponsor	Boehringer Ingelheim
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	340
Start date	7 June 2013
Primary completion	22 August 2018
Estimated completion	2 October 2024
Sites	53 locations across Hong Kong, Taiwan, South Korea, Philippines, Thailand, China, Egypt, India

Drugs / interventions tested

• Methotrexate — full drug profile →
• Afatinib (afatinib) — full drug profile →

Conditions studied

• Head and Neck Neoplasms — all drugs for Head and Neck Neoplasms →

Sponsor

Boehringer Ingelheim — full company profile →

Who can join

18 and older, any sex, with Head and Neck Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response (OR) Secondary · From randomization until earliest of disease progression, death, or interim cut-off date (11-Apr-2019). Up to 35 months.

Objective response (OR) defined as the number of patients with best overall response of complete response (CR) or partial response (PR), according to RECIST 1.1. Complete response (CR) is defined as the disappearance of all target lesions and partial response (PR) is defined as decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. Patients who did not show CR or PR were considered non-responders, irrespective of protocol violations or missing data.

Group	Value	95% CI
Afatinib 40 mg	64
Methotrexate 40 mg	14

Progression Free Survival (PFS) Primary · From randomization until disease progression, death, or primary completion date, whichever occurs first. Up to 35 months.

Progression-free survival (PFS) was defined as the time from the date of randomization to the date of disease progression (PD) evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (v1.1). or to the date of death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. PFS parameters were calculated based on Kaplan-Meier curves generated for each group.

Group	Value	95% CI
Afatinib 40 mg	2.86	2.79 – 3.71
Methotrexate 40 mg	2.56	1.51 – 2.79

Overall Survival (OS) Secondary · From randomization until death. Up to 6 years.

Overall survival (OS) defined as the time from the date of randomization to the date of death, regardless of its cause. OS parameters were calculated based on Kaplan-Meier curves generated for each group.

Group	Value	95% CI
Afatinib 40 mg	6.93	6.31 – 8.41
Methotrexate 40 mg	6.41	5.16 – 8.38

Time to Deterioration in Global Health Status Secondary · From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 30 months.

Time to deterioration in global health status was defined as the time from randomization to the first decrease of 10 points on the global health/quality of life (QoL) scale. Patients with no deterioration (including those with disease progression) were censored at the last available health-related quality of life (HRQoL) assessment. The global health status (global health/QoL scale) was evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), a 30-item instrument designed to measure quality of life in cancer patients. It

Group	Value	95% CI
Afatinib 40 mg	4.17	3.65 – 4.40
Methotrexate 40 mg	2.83	2.63 – 7.75

Time to Deterioration in Pain Symptoms Secondary · From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.

Time to deterioration in pain symptoms was defined as the time from randomization to the first decrease of 10 points on the pain scale. Patients with no deterioration (including those with disease progression) were censored at their last available health-related quality of life (HRQoL) assessment. The pain scale was evaluated using the pain module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Head and Neck Cancer (EORTC QLQ-H\&N35), which is designed to measure quality of life in head and neck cancer patients. It is composed of 4 questions,

Group	Value	95% CI
Afatinib 40 mg	3.65	3.02 – 4.40
Methotrexate 40 mg	2.96	2.63 – 8.25

Time to Deterioration in Swallowing Secondary · From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.

Time to deterioration in swallowing was defined as the time from randomization to the first decrease of 10 points on the swallowing scale. Patients with no deterioration (including those with disease progression) were censored at their last available health-related quality of life (HRQoL) assessment. The swallowing scale was evaluated using the swallowing module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Head and Neck Cancer (EORTC QLQ-H\&N35), which is designed to measure swallowing difficulties in head and neck cancer patients. It is c

Group	Value	95% CI
Afatinib 40 mg	4.11	2.86 – 4.27
Methotrexate 40 mg	3.29	2.56 – 7.39

Change in Global Health Status Over Time Secondary · Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

Change in global health status over time was defined as the mean global health/QoL scale score up to the median follow-up time, describing the average global health status derived from the cumulative change over time, measured by the EORTC QLQ-C30. The EORTC QLQ-C30 is a 30-item questionnaire measuring quality of life in cancer patients (0 to 100, higher scores indicate better health/QoL). A mixed-effects growth curve model with a piecewise linear profile adjusted for baseline ECOG performance score and prior EGFR-targeted antibody use in R/M HNSCC was used. The change over time was calculate

Group	Value	95% CI
Afatinib 40 mg	22.9	± 3.53
Methotrexate 40 mg	15.0	± 3.79

Change in Pain Scale Score Over Time Secondary · Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

Change in pain scale score over time was defined as the mean pain scale score up to the median follow-up time, describing the average pain score derived from the cumulative change over time, measured by the EORTC QLQ-H\&N35 pain module. The EORTC QLQ-H\&N35 pain module is a 4-question tool measuring pain in the mouth, jaw, throat, and soreness in the mouth (0 to 100, higher score = greater pain). A longitudinal mixed-effects growth curve model with a piecewise linear profile adjusted for baseline ECOG performance score and prior EGFR-targeted antibody use in R/M HNSCC was used. The change over

Group	Value	95% CI
Afatinib 40 mg	7.6	± 2.96
Methotrexate 40 mg	11.3	± 3.39

Change in Swallowing Scale Scores Over Time Secondary · Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

Change in swallowing scale score over time was defined as the mean swallowing scale score up to the median follow-up time, describing the average swallowing score derived from the cumulative change over time. It was assessed by EORTC QLQ-H\&N35 swallowing module, a 4-question tool measuring problems swallowing liquids, pureed food, solid food, and choking when swallowing (0 to 100, higher score = greater difficulty swallowing). A longitudinal mixed-effects growth curve model with a piecewise linear profile adjusted for baseline ECOG and prior EGFR-targeted antibody use in R/M HNSCC was used. T

Group	Value	95% CI
Afatinib 40 mg	10.1	± 3.44
Methotrexate 40 mg	14.1	± 3.85

Number of Participants With Improvement in Pain Scale Score Secondary · Up to 37 months.

The number of participants with an improvement in pain scale scores is reported. Improvement was defined as a score that increases by at least 10 points (on a 0-100 point scale) from baseline at any time during the study. If a patient did not show improvement, worsening was defined as a 10-point decrease at any time during the study. Patients who neither improve nor worsen were considered stable. The pain scale was assessed using the pain module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Head and Neck Cancer (EORTC QLQ-H\&N 35). This quest

Group	Value	95% CI
Afatinib 40 mg	64
Methotrexate 40 mg	18
Afatinib 40 mg	59
Methotrexate 40 mg	28
Afatinib 40 mg	68
Methotrexate 40 mg	25

Number of Participants With Improvement in Swallowing Scale Score Secondary · Up to 37 months.

The number of participants with an improvement in swallowing scale scores is reported. Improvement was defined as a score that increases by at least 10 points (on a 0-100 point scale) from baseline at any time during the study. If a patient did not show improvement, worsening was defined as a 10-point decrease at any time during the study. Patients who neither improve nor worsen were considered stable. The swallowing scale was assessed using the swallowing module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Head and Neck Cancer (EORTC QLQ-H\

Group	Value	95% CI
Afatinib 40 mg	65
Methotrexate 40 mg	13
Afatinib 40 mg	55
Methotrexate 40 mg	32
Afatinib 40 mg	70
Methotrexate 40 mg	26

Number of Participants With Improvement in Overall Health Rate of the Global Health Status Secondary · Up to 37 months.

The number of participants with an improvement in the overall health rate of global health status is reported. Improvement was defined as a score that increases by at least 10 points (on a 0-100 point scale) from baseline at any time during the study. If a patient did not show improvement, worsening was defined as a 10-point decrease at any time during the study. Patients who neither improve nor worsen were considered stable. The global health status (global health/QoL scale) was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (E

Group	Value	95% CI
Afatinib 40 mg	92
Methotrexate 40 mg	21
Afatinib 40 mg	33
Methotrexate 40 mg	19
Afatinib 40 mg	66
Methotrexate 40 mg	31

Adverse events — posted to ClinicalTrials.gov

Time frame: All cause- mortality: From randomization until individual end of study. Up to 6 years. Adverse events reporting: From first drug administration until last drug administration, plus residual effect period. Up to approximately 6 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Afatinib 40 mg

Serious: 90/228 (39%)

Deaths: 205/228

Methotrexate 40 mg

Serious: 36/104 (35%)

Deaths: 94/112

Serious adverse events (123 terms)

Reaction	System	Afatinib 40 mg	Methotrexate 40 mg
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Dysphagia	Gastrointestinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Vomiting	Gastrointestinal disorders	—	—
Death	General disorders	—	—
General physical health deterioration	General disorders	—	—
Pyrexia	General disorders	—	—
Hypercalcaemia	Metabolism and nutrition disorders	—	—
Asthenia	General disorders	—	—
Cellulitis	Infections and infestations	—	—
Lung infection	Infections and infestations	—	—
Respiratory tract infection	Infections and infestations	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Skin infection	Infections and infestations	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—

Other adverse events (33 terms — click to expand)

Reaction	System	Afatinib 40 mg	Methotrexate 40 mg
Diarrhoea	Gastrointestinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Weight decreased	Investigations	—	—
Paronychia	Infections and infestations	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Asthenia	General disorders	—	—
Mouth ulceration	Gastrointestinal disorders	—	—
Dermatitis acneiform	Skin and subcutaneous tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Mucosal inflammation	General disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Pyrexia	General disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	—	—
Leukopenia	Blood and lymphatic system disorders	—	—
Blood creatinine increased	Investigations	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
White blood cell count decreased	Investigations	—	—
Skin fissures	Skin and subcutaneous tissue disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Neutrophil count decreased	Investigations	—	—
Haemoglobin decreased	Investigations	—	—
Platelet count decreased	Investigations	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—

Most-reported serious reactions: Malignant neoplasm progression, Dysphagia, Dyspnoea, Pneumonia, Respiratory failure, Anaemia, Hyponatraemia, Tumour haemorrhage.

Data from ClinicalTrials.gov NCT01856478 adverse events section.

Sponsor's own description

This randomized, open-label, phase III study will be performed in patients with recurrent and/or metastatic head and neck cancer which has progressed after platinum-based therapy. The objectives of this trial are to compare the efficacy and safety of afatinib versus methotrexate.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.
   Seiwert TY, Fayette J, Cupissol D, Del Campo JM, et al · · 2014 · cited 131× · PMID 24928832 · DOI 10.1093/annonc/mdu216
2. Metastatic disease in head & neck oncology.
   Pisani P, Airoldi M, Allais A, Aluffi Valletti P, et al · · 2020 · cited 128× · PMID 32469009 · DOI 10.14639/0392-100x-suppl.1-40-2020
3. HER2 as a therapeutic target in head and neck squamous cell carcinoma.
   Pollock NI, Grandis JR. · · 2015 · cited 79× · PMID 25424855 · DOI 10.1158/1078-0432.ccr-14-1432
4. Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.
   Guo Y, Ahn MJ, Chan A, Wang CH, et al · · 2019 · cited 49× · PMID 31501887 · DOI 10.1093/annonc/mdz388
5. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors.
   Sacco AG, Worden FP. · · 2016 · cited 46× · PMID 27110122 · DOI 10.2147/ott.s93720
6. Current Insights and Progress in the Clinical Management of Head and Neck Cancer.
   Amaral MN, Faísca P, Ferreira HA, Gaspar MM, et al · · 2022 · cited 32× · PMID 36551565 · DOI 10.3390/cancers14246079
7. Simultaneous targeting of EGFR, HER2, and HER4 by afatinib overcomes intrinsic and acquired cetuximab resistance in head and neck squamous cell carcinoma cell lines.
   De Pauw I, Lardon F, Van den Bossche J, Baysal H, et al · · 2018 · cited 32× · PMID 29603584 · DOI 10.1002/1878-0261.12197
8. Shooting at Moving and Hidden Targets-Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas.
   Kałafut J, Czerwonka A, Anameriç A, Przybyszewska-Podstawka A, et al · · 2021 · cited 21× · PMID 34944837 · DOI 10.3390/cancers13246219