Nivolumab and Oxaliplatin with or without Ipilimumab for the Treatment of Advanced Squamous or Non-squamous Non-small Cell Lung Cancer

Inclusion Criteria

• Histologically or cytologically confirmed, advanced non-squamous or squamous NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging system)
• Last line of therapy for advanced non-squamous or squamous NSCLC must be with an anti-PD1 or PDL1 antibody with confirmed progression on or after that treatment. Patients may have received no more than 3 lines of prior therapy including no more than 2 prior lines of therapy containing a PD-(L)-2 antibody. Patients must have received prior cisplatin or carboplatin based doublet chemotherapy
• Patients with a history of treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: * No ongoing requirement for corticosteroids as therapy for CNS disease * No stereotactic radiation with 7 days or whole-brain radiation within 14 days prior to randomization * No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study * Patients with new asymptomatic CNS metastases detected at the screening scan may receive radiation therapy and/or surgery for CNS metastases at the discretion of the treating team. Following treatment, these patients may then be eligible, if all other criteria are met
• Patients will be required to undergo a research tumor core biopsy during study screening and again on therapy on study therefore a lesion amenable to core biopsy is required for correlative study enrollment * Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or cell smears), brushing, cell pellet from pleural effusion, and lavage samples are not acceptable * Tumor tissue from bone metastases that have been decalcified is not acceptable * For core needle biopsy specimens, at least four and preferably six core embedded in a single paraffin block, should be submitted for evaluation
• Measurable disease, as defined by RECIST v1.1 - previously irradiated lesions can only be considered measurable disease if disease progression has been unequivocally documented at that site since radiation and the previously irradiated lesion is not the only site of measurable disease
• Absolute neutrophil count (ANC) > 1500 cells/mL without granulocyte colony-stimulating factor support (within 14 days prior to randomization)
• Lymphocyte > 500 cells/mL (within 14 days prior to randomization)
• Platelet count > 100,000 cells/mL without transfusion (within 14 days prior to randomization)
• Hemoglobin > 9.0 g/dL (within 14 days prior to randomization)
• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) (within 14 days prior to randomization) with the following exceptions: * Patients with documented liver metastases: AST and/or alanine aminotransferase (ALT) > 5 x ULN * Patients with documented liver or bone metastases: alkaline phosphatase > 5 x ULN
• ALT =< 2.5 x ULN (within 14 days prior to randomization) with the following exceptions: * Patients with documented liver metastases: AST and/or ALT > 5 x ULN * Patients with documented liver or bone metastases: alkaline phosphatase > 5 x ULN
• Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to randomization) with the following exceptions: * Patients with documented liver metastases: AST and/or ALT > 5 x ULN * Patients with documented liver or bone metastases: alkaline phosphatase > 5 x ULN
• Serum bilirubin < 1.5 x ULN (within 14 days prior to randomization) * Patients with known Gilbert disease: serum bilirubin > 3 x ULN
• Calculated creatinine clearance (CrCl) > 45 mL/min
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly effective form(s) of contraception during study treatment that results in a low failure rate of < 1% per year when used consistently and correctly. Female patients should continue contraception use for 5 months after the last dose of nivolumab and ipilimumab and for 6 months after the last dose of oxaliplatin. Make patients treated with chemotherapy should continue contraception use for 7 months after the last dose of chemotherapy. Men should refrain from donating sperm during this same period. Such methods include combined (estrogen and progestogen containing) hormonal contraception, with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only one partner during the study duration), and sexual abstinence * Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drug. The same rules are valid for male patients involved in this study if they have a partner of childbearing potential. Male patients must always use a condom * Women who are not postmenopausal (> 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug

Exclusion Criteria

• Women who are pregnant, lactating, or intending to become pregnant during the study
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the nivolumab or ipilimumab formulation
• History of autoimmune disease, including, but not limited to, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis * Patients with a history of autoimmune-related hypothyroidism on thyroid-replacement therapy are eligible for this study * Patients with controlled type 1 diabetes mellitus on an insulin regimen are eligible for this study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions ** Rash must cover less than 10% of body surface area ** Disease is well controlled at baseline and only requiring low potency topical steroids ** No acute exacerbations of underlying condition within the last 12 months requiring treatment with either PUVA (psoralen plus ultraviolet A radiation), methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Major surgical procedure other than for diagnosis within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study
• Prior allogeneic bone marrow transplantation or solid organ transplantation
• Patients with illnesses or conditions that interfere with their capacity to understand, follow, and/or comply with study procedures
• Treatment with any approved anti-cancer therapy within 2 weeks prior to initiation of study treatment
• Botanical preparations intended for general health support or to treat the disease under study within 4 weeks prior to randomization
• Treatment with any other investigational agent with therapeutic intent within 21 days prior to enrollment
• Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to enrollment * Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible
• Prior treatment with CD137 agonists or patients who have had prior anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) treatment may be enrolled, provided the following requirements are met: * Last dose of anti-CTLA-4 at least 6 weeks prior to randomization * No history of severe immune related adverse effects from anti-CTLA-4 (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
• History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds
• Grade > 2 peripheral neuropathy as defined by the National Cancer Institute (NCI) CTCAE v5.0 criteria
• CrCl < 45 mL/min
• Known hypersensitivity
• History of radiation therapy within 7 days prior to initiating