The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

Inclusion Criteria:

• Participants must have histologic or cytological diagnosis of advanced/metastatic Non-Small Cell Lung Cancer (NSCLC) with no curative treatment options. For those with mixed histology, there must be a predominant histology.

• 18 years of age or older on day of signing informed consent.

• Life expectancy of at least 3-6 months.

• Eastern Cooperative Oncology Group (ECOG) performance status score 0 and 1

• For phase I trial portion, treatment naïve or patients previously treated with chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed. Patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of that therapy (and will be considered treatment naïve in the Stage IV setting). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy.

• For phase II trial portion, Patients will be enrolled as two parallel cohorts:

  • A.) Arm A (treatment naïve): Patients who are newly diagnosed and treatment naïve. Patient who underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months from completion of therapy. Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy.
  • B.) Arm B (Immunotherapy pre-treated group): Patients who have received prior immunotherapy. Patients who are primary refractory to immunotherapy (i.e., Patients who were previously treated with immunotherapy and did not at least achieve stable disease on first imaging assessment on immunotherapy) or have relapsed disease (i.e., Patients that were treated with immunotherapy, achieved at least stable disease on first imaging assessment and subsequently developed disease progression or relapse). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy

• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

• QTcB must be <470 ms for males and <480 ms for females.

• Adequate normal organ and marrow function as defined below:

  • Absolute neutrophil count (ANC) >1.5 x 10^9/L (> 1500 per mm^3)
  • Hemoglobin ≥ 9.0 g/dL
  • Platelet count ≥ 100 x 10^9/L (>100,000 per mm^3)
  • Total bilirubin ≤ 1.5 X normal institutional limits. For patients with liver metastasis: total bilirubin must be within normal limits.
  • Proteinuria less than Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater
  • (Except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
  • AST (SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of norma (ULN)l or ≤ 2.5 X ULN for patients with liver metastases. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
  • Serum creatinine CL ≤ 1.5 X ULN or creatinine clearance > 45 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

• Have archival tissue where available.

• In addition, patients enrolled on the clinical trial must be willing and able to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Patients for whom newly obtained samples cannot be provided may submit an archived specimen only upon agreement from the Sponsor.

• Female participants of childbearing potential should have a negative urine or serum pregnancy within 72 hours before receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Ability to understand and willingness to provide written informed consent signed and dated prior to admission to the study in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines and to the local legislation.

Exclusion Criteria:

• Concurrent use of other anticancer agents including chemotherapy, targeted therapy, radiotherapy or immunotherapy not otherwise specified in the protocol.

• Concurrent use of other investigational drugs or treatment in another clinical trial with a non- FDA-approved medication within the past 4 weeks before start of therapy.

• Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 2 weeks prior to treatment with the trial drug.

• Radiotherapy (except for brain and extremities or stereotactic treatment) within the past 2 weeks prior to treatment with the trial drug.

• In immunotherapy pretreated patients, any history of dose-limiting toxicity with prior immunotherapy agents, including grade 3/4 immune-related adverse events (irAEs); irreversible irAEs; Grade ≥3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant clinical sequelae.

• Prior treatment with nintedanib (BIBF1120).

• Known hypersensitivity to nintedanib, nivolumab, ipilimumab, peanut or soy or any other trial drug, or their excipients.

• Any toxicity (>CTCAE version 5 grade 3) from previous anti-cancer therapy that has not resolved to a Grade 1. Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy, alopecia).

• History of leptomeningeal carcinomatosis.

• Radiotherapy to a target lesion within the past 3 months prior to baseline imaging unless that area has demonstrated progression.

• Active brain metastases (e.g., stable for <2 weeks, symptomatic, no adequate previous treatment, requiring treatment with anti-convulsants); dexamethasone therapy will be allowed if administered as stable or decreasing dose for at least 3 weeks before randomization otherwise no steroids to exceed prednisone 10 mg/day prior to starting trial treatment. Symptomatic or uncontrolled central nervous system (CNS) metastasis.

• Current or prior use of immunosuppressive medication 7 days before the first dose of nivolumab or ipilimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. A brief course (≤28 days) of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted. Topical corticosteroids are permitted.

• Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, type I diabetes mellitus or residual hypothyroidism due to autoimmune condition only requiring hormone replacement, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.

• Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels.

• Has known history of, or any evidence of active, non-infectious pneumonitis.

• Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or antiplatelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day.

• Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.

• History of clinically significant hemorrhagic or thromboembolic event in the past 6 months.

• Known inherited predisposition to bleeding or thrombosis.

• Significant cardiovascular diseases (i.e., uncontrolled hypertension, unstable angina, history of infarction within the past 3 months prior to start of study treatment, congestive heart failure > New York Heart Association (NYHA) II, serious cardiac arrhythmia).

• Coagulation parameters: International normalized ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN.

• History of another primary malignancy within the past 2 years except for:

  • Basal cell skin cancer
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ)

• Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)

• History of known active primary immunodeficiency

• History of allogeneic organ transplant

• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study treatment.

• Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug

• Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastrointestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study

• Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g., such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) for the duration specified during the trial and after end of active therapy

• Pregnancy or breastfeeding female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment

• Psychological, familial, sociological, or geographical factors potentially hampering compliance with the study protocol and follow-up schedule

• Active alcohol or drug abuse

• Significant weight loss (> 20% of Body Weight) within past 6 months prior to inclusion into the trial

• History of active tuberculosis