The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary or acquired resistance to anti- programmed death 1 (PD-1) axis therapy can lead to objective radiographic tumor regression.

Approximately 20 percent of unselected patients with advanced non-small cell lung cancer (NSCLC) and progression during or after standard first line chemotherapy will experience tumor response to nivolumab. Treatment options for patients who are not responsive to programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary resistance are poorly understood.

The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of advanced melanoma based on superiority to either agent alone5. The results of a phase I study evaluating combination therapy with nivolumab and ipilimumab in patients with advanced NSCLC (NCT01454102) were presented at the annual American Society of Clinical Oncology (ASCO) meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks yielded an objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of 39%, with one-year survival rate of 69% and grade 3-4 treatment-related adverse event rate of 33%. These results prompted an ongoing phase III study comparing this regimen to standard first line chemotherapy, nivolumab monotherapy or combination therapy with chemotherapy and nivolumab for patients with advanced NSCLC (NCT02477826).

The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor regression. It is hypothesized that ipilimumab will enable more effective immune priming in some patients, resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor, as well as depletion of tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1 inhibition in the tumor will enable effective anti-tumor attack by tumor-specific T cells. Serial tumor biopsies and blood collections will allow interrogation of changes in the tumor microenvironment (and periphery) that support this hypothesis.

The investigators will primarily enroll patients who have experienced progression of NSCLC after anti-PD-1- axis therapy without initial response to such therapy ('primary resistance'). A smaller cohort of patients with acquired resistance to anti-PD-1 axis therapy (i.e. progression after initial response) will additionally be accrued.

The study record was updated to add individual arms for those with primary resistance and acquired resistance. The intent of the study is not to compare these treatment arms.

Inclusion Criteria

A. Signed Informed Consent B. Ability to comply with the protocol C. Age ≥18 years D. Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the American Joint Committee /AJCC staging system) E. ECOG performance status of 0 to 2 F. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can be counted as target lesions if clearly progressing after radiation.

G. Chemotherapy-naive and treated patients will be eligible, with no limit on number of prior therapies. Patients with NSCLC known to harbor an ALK rearrangement, or EGFR mutation known to be sensitive to FDA-approved tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression (during or after treatment) or intolerance to an FDA approved EGFR TKI or ALK TKI, respectively.

1. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor must have received prior osimertinib
2. Patients with crizotinib-treated ALK rearranged NSCLC must have received a next generation ALK inhibitor (e.g. ceritinib, alectinib or brigatinib) H. Prior palliative radiotherapy must have been completed at least 2 weeks before the first dose of study drug.

I. Anti- PD-1 Axis therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab) must be the most recent systemic anti-tumor treatment received in all patients, with documented progressive disease. Last administration of anti-PD-1 axis therapy must have been at least 3 weeks before the first dose of study drug.

a. Patients to be enrolled to the primary cohort (primary resistance) must have had progressive disease or stable disease less than 24 weeks as the best clinical response to anti-PD-1-axis monotherapy b. Patients to be enrolled to the exploratory cohort (acquired resistance) must have had stable disease for at least 24 weeks, partial response, or complete response as the best clinical response to anti-PD-1-axis monotherapy, with subsequent progression of disease J. At least one tumor amenable to incisional, excisional, core or forceps (transbronchial) biopsy. Patients must be willing to undergo tumor biopsies before starting trial therapy, and 9 to 10 weeks after initiation of therapy.

a. If the initial biopsy will be excisional, the excised tumor cannot be counted as a target lesion and there must be another lesion amenable to incisional, excisional, core or forceps biopsy. In this scenario, the second biopsy can only be excisional if the lesion to be excised is not a target lesion. b. Cytology tumor specimens (e.g. from fine-needle biopsies, or drainage of pleural/ pericardial or ascites fluid) are not acceptable. Biopsies of bone lesions that do not have a soft tissue component are also not acceptable (i.e. decalcified tumor samples are not acceptable).

K. 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 (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of trial therapy. Highly effective contraception is one with a failure rate of <0.1%. Birth control pills on their own do not achieve that rate.

1. Women of childbearing potential must have a negative pregnancy test (serum or urine) within 72 hours of the start of study drug administration
2. Women who have recently given birth must no longer be breastfeeding

L. Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:

- Neutrophils ≥1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)

• Platelets ≥75,000/μL (transfusion to achieve this level is not permitted within 2 weeks of the first study drug administration)
• Hemoglobin ≥9.0 g/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x institutional upper limit of normal (ULN) with the following exceptions: Patients with documented liver metastases: AST and/or ALT≤5 x ULN
• Serum bilirubin ≤1.5 x ULN (Patients with known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled)
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min

Exclusion Criteria

A. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of inhaled steroids or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement, or psoriasis not requiring systemic therapy (within the past 3 years) will not be excluded from the study. B. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity C. Subjects must not have a history of life-threatening toxicity related to prior anti-PD-1 axis therapy a. Subjects with history of anti-PD-1 axis therapy toxicities that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis) are eligible.

D. Prior treatment with anti-CTLA-4 therapeutic antibodies

E. Symptomatic or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:

1. No evidence of interim progression between the completion of CNS-directed therapy and the start of trial therapy.
2. No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose are allowed.
3. Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or wholebrain radiation at least 2 weeks prior to Cycle 1, Day 1 F. History of leptomeningeal carcinomatosis G. Prior palliative radiotherapy outside the CNS within 2 weeks of the first dose of study drug.

H. Treatment with systemic immunosuppressive medications (including but not limited to, dexamethasone at doses > 2 mg daily (or equivalent dose of other corticosteroids), cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiating trial therapy (Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs are permitted. Replacement steroids are also permitted).

I. Subjects must not have received vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to the first dose of study drug.

a. The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without restriction.

J. Any approved systemic anti-cancer therapy, within 3 weeks prior to initiation of study treatment; the following exception is allowed:

• TKIs approved for treatment of NSCLC discontinued > 7 days prior to Cycle 1, Day 1. The baseline scan must be obtained after discontinuation of prior TKIs.

K. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment; the following exceptions are allowed:

• Unapproved/experimental TKIs discontinued 14 days prior to Cycle 1, Day 1 L. Known infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no evidence of active or chronic infection, may be eligible.
• Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by polymerase chain reaction are eligible.

M. Active systemic infection requiring systemic antibiotic treatment within 72 hours prior to first dose of study treatment N. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements O. Major surgery or traumatic injury within 4 weeks of starting study drug P. Women who are pregnant or lactating. Q. Any underlying medical condition that in the Principal Investigator's opinion will make the administration of study drug hazardous to the patient or would obscure the interpretation of adverse events.

Up to 4 years

Originally reported were deaths that occurred during treatment or within 30 days of treatment, the all cause mortality was updated to reflect a longer follow up time period.