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A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

Primary Objective a. Phase II: To evaluate if there is sufficient evidence to continue to the Phase III component by comparing progression-free survival (PFS) between patients randomized to afatinib in combination with cetuximab versus afatinib alone in the first-line treatment of patients with advanced EGFR-mutant NSCLC. b. Phase III: To determine the efficacy of the combination of afatinib and cetuximab compared to afatinib alone as measured by overall survival (OS) in the first-line treatment of patients with advanced EGFR-mutant NSCLC. Secondary Objectives a. To evaluate the overall response rate (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease treated with afatinib plus cetuximab compared to afatinib alone. b. To assess the safety of each treatment arm when used in the first-line setting. c. To compare time to treatment failure and time to treatment discontinuation (as defined in Sections 10.5 and 10.6) between randomized to afatinib in combination with cetuximab versus afatinib alone. Translational Objectives a. To investigate the molecular mechanisms that confer benefit from afatinib and afatinib plus cetuximab by evaluating whether the presence of de novo EGFR T790M mutation or other molecular alterations in the pre-treatment tumor influence the clinical outcomes. b. To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment. c. To evaluate the frequency of known mechanisms of resistance to EGFR-directed therapies in the context of afatinib plus cetuximab and afatinib alone treatment. d. To identify potential novel predictors of benefit to afatinib plus cetuximab. e. To identify potential new mechanisms of resistance to EGFR-directed therapies. f. To establish patient-derived xenografts (PDXs) from a subset of patients by rebiopsy at the time of progressive disease for drug testing and genomic analysis. g. To assess whether circulating tumor markers can be used as indicators of sensitivity and resistance to afatinib plus cetuximab and afatinib alone. h. To determine whether the levels of EGFR protein by immunohistochemistry predict for benefit to afatinib plus cetuximab and afatinib alone.

Primary Objective a. Phase II: To evaluate if there is sufficient evidence to continue to the Phase III component by comparing progression-free survival (PFS) between patients randomized to afatinib in combination with cetuximab versus afatinib alone in the first-line treatment of patients with advanced EGFR-mutant NSCLC. b. Phase III: To determine the efficacy of the combination of afatinib and cetuximab compared to afatinib alone as measured by overall survival (OS) in the first-line treatment of patients with advanced EGFR-mutant NSCLC. Secondary Objectives a. To evaluate the overall response rate (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease treated with afatinib plus cetuximab compared to afatinib alone. b. To assess the safety of each treatment arm when used in the first-line setting. c. To compare time to treatment failure and time to treatment discontinuation (as defined in Sections 10.5 and 10.6) between randomized to afatinib in combination with cetuximab versus afatinib alone. Translational Objectives a. To investigate the molecular mechanisms that confer benefit from afatinib and afatinib plus cetuximab by evaluating whether the presence of de novo EGFR T790M mutation or other molecular alterations in the pre-treatment tumor influence the clinical outcomes. b. To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment. c. To evaluate the frequency of known mechanisms of resistance to EGFR-directed therapies in the context of afatinib plus cetuximab and afatinib alone treatment. d. To identify potential novel predictors of benefit to afatinib plus cetuximab. e. To identify potential new mechanisms of resistance to EGFR-directed therapies. f. To establish patient-derived xenografts (PDXs) from a subset of patients by rebiopsy at the time of progressive disease for drug testing and genomic analysis. g. To assess whether circulating tumor markers can be used as indicators of sensitivity and resistance to afatinib plus cetuximab and afatinib alone. h. To determine whether the levels of EGFR protein by immunohistochemistry predict for benefit to afatinib plus cetuximab and afatinib alone.