LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy

Study Overview
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Brief Summary
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This randomised, open-label phase III trial will be performed in patients with advanced squamous cell carcinoma of the lung requiring second-line treatment after receiving first-line platinum-based chemotherapy. The primary objective of this trial is to compare the efficacy of BIBW 2992 to erlotinib as second-line treatment in this group of patients.

Official Title
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LUX-Lung 8: A Randomized, Open-label Phase III Trial of Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung as Second-line Therapy Following First-line Platinum-based Chemotherapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: afatinib
* Drug: erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of advanced stage NSCLC squamous histology. Platinum-based doublet chemotherapy as 1st line treatment of Stage IIIB/IV NSCLC. Eligible to receive 2nd line therapy in the opinion of the investigator. Measurable disease according to RECIST 1.1. Adequate Performance Status. Availability of tumour tissue material for correlative studies. Archived tumour tissue is acceptable. Adequate organ function. Age = 18 years and above. Written informed consent that is consistent with International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines. Exclusion criteria: Prior treatment with Epidermal Growth Factor Receptor (EGFR) directed small molecules or antibodies. Radiotherapy within 4 weeks prior to randomization. Active brain metastases . Any other current malignancy or malignancy diagnosed within the past three (3) years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer). Known pre-existing interstitial lung disease. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended. Female patients of childbearing potential (see Section 4.2.3.3) who: are nursing or are pregnant or are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study and/or do not agree to submit to pregnancy testing required by this protocol. Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier. Known or suspected active drug or alcohol abuse in the opinion of the investigator. Any contraindications for therapy with afatinib or erlotinib. Known hypersensitivity to erlotinib, afatinib or the excipients of any of the trial drugs. Major surgery within 4 weeks of starting study treatment. Prior participation in an afatinib clinical study, even if not assigned to afatinib. Use of any investigational drug within 4 weeks of randomisation (unless a longer time period is required by local regulations or by the guidelines for the investigational product). Patients without Progression of their lung cancer.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afatinib<br>Patients receive afatinib tablets once daily | Drug: afatinib<br>* Afatinib taken once daily, continuously until disease progression or unacceptable toxicity.<br>|
| Active Comparator: Erlotinib<br>Patients receive erlotinib tablets once daily | Drug: erlotinib<br>* erlotinib taken once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 | Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize) or worsen (progress) during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint. | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | 
| Number of Participants With Objective Response According to RECIST 1.1 | A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | 
| Number of Participants With Disease Control According to RECIST 1.1 | Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | 
| Tumour Shrinkage | Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race. | First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). | 
| Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire | Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time. | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | 
| Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. | Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration. | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). | 
| Change in Score Over Time in Coughing,Dyspnoea and Pain | Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race. | From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). |