BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

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 adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.

Official Title
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A Randomised, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients With Stage IIIB or IV Adenocarcinoma of the Lung Harbouring an EGFR Activating Mutation

Conditions
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Carcinoma, Non-Small-Cell Lung, Adenocarcinoma

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: BIBW 2992
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. Epidermal Growth Factor Receptor mutation detected by central laboratory analysis of tumour biopsy material. Measurable disease according to RECIST 1.1. Eastern Cooperative Oncology Group score of 0 or 1. Age >/= 18 years. Life expectancy of at least three months. Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice guidelines. Exclusion criteria: Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and randomisation. Prior treatment with Epidermal Growth Factor Receptor targeting small molecules or antibodies. Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomisation. Active brain metastases Any other current malignancy or malignancy diagnosed within the past five years Known pre-existing interstitial lung disease. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom. History or presence of clinically relevant cardiovascular abnormalities. Any other concomitant serious illness or organ system dysfunction. Adequate absolute neutrophil count and platelet count Adequate liver and kidney function Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

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: BIBW 2992<br>BIBW 2992 tablet once daily until progression | Drug: BIBW 2992<br>* BIBW 2992 once daily until progression<br>|
| Active Comparator: Cisplatin/Pemetrexed<br>Cisplatin and Pemetrexed IV once every 3 weeks for up to 6 cycles | Drug: Pemetrexed<br>* Pemetrexed IV given once every 3 weeks for up to 6 cycles<br>Drug: Cisplatin<br>* Cisplatin IV given once every 3 weeks for up to 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Time | PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates. | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Objective Response (OR) | OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1. | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | 
| Percentage of Participants With Disease Control (DC) | DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1. | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | 
| Overall Survival (OS) Time | OS was defined as time from randomisation to death. | From randomisation to cut-off date (17MAR2017). | 
| Tumour Shrinkage | Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race. | Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression | 
| Change From Baseline in Body Weight | Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm. | Baseline and throughout the trial until progression (every 3 weeks), up to 28 months. | 
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. Dead. | Throughout the trial until progression (every 3 weeks), up to 28 months. | 
| Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing | HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. | Throughout the trial until progression (every 3 weeks). | 
| HRQOL: Time to Deterioration in Dyspnoea | HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. | Throughout the trial until progression (every 3 weeks). | 
| HRQOL: Time to Deterioration in Pain | HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. | Throughout the trial until progression (every 3 weeks). | 
| Trough Plasma Concentrations of Afatinib at Day 22 | Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. | Day 22. | 
| Trough Plasma Concentrations of Afatinib at Day 29 | Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. | Day 29. | 
| Trough Plasma Concentrations of Afatinib at Day 43 | Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. | Day 43. |