Afatinib and Necitumumab in Patients With EGFR Mutation Positive Advanced or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria:

   - Signed and dated written informed consent

   - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

   - Histologically or cytologically-confirmed advanced or metastatic non-small cell lung
   cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed

   - Progression on a first generation EGFR TKI (T790M negative), or progression on a third
   generation TKI (if T790M positive at time of progression on a first or second
   generation TKI)

   - At least one measurable lesion as defined by Response Evaluation Criteria in Solid
   Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic
   resonance imaging (MRI)

   - Patient consents to undergo a medically safe tumor biopsy at time of disease
   progression for mutation analysis

   - Leukocytes >= 3,000/uL

   - Absolute neutrophil count (ANC) >= 1,500/uL

   - Platelets >= 100,000/uL

   - Hemoglobin >= 9 g/dL

   - Serum albumin >= 2.5 g/dL

   - Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)

   - Total bilirubin =< 1.5 times upper limit of normal (ULN)

   - Alkaline phosphatase (ALP) =< 3.0 x ULN

   - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for
   patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable

   * Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin >
   2 x ULN, clinical and laboratory monitoring should be initiated by the investigator;
   for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at
   ALT > 2 x baseline

   - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
   within 14 days prior to receiving first dose of study medication; and additionally
   agree to use at least two methods of birth control or abstain from heterosexual
   intercourse from the time of signing consent, and until 6 months after patient's last
   dose of study drug

   * WOCBP of childbearing potential are defined as those not surgically sterile or not
   post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a
   bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24
   months in the absence of an alternative medical cause, then patient will be considered
   a female of childbearing potential); postmenopausal status in females under 55 years
   of age should be confirmed with a serum follicle-stimulating hormone (FSH) level
   within laboratory reference range for postmenopausal women

   - WOCBP must agree to follow instructions for method(s) of contraception from the time
   of signing consent and until 6 months after last dose of study therapy

   - Men able to father children who are sexually active with WOCBP must agree to follow
   instructions for method(s) of contraception from the time of signing consent and until
   6 months after last dose of study therapy; men able to father children are defined as
   those who are not surgically sterile (i.e. patient has not had a vasectomy)

Exclusion Criteria:

   - Prior treatment against NSCLC with an EGFR monoclonal antibody

   - Prior afatinib therapy, unless patient received an intervening third generation EGFR
   TKI after concluding prior afatinib and before enrollment on this clinical study

   - Less than 3 days from prior treatment with EGFR TKI; patients with adverse events
   related to prior EGFR TKI must recover to Common Terminology Criteria for Adverse
   Events (CTCAE) =< grade 1 to be eligible

   - History of arterial or venous thromboembolism within 3 months prior to study
   enrollment; patients with a history of venous thromboembolism beyond 3 months prior to
   study enrollment can be enrolled if they are appropriately treated with low molecular
   weight heparin

   - Subjects with a history of interstitial lung disease (e.g., sarcoidosis) that is
   symptomatic or may interfere with the detection or management of suspected
   drug-related pulmonary toxicity; subjects with chronic obstructive pulmonary disease
   (COPD) whose disease is controlled at study entry are allowed

   - Symptomatic brain metastases; stable and treated central nervous system (CNS) disease
   allowed; patients with treated, asymptomatic brain metastases are eligible if there
   has been no change in brain disease status for at least two (2) weeks prior to
   initiating study treatment; anticonvulsant therapy will be allowed if patient is on a
   stable or decreasing dose of anticonvulsant treatment for at least two (2) weeks prior
   to initiating study treatment

   - Subjects with carcinomatous meningitis

   - Prior radiotherapy or radiosurgery < 2 weeks prior to starting study treatment

   - Current symptomatic congestive heart failure (New York Heart Association
   classification >= grade III), unstable cardiac arrhythmia requiring therapy (e.g.
   medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest
   discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100
   mmHg); or any of the following occurring within 6 months (180 days) prior to first
   dose of study treatment: myocardial infarction, coronary/peripheral artery bypass
   graft, cerebrovascular accident or transient ischemic attack; use of antihypertensive
   medication to control blood pressure is allowed

   - Patient is pregnant or breastfeeding, or plans to become pregnant or father children
   from time of signing consent and lasting until 6 months after the last dose of trial
   treatment

   - Previous or concomitant malignancies at other sites, except effectively treated
   non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ
   or effectively treated malignancy that has been in remission for more than 3 years and
   is considered to be cured AND no additional therapy is ongoing and required during the
   study period with the exception of bisphosphonates and anti-androgens and/or
   gonadorelin analogues for the treatment of prostate cancer are permitted; subjects
   with other active malignancy requiring concurrent intervention are excluded

   - Requiring treatment with any of the prohibited concomitant medications listed that
   cannot be stopped for the duration of trial participation

   - Any history or presence of poorly controlled gastrointestinal disorders that could
   affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis,
   chronic diarrhea, malabsorption)

   - Recent (within 30 days before enrollment) or concurrent yellow fever vaccination

   - All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue,
   or peripheral neuropathy must have resolved to grade 1 (National Cancer Institute
   [NCI] CTCAE version 4) or baseline before administration of study drug

   - The patient has any ongoing or active infection, including active tuberculosis; Note:
   a urinary tract infection controlled with oral antibiotics initiated at least 7 days
   prior to study entry is acceptable

   - Known positive test for hepatitis B, hepatitis C, human immunodeficiency virus (HIV),
   or acquired immunodeficiency syndrome (AIDS)

   - The patient has a known allergy/history of hypersensitivity reaction to any of the
   treatment components, including any ingredient used in the formulation of necitumumab,
   or any other contraindication to one of the administered treatments

   - Known hypersensitivity to afatinib or the excipients of any of the trial drugs

   - History of severe hypersensitivity reactions to other monoclonal antibodies

   - Subjects who are compulsorily detained for treatment of either a psychiatric or
   physical (e.g. infectious disease) illness

   - Any other serious or uncontrolled medical disorder, active infection, physical exam
   finding, laboratory finding, altered mental status, or psychiatric condition that, in
   the opinion of the investigator, would limit a subject's ability to comply with the
   study requirements, substantially increase risk to the subject, or impact the
   interpretability of study results