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CompletedNCT01856478Updated Jan 12, 2026Results posted

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

A Phase 3 interventional study of Methotrexate and Afatinib in Head and Neck Neoplasms, sponsored by Boehringer Ingelheim. Completed at 53 sites in 8 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-01-12.

Sponsored by Boehringer Ingelheim · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
340
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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.

02

Conditions studied

  • Head and Neck Neoplasms
03

In context

Head and Neck Neoplasms

2,344 studies on the registry are indexed under Head and Neck Neoplasms; 551 are open to participants now.

This study's enrollment of 340 is above the median of 47 across 1,751 interventional studies indexed under Head and Neck Neoplasms.

Browse Head and Neck Neoplasms studies →

Lead sponsor

Boehringer Ingelheim is the lead sponsor of 2,245 studies on the registry; 58 are open to participants now.

Of its 162 completed or terminated interventional studies of FDA-regulated products, 116 (72%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not amenable for salvage surgery or radiotherapy.
  • Documented progressive disease based on investigator assessment according to RECIST, following receipt of a cisplatin and/or carboplatin and/or Nedaplatin based regimen administered for recurrent and/or metastatic disease independent of whether patient progressed during or after platinum based therapy.
  • Measurable disease according to RECIST (version 1.1).
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Visit 2.
  • Male and female patients age is 18 years or older
  • Signed and dated written informed consent that is in compliance with ICH-GCP and local law.

Exclusion criteria

Exclusion criteria:

  • Progressive disease within three months after completion of curatively intended treatment for locoregionally advanced or for metastatic head and neck squamous cell cancer (HNSCC).
  • Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands.
  • Any other than one previous platinum based systemic regimen given for recurrent and/or metastatic disease, with the exception of immunotherapy used either before or after platinum based treatment. Re-challenge with the platinum based regimen after a temporary break is considered an additional line regimen only in case of progression within the break.
  • Prior treatment with EGFR-targeted small molecules.
  • Treatment with any investigational drug less than four weeks or anti-cancer therapy less than three weeks prior to randomization (except palliative radiotherapy to bones to alleviate pain).
  • Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted antibodies.
  • Previous tumour bleeding CTCAE grade =3.
  • Requirement for treatment with any of the prohibited concomitant medications.
  • Major surgical or planned procedure less than four weeks prior to randomization (isolated biopsies are not considered as major surgical procedures).

  • Any other malignancy unless free of disease for at least five years except for:

    • Other HNSCC of a location as described in inclusion criterion number 1
    • Appropriately treated superficial basal cell skin cancer
    • Surgically cured cervical cancer in situ
    • For Korea: endoscopically cured superficial esophageal and/or gastric cancer is allowed
  • Known lesion or signs of brain metastasis.
  • Known pre-existing interstitial lung disease (ILD).
  • Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification =III, unstable angina, myocardial infarction within six months prior to randomization, or poorly controlled arrhythmia.
  • Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom in the opinion of the investigator, e.g. Crohn's disease, malabsorption or CTCAE grade >1 diarrhoea of any aetiology at randomization.
  • Known HIV, active hepatitis B, active hepatitis C, and/or other known severe infections, including but not limited to tuberculosis, as judged by the investigator.
  • Other significant disease that in the investigator's opinion would exclude the subject from the trial.

  • Screening laboratory values:

    • Absolute neutrophil count (ANC) \<1.5x10\^9/l
    • Platelet count \<75x10\^9/l
    • Total bilirubin >1.5 times the upper limit of normal (ULN)
    • Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times the ULN (if related to liver metastases >5 times the ULN)
    • Calculated creatinine clearance \<50 ml/min (as evidenced by using the Cockcroft-Gault formula).
  • Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or to use adequate contraception during the trial and for at least six months after end of treatment. Adequate methods of contraception and definition of child-bearing potential.
  • Pregnancy or breast feeding.
  • Known or suspected hypersensitivity to any of the study medications or their excipients.
  • Patients unable to comply with the protocol, in the opinion of the investigator.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
340 participants (actual)

Study arms

  • Experimental
    Afatinib 40 mg

    Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after being treated with platinum-based therapy took, orally, once daily one film-coated tablet of afatinib. Patients started with a 40 milligrams (mg) dose which could be escalated to 50 mg and/or reduced to 40 mg, 30 mg, or 20 mg, according to the absence of presence of drug-related adverse events (AEs).

    Drug: Afatinib

  • Active comparator
    Methotrexate 40 mg

    Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after being treated with platinum-based therapy received once weekly an intravenous bolus injection of methotrexate. Patients started with a 40 milligrams (mg) per square meter of body surface area (m\^2) dose which could be escalated to 50 mg/m\^2 and/or reduced to 40 mg/m\^2, 30 mg/m\^2, or 20 mg/m\^2, according to the absence of presence of drug-related adverse events (AEs).

    Drug: Methotrexate

Interventions

  • DrugMethotrexate

    intravenous bolus injection once weekly

  • DrugAfatinib

    oral intake of one film-coated tablet once daily

06

What researchers measure

Primary outcomes

  1. Progression Free Survival (PFS)

    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.

    Time frame: From randomization until disease progression, death, or primary completion date, whichever occurs first. Up to 35 months.

Secondary outcomes

  1. Objective Response (OR)

    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.

    Time frame: From randomization until earliest of disease progression, death, or interim cut-off date (11-Apr-2019). Up to 35 months.

  2. Overall Survival (OS)

    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.

    Time frame: From randomization until death. Up to 6 years.

  3. Time to Deterioration in Global Health Status

    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 is composed of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score represents better global health status and quality of life.

    Time frame: From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 30 months.

  4. Time to Deterioration in Pain Symptoms

    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, inquiring about pain in the mouth, pain in the jaw, soreness in the mouth, and a painful throat. The scale ranges from 0 to 100, where a higher score represents a higher symptom burden.

    Time frame: From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.

  5. Time to Deterioration in Swallowing

    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 composed of 4 questions, inquiring about problems swallowing liquids, pureed food, solid food, and choking when swallowing. The scale ranges from 0 to 100, where a higher score represents greater difficulty in swallowing.

    Time frame: From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.

  6. Change in Global Health Status Over Time

    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 calculated by dividing the area under the estimated growth curve (AUC) up to the median follow-up time by the median follow-up time. Timeframe: The model included measures at baseline and at the following timepoints, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months).

    Time frame: Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

  7. Change in Pain Scale Score Over Time

    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 time was calculated by dividing the area under the estimated growth curve (AUC) up to median follow-up time by the median follow-up time. Timeframe: The model included measures at baseline and at, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months).

    Time frame: Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

  8. Change in Swallowing Scale Scores Over Time

    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. The change over time was calculated by dividing the area under the estimated growth curve (AUC) up to median follow-up time by the median follow-up time. Timeframe: the model included measures at baseline and at, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months)

    Time frame: Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.

  9. Number of Participants With Improvement in Pain Scale Score

    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 questionnaire is designed to measure the quality of life in patients with head and neck cancer. It consists of four questions that inquire about pain in the mouth, pain in the jaw, soreness in the mouth, and a painful throat. The scale ranges from 0 to 100, where a higher score indicates a greater symptom burden.

    Time frame: Up to 37 months.

  10. Number of Participants With Improvement in Swallowing Scale Score

    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\&N 35). This questionnaire is designed to measure swallowing difficulties in patients with head and neck cancer. It consists of four questions that inquire about problems swallowing liquids, pureed food, solid food, and choking when swallowing. The scale ranges from 0 to 100, where a higher score indicates greater difficulty in swallowing.

    Time frame: Up to 37 months.

  11. Number of Participants With Improvement in Overall Health Rate of the Global Health Status

    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 (EORTC QLQ-C30), a 30-item instrument designed to measure quality of life in all cancer patients. It consists of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score indicates better global health status and quality of life.

    Time frame: Up to 37 months.

  12. Number of Participants With Improvement in Quality of Life Rate of the Global Health Status

    The number of participants with an improvement in the quality of life rating 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 (EORTC QLQ-C30), a 30-item instrument designed to measure quality of life in all cancer patients. It consists of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score indicates better global health status and quality of life.

    Time frame: Up to 37 months.

07

Results

Posted Jan 12, 2026

Participant flow

Randomized, multicenter, open-label, active-control study with two parallel groups to investigate the efficacy and safety of afatinib versus methotrexate in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Eligible patients were stratified by their Eastern Cooperative Oncology Group (ECOG) performance score and prior use of EGFR-targeted antibody therapy in the R/M. Patients were randomized to either afatinib or methotrexate in a 2:1 ratio.

Participant flow — Overall Study
MilestoneAfatinib 40 mgMethotrexate 40 mg
Started228112
Treated228104
Completed00
Not completed228112
Withdrew: Not treated08
Withdrew: Progressive disease per recist14649
Withdrew: Worsening of underlying cancer62
Withdrew: Adverse events5730
Withdrew: Non-compliant with protocol11
Withdrew: Lost to follow-up11
Withdrew: Refused to continue trial medication1311
Withdrew: Other reason than listed410

Outcome measures

SecondaryObjective Response (OR)

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.

Time frame:
From randomization until earliest of disease progression, death, or interim cut-off date (11-Apr-2019). Up to 35 months.
Reported as:
Count of participants · Participants
Objective Response (OR)
ParticipantsAfatinib 40 mgMethotrexate 40 mg
Objective Response (OR)6414
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Cochran-Mantel-Haenszel · p = 0.0016 (Null hypothesis: Afatinib and methotrexate have an equal response rate.) · Odds ratio (or): 2.76 · 95% CI 1.47 to 5.18Linear regression stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate the OR of response and its confidence interval. Data presented as Afatinib versus Methotrexate.
PrimaryProgression Free Survival (PFS)

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.

Time frame:
From randomization until disease progression, death, or primary completion date, whichever occurs first. Up to 35 months.
Reported as:
Median · Months
Progression Free Survival (PFS)
MonthsAfatinib 40 mgMethotrexate 40 mg
Progression Free Survival (PFS)2.86 (2.79 to 3.71)2.56 (1.51 to 2.79)
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Log Rank · p = 0.0005 (Null hypothesis: Afatinib and methotrexate are equally effective in terms of PFS.) · Hazard ratio (hr): 0.627 · 95% CI 0.478 to 0.823Cox proportional hazards model stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate HR and its confidence interval. Data presented as Afatinib versus Methotrexate.
SecondaryOverall Survival (OS)

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.

Time frame:
From randomization until death. Up to 6 years.
Reported as:
Median · Months
Overall Survival (OS)
MonthsAfatinib 40 mgMethotrexate 40 mg
Overall Survival (OS)6.93 (6.31 to 8.41)6.41 (5.16 to 8.38)
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Log Rank · p = 0.3162 · Hazard ratio (hr): 0.881 · 95% CI 0.687 to 1.129Cox proportional hazards model stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate HR and its confidence interval. Data presented as Afatinib versus Methotrexate.
SecondaryTime to Deterioration in Global Health Status

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 is composed of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score represents better global health status and quality of life.

Time frame:
From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 30 months.
Reported as:
Median · Months
Time to Deterioration in Global Health Status
MonthsAfatinib 40 mgMethotrexate 40 mg
Time to Deterioration in Global Health Status4.17 (3.65 to 4.40)2.83 (2.63 to 7.75)
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Log Rank · p = 0.2121 · Hazard ratio (hr): 0.79 · 95% CI 0.54 to 1.15Cox proportional hazards model stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate HR and its confidence interval. Data presented as Afatinib versus Methotrexate.
SecondaryTime to Deterioration in Pain Symptoms

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, inquiring about pain in the mouth, pain in the jaw, soreness in the mouth, and a painful throat. The scale ranges from 0 to 100, where a higher score represents a higher symptom burden.

Time frame:
From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.
Reported as:
Median · Months
Time to Deterioration in Pain Symptoms
MonthsAfatinib 40 mgMethotrexate 40 mg
Time to Deterioration in Pain Symptoms3.65 (3.02 to 4.40)2.96 (2.63 to 8.25)
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Log Rank · p = 0.9888 · Hazard ratio (hr): 1.00 · 95% CI 0.67 to 1.49Cox proportional hazards model stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate HR and its confidence interval. Data presented as Afatinib versus Methotrexate.
SecondaryTime to Deterioration in Swallowing

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 composed of 4 questions, inquiring about problems swallowing liquids, pureed food, solid food, and choking when swallowing. The scale ranges from 0 to 100, where a higher score represents greater difficulty in swallowing.

Time frame:
From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.
Reported as:
Median · Months
Time to Deterioration in Swallowing
MonthsAfatinib 40 mgMethotrexate 40 mg
Time to Deterioration in Swallowing4.11 (2.86 to 4.27)3.29 (2.56 to 7.39)
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Log Rank · p = 0.6260 · Hazard ratio (hr): 0.91 · 95% CI 0.62 to 1.34Cox proportional hazards model stratified by baseline ECOG performance score and use of prior EGFR-targeted antibody in the R/M setting was used to calculate HR and its confidence interval. Data presented as Afatinib versus Methotrexate.
SecondaryChange in Global Health Status Over Time

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 calculated by dividing the area under the estimated growth curve (AUC) up to the median follow-up time by the median follow-up time. Timeframe: The model included measures at baseline and at the following timepoints, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months).

Time frame:
Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
Reported as:
Least squares mean · Units on a scale
Change in Global Health Status Over Time
Units on a scaleAfatinib 40 mgMethotrexate 40 mg
Change in Global Health Status Over Time22.9 ± 3.5315.0 ± 3.79
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · t-test, 2 sided · p = 0.0005 · Adjusted mean difference: 7.9 · 95% CI 3.45 to 12.36Calculated as \[Afatinib\]-\[Methotrexate\]
SecondaryChange in Pain Scale Score Over Time

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 time was calculated by dividing the area under the estimated growth curve (AUC) up to median follow-up time by the median follow-up time. Timeframe: The model included measures at baseline and at, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months).

Time frame:
Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
Reported as:
Least squares mean · Units on a scale
Change in Pain Scale Score Over Time
Units on a scaleAfatinib 40 mgMethotrexate 40 mg
Change in Pain Scale Score Over Time7.6 ± 2.9611.3 ± 3.39
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · t-test, 2 sided · p = 0.1090 · Adjusted mean difference: -3.8 · 95% CI -8.39 to 0.84Calculated as \[Afatinib\]-\[Methotrexate\]
SecondaryChange in Swallowing Scale Scores Over Time

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. The change over time was calculated by dividing the area under the estimated growth curve (AUC) up to median follow-up time by the median follow-up time. Timeframe: the model included measures at baseline and at, if available: Week 6, 12, 18, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, individual end of treatment (EOT; up to 36 months), and individual follow-up visit (EOT + 4 weeks, up to 37 months)

Time frame:
Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
Reported as:
Least squares mean · Units on a scale
Change in Swallowing Scale Scores Over Time
Units on a scaleAfatinib 40 mgMethotrexate 40 mg
Change in Swallowing Scale Scores Over Time10.1 ± 3.4414.1 ± 3.85
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · t-test, 2 sided · p = 0.1819 · Adjusted mean difference: -3.9 · 95% CI -9.73 to 1.85Calculated as \[Afatinib\]-\[Methotrexate\]
SecondaryNumber of Participants With Improvement in Pain Scale Score

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 questionnaire is designed to measure the quality of life in patients with head and neck cancer. It consists of four questions that inquire about pain in the mouth, pain in the jaw, soreness in the mouth, and a painful throat. The scale ranges from 0 to 100, where a higher score indicates a greater symptom burden.

Time frame:
Up to 37 months.
Reported as:
Count of participants · Participants
Number of Participants With Improvement in Pain Scale Score
ParticipantsAfatinib 40 mgMethotrexate 40 mg
Improved6418
Stable5928
Worsened6825
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Regression, Logistic · p = 0.222 · Odds ratio (or): 1.46Afatinib versus Methotrexate
SecondaryNumber of Participants With Improvement in Swallowing Scale Score

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\&N 35). This questionnaire is designed to measure swallowing difficulties in patients with head and neck cancer. It consists of four questions that inquire about problems swallowing liquids, pureed food, solid food, and choking when swallowing. The scale ranges from 0 to 100, where a higher score indicates greater difficulty in swallowing.

Time frame:
Up to 37 months.
Reported as:
Count of participants · Participants
Number of Participants With Improvement in Swallowing Scale Score
ParticipantsAfatinib 40 mgMethotrexate 40 mg
Improved6513
Stable5532
Worsened7026
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Regression, Logistic · p = 0.012 · Odds ratio (or): 2.37Afatinib versus Methotrexate
SecondaryNumber of Participants With Improvement in Overall Health Rate of the Global Health Status

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 (EORTC QLQ-C30), a 30-item instrument designed to measure quality of life in all cancer patients. It consists of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score indicates better global health status and quality of life.

Time frame:
Up to 37 months.
Reported as:
Count of participants · Participants
Number of Participants With Improvement in Overall Health Rate of the Global Health Status
ParticipantsAfatinib 40 mgMethotrexate 40 mg
Improved9221
Stable3319
Worsened6631
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Regression, Logistic · p = 0.008
SecondaryNumber of Participants With Improvement in Quality of Life Rate of the Global Health Status

The number of participants with an improvement in the quality of life rating 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 (EORTC QLQ-C30), a 30-item instrument designed to measure quality of life in all cancer patients. It consists of the overall health rating and the quality of life rating. The scale ranges from 0 to 100, where a higher score indicates better global health status and quality of life.

Time frame:
Up to 37 months.
Reported as:
Count of participants · Participants
Number of Participants With Improvement in Quality of Life Rate of the Global Health Status
ParticipantsAfatinib 40 mgMethotrexate 40 mg
Improved8523
Stable3016
Worsened7632
Statistical analysis
  • Afatinib 40 mg vs Methotrexate 40 mg · Regression, Logistic · p = 0.091

Adverse events

Collected over 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.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Afatinib 40 mg205/228 (89.9%)90/228 (39.5%)217/228 (95.2%)
Methotrexate 40 mg94/112 (83.9%)36/104 (34.6%)89/104 (85.6%)
Most frequent serious events
Showing 10 of 123
Most frequent serious events
EventAfatinib 40 mgMethotrexate 40 mg
PneumoniaInfections and infestations7/2286/104
Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)12/2281/104
DysphagiaGastrointestinal disorders9/2282/104
PyrexiaGeneral disorders0/2284/104
DyspnoeaRespiratory, thoracic and mediastinal disorders8/2283/104
Respiratory failureRespiratory, thoracic and mediastinal disorders7/2281/104
AnaemiaBlood and lymphatic system disorders5/2283/104
Lung infectionInfections and infestations3/2283/104
HyponatraemiaMetabolism and nutrition disorders5/2280/104
Tumour haemorrhageNeoplasms benign, malignant and unspecified (incl cysts and polyps)5/2282/104
Most frequent other events
Showing 10 of 33
Most frequent other events
EventAfatinib 40 mgMethotrexate 40 mg
DiarrhoeaGastrointestinal disorders169/22810/104
RashSkin and subcutaneous tissue disorders100/2288/104
StomatitisGastrointestinal disorders44/22811/104
Weight decreasedInvestigations44/22816/104
ParonychiaInfections and infestations42/2280/104
AnaemiaBlood and lymphatic system disorders30/22819/104
PyrexiaGeneral disorders13/22818/104
LeukopeniaBlood and lymphatic system disorders1/22816/104
FatigueGeneral disorders20/22815/104
Decreased appetiteMetabolism and nutrition disorders32/22812/104

Baseline characteristics

Randomized Set (RS): all patients who are randomized, regardless of taking investigational treatment.

Age, Continuous
Age, Continuous(Years)Afatinib 40 mgMethotrexate 40 mgTotal
Mean54.7 ± 9.7956.4 ± 9.3655.2 ± 9.67
Sex: Female, Male
Sex: Female, Male(Participants)Afatinib 40 mgMethotrexate 40 mgTotal
Female351348
Male19399292
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Afatinib 40 mgMethotrexate 40 mgTotal
American Indian or Alaska Native000
Asian215107322
Native Hawaiian or Other Pacific Islander000
Black or African American000
White13518
More than one race000
Unknown or Not Reported000
08

Study locations

53 sites
  • Beijing Chao-Yang Hospital
    Beijing, 100020, China
  • Cancer Hospital of Chinese Academy of Medical Science
    Beijing, 100021, China
  • Navy General Hospital
    Beijing, 100037, China
  • Peking Union Medical College Hospital
    Beijing, 100730, China
  • The First Affiliated Hospital Of Bengbu Medical College
    Bengbu, 233004, China
  • The First Hospital of Jilin University
    Changchun, 130021, China
  • Sichuan Cancer Hospital
    Chengdu, 610041, China
  • West China Hospital
    Chengdu, 610042, China
  • Sun Yat-Sen University Cancer Center
    Guangzhou, 510060, China
  • Zhejiang Cancer Hospital
    Hangzhou, 310022, China
  • Harbin Medical University Cancer Hospital
    Harbin, 150081, China
  • the 81th Hospital of PLA
    Nanjing, 210002, China
  • Renji Hospital Shanghai Jiaotong Univesrity School of Medicine
    Shanghai, 200001, China
  • Shanghai Changzheng Hospital
    Shanghai, 200003, China
  • Shanghai Ninth People's Hospital
    Shanghai, 200011, China
  • Fudan University Shanghai Cancer Center
    Shanghai, 200032, China
  • Shanghai Ninth People's Hospital
    Shanghai, 200125, China
  • Wuhan Union Hospital
    Wuhan, 430022, China
  • Tongji Hospital, Tongji University
    Wuhan, 430030, China
  • Alexandria Clinical Research Center
    Alexandria, 21131, Egypt
  • National Cancer Institute, Cairo University
    Cairo, 11796, Egypt
  • Mansoura University Faculty of Medicine
    Dakahlia, 35516, Egypt
  • Pamela Youde Nethersole Eastern Hospital
    Hong Kong, 999077, Hong Kong
  • Queen Mary Hospital
    Hong Kong, 999077, Hong Kong
  • Prince of Wales Hospital
    Shatin, 999077, Hong Kong
  • Sujan Surgical Cancer Hospital
    Amravati, 444606, India
  • Pristine Hospital
    Bengaluru, 560086, India
  • Acharya Tulsi Regional Cancer Treatment & Research Institute
    Bikaner, 334001, India
  • Rajiv Gandhi Government General Hospital
    Chennai, 600003, India
  • M N J Institute of Oncology and Regional Cancer Centre
    Hyderabad, 500004, India
  • Geetanjali Medical College and Hospital
    Jaipur, 313002, India
  • J K Cancer Institute
    Kanpur, 208005, India
  • B. P .Poddar Hospital & Medical Research Ltd.
    Kolkata, West Bengal, 700053, India
  • King George Medical University
    Lucknow, 226003, India
  • Government Medical College & Hospital
    Nagpur, 440009, India
  • Shatabdi Hospital, Nashik
    Nashik, 422002, India
  • Ruby Hall Clinic
    Pune, 411001, India
  • Noble Hospital Pvt Ltd
    Pune, 411013, India
  • Perpetual Succour Hospital (Cebu)
    Cebu City, 6000, Philippines
  • St. Luke's Medical Center
    Quezon City, 1102, Philippines
  • National Cancer Center
    Goyang, 10408, South Korea
  • Severance Hospital
    Seoul, 120-752, South Korea
  • Samsung Medical Center
    Seoul, 135-710, South Korea
  • The Catholic University of Korea, Seoul St.Mary's Hospital
    Seoul, 137-701, South Korea
  • Asan Medical Center
    Seoul, 138-736, South Korea
  • Keelung Chang Gung Memorial Lover's Lake Branch
    Keelung, 204, Taiwan
  • Taichung Veterans General Hospital
    Taichung, 407, Taiwan
  • National Taiwan University Hospital
    Taipei, 100, Taiwan
  • Tri-Service General Hospital
    Taipei, 11490, Taiwan
  • Maharaj Nakom Chiangmai Hospital
    Chiang Mai, 50200, Thailand
  • Srinagarind Hospital
    Muang, 40002, Thailand
  • Naresuan University Hospital
    Phitsanulok, 65000, Thailand
  • Songklanagarind Hospital
    Songkhla, 90110, Thailand
09

References and documents

Publications

  • Guo Y, Ahn MJ, Chan A, Wang CH, Kang JH, Kim SB, Bello M, Arora RS, Zhang Q, He X, Li P, Dechaphunkul A, Kumar V, Kamble K, Li W, Kandil A, Cohen EEW, Geng Y, Zografos E, Tang PZ. 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. Ann Oncol. 2019 Nov 1;30(11):1831-1839. doi: 10.1093/annonc/mdz388. PubMed 31501887 ↗

Related links

Study documents

  • Study protocol · Jan 3, 2019
  • Statistical analysis plan · Apr 1, 2016

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

Supporting information: Study protocol, Sap, Csr

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 12, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01856478
Lead sponsor
Boehringer Ingelheim
Responsible party
Sponsor
First posted
May 17, 2013
Start date
Jun 7, 2013
Primary completion
Aug 22, 2018
Completion
Oct 2, 2024
Results posted
Jan 12, 2026
Last update
Jan 12, 2026

Study contacts

Boehringer Ingelheim
study chair · Boehringer Ingelheim
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jan 2026. You cannot join it, but the record below documents what was studied.

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