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 Randomised, Open-label, Phase III Study to Evaluate the Efficacy and Safety of Oral Afatinib (BIBW 2992) Versus Intravenous Methotrexate in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Who Have Progressed After Platinum-based Therapy.

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.

Study Overview

• Status: Completed
• Conditions: Head and Neck Neoplasms
• Intervention / Treatment: Drug: Afatinib; Drug: Methotrexate

• Study Type: Interventional
• Enrollment (Actual): 340
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; oral intake of one film-coated tablet once daily
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; intravenous bolus injection once weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization until disease progression, death, or primary completion date, whichever occurs first. Up to 35 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization until earliest of disease progression, death, or interim cut-off date (11-Apr-2019). Up to 35 months.
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.	From randomization until death. Up to 6 years.
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.	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 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.	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	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.	From randomization until the earliest of deterioration, death, discontinuation with death within 4 weeks, or primary analysis date. Up to 19 months.
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).	Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
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).	Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
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)	Mean change over time is reported up to 12 weeks. Detailed time frame in the endpoint description.
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.	Up to 37 months.
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.	Up to 37 months.
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.	Up to 37 months.
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.	Up to 37 months.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

General 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2013
• Primary Completion (Actual): August 22, 2018
• Study Completion (Actual): October 2, 2024

Study Registration Dates

• First Submitted: May 15, 2013
• First Submitted That Met QC Criteria: May 15, 2013
• First Posted (Estimated): May 17, 2013

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 7, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Pterins; Pteridines; Aminopterin; Quinazolines; Afatinib; Methotrexate
• Other Study ID Numbers: 1200.161; 1200-0161 (Other Identifier: Boehringer Ingelheim)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.

IPD Sharing Access Criteria

For study documents - upon signing of a 'Document Sharing Agreement'.

For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR