This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

PRIMARY OBJECTIVES:

I. 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 (afatinib dimaleate) in combination with cetuximab versus afatinib alone in the first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). (Phase II) II. 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. (Phase III)

SECONDARY OBJECTIVES:

I. 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.

II. To assess the safety of each treatment arm when used in the first-line setting.

III. To compare time to treatment failure and time to treatment discontinuation between randomized to afatinib in combination with cetuximab versus afatinib alone.

TERTIARY OBJECTIVES:

I. 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.

II. To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment.

III. To evaluate the frequency of known mechanisms of resistance to EGFR-directed therapies in the context of afatinib plus cetuximab and afatinib alone treatment.

IV. To identify potential novel predictors of benefit to afatinib plus cetuximab.

V. To identify potential new mechanisms of resistance to EGFR-directed therapies.

VI. To establish patient-derived xenografts (PDXs) from a subset of patients by re-biopsy at the time of progressive disease for drug testing and genomic analysis.

VII. To assess whether circulating tumor markers can be used as indicators of sensitivity and resistance to afatinib plus cetuximab and afatinib alone.

VIII. To determine whether the levels of EGFR protein by immunohistochemistry predict for benefit to afatinib plus cetuximab and afatinib alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-28 and cetuximab intravenously (IV) over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive afatinib dimaleate as in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC)
• Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
• Patients must have tissue available and must agree to submission of tissue and blood; one to two paraffin-embedded tissue blocks or 15-20 unstained slides are requested (a minimum of 12 slides is required); cytology (i.e. fine-needle aspirations, pleural effusion specimens) is acceptable if a cell block or sufficient unstained slides are available; tumor material must be reviewed by a local pathologist who must confirm that at least 100 viable tumor cells are present in the sample and sign the S1403 Pathology Review Form; patients must also be willing to submit blood samples for correlative research at baseline, during treatment and at progression
• Patients enrolled at sites participating in the Repeat Biopsy Study must agree to submission of tissue obtained by a repeat biopsy performed at the time of disease progression
• Patients must not have received any prior systemic anticancer therapy for advanced or metastatic disease including chemotherapy or EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, afatinib, or any experimental EGFR tyrosine kinase inhibitors [TKI] agents); prior chemotherapy for non-metastatic disease (i.e. adjuvant therapy or concurrent chemo-radiotherapy) is allowed as long as > 12 months has passed since completion of therapy; adjuvant EGFR-directed therapy is not allowed; local therapy (i.e. palliative radiotherapy) is allowed as long as a period of 7 days has passed since the last dose was received and the patient has recovered from any associated toxicity at the time of registration
• Patients may have measurable or non-measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease; in order to qualify as measurable, measurable disease must be outside previous radiation field; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
• Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration; patient must not have symptomatic brain metastases or evidence of leptomeningeal carcinomatosis; patients with asymptomatic brain metastases are eligible if off of steroids for at least 7 days prior to registration without development of symptoms
• Patients must not have any known clinically active interstitial lung disease
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 75,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or =< 5 x IULN for patients with known liver metastases)
• Serum creatinine =< 1.5 x IULN OR measured or calculated creatinine clearance >= 60 mL/min
• Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc)
• Patients must be able to swallow medication by oral route
• Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50%
• Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed
• Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive
• Patients must not have 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 study drug
• Patients must not be planning to receive any other investigational agents during the course of protocol treatment
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab
• Prestudy history and physical must be obtained with 28 days prior to registration
• Patients must have Zubrod performance status of 0 - 2
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
• Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system