Study of Nivolumab Verses Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer

Inclusion Criteria: i. Signed informed consent ii. Male or female, 21 years or older * Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug * Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab * Women must not be breastfeeding * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception * WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 milli-international units per millilitre (mIU/mL). * Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days. iii. Advanced EGFR+ NSCLC iv. Eastern Cooperative Oncology Group (ECOG) 0-2 performance status v. Progressed on one line of standard EGFR TKI and not more than one line of chemotherapy; 3rd generation EGFR TKI for patients with T790M mutation is allowed * A 14-day washout period is required for EGFR TKI for patients who received this as the last therapy before recruitment * A 28-day washout period is required for chemotherapy for patients who received this as the last therapy before recruitment. All drug-related toxicities should have returned to baseline with the exception of neuropathy, fatigue, and alopecia. vi. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization/registration * White Blood Cell (WBC) ≥ 2000/µL * Neutrophils ≥ 1000/µL * Platelets ≥ 100 x 10\^3/µL * Hemoglobin \> 9.0 g/dL * Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula below): * Aspartate Aminotransferase/ Alanine Aminotransferase (AST/ALT) ≤ 3 x ULN * Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) vii. Measurable disease, as defined by RECIST v1.1; Previously irradiated lesions can only be considered as measurable disease if disease progression has been unequivocally documented at that site since radiation. viii. Patients with a history of treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: 1. Measurable disease outside CNS 2. No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed 3. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization 4. No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study ix. Tumor sites amenable for CT-guided core biopsies or trucut biopsies x. Willing to undergo 2 biopsies and contribute research bloods for the study. Archived tissue that is less than 6 months old is acceptable as an alternative to biopsy at screening if a biopsy is not feasible; patients from arm A must be willing to undergo biopsy as baseline upon clear-cut disease progression and on-treatment repeat biopsy before they are allowed to cross over to receive ipilimumab in addition to nivolumab. xi. Patients with confirmed concomitant HBV infection that are eligible for inclusion must be treated with antiviral therapy prior to enrollment to ensure adequate viral suppression (HBV DNA \< 2000 IU/mL), must remain on antiviral therapy for the study duration, and continue therapy for 6 months after the last dose of investigational product(s). Subjects with confirmed Hepatitis C (HCV) infection who are negative for HBsAg and positive for anti-HBc, are eligible but must be started on active antiviral therapy (for HBV) prior to their first dose of investigational product. xi. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception and to continue its use for 90 days after the last dose of nivolumab xii. Women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 24 hours prior to initiation of study drug xiii. Available for follow-up Exclusion Criteria: i. Symptomatic brain or leptomeningeal metastases (patients who have treated stable brain or Leptomeningeal disease are eligible; there is no magnetic resonance imaging (MRI) evidence of progression for \[lowest minimum is 4 weeks or more\] after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration). ii. Poor performance status of ECOG 3-4 iii. Tumour sites not amenable to CT-guided core biopsies or trucut biopsies; However waiver for this criterion can be given for selected patients on a case-by-case basis for patients with sites of disease that are technically difficult to access after discussion with interventional radiologist. Waivers are allowed for not more than 70 patients for this study in order to allow sufficient number of quality tumour biopsies for biomarker analysis in this study. Waivers would have to be approved by the Principal Investigator. iv. Unwilling to undergo 2 biopsies and contribute research bloods for the study v. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins vi. Concurrent Autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. vii. Prior treatment with other anti-Programmed cell death protein 1 (anti-PD1) or anti-PDL1 or anti-CTLA4 therapies viii. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents) within 2 weeks prior to randomization 1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study. 2. Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments done by MRI. 3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. ix. Active interstitial lung disease or history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan; History of radiation pneumonitis in the radiation field (fibrosis) is permitted. x. Active tuberculosis xi. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) xii. Prior allogeneic bone marrow transplantation or solid organ transplant xiii. Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study xiv. Not available for follow-up and unlikely to be compliant with follow-up or protocol requirements