This is a single center, phase Ib/II study combining an anti-PD-1 antibody and an anti-CTLA-4 antibody with IL-15. It is testing the hypothesis that the addition of nogapendekin alfa inbakicept to nivolumab and ipilimumab will augment the clinical activity of those two drugs.

Inclusion Criteria:

• Histologically or cytologically confirmed, previously untreated or recurrent metastatic NSCLC.

• Availability of archival biopsy tissue or willingness to undergo a biopsy prior to C1D1 for biomarker analysis, including PD-L1 by IHC using a CLIA-certified test. Results of the PD-L1 testing are not required for enrollment.

• Measurable disease per RECIST 1.1.

• At least 18 years of age.

• ECOG performance status ≤ 1

• Adequate organ and marrow function, as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9.0 g/dL
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN without hepatic metastasis and ≤ 5 x IULN with hepatic metastasis
  • Total bilirubin ≤ 2 x IULN (except participants with Gilbert's syndrome who must have total bilirubin < 3.0 mg/dL)
  • Creatinine clearance > 30 mL/min by Cockcroft-Gault
  • INR ≤ 1.5 unless using therapeutic anticoagulation
  • PTT/aPTT < 1.5 x IULN unless using therapeutic anticoagulation

• Patients with brain metastases are eligible if they have previously treated with surgery or radiation therapy, are neurologically stable after a washout period of at least 2 weeks, and are not receiving corticosteroids at dose higher than 10 mg of prednisone or equivalent on C1D1.

• The effects of the treatment regimen on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use highly effective methods of contraception, according to the protocol, from the time of consent through 6 months after the last dose of study treatment.

• Ability to understand and willingness to sign an IRB-approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Mixed histology including small cell lung cancer.

• Tumor harboring any of the following:

  • classic EGFR mutations
  • HER2 mutation
  • ALK fusion
  • ROS1 fusion
  • RET fusion
  • NTRK fusion
  • MET Exon14 skipping mutation
  • BRAF V600E mutation

• Use of any live vaccines within 28 days of C1D1.

• Prior chemotherapy in the adjuvant setting or during concurrent radiation therapy for locally advanced disease within 12 months prior to enrollment. If the interval from the last treatment is 12 months or longer, the patient is eligible.

• Radiation therapy within 14 days prior to C1D1.

• History of major surgery within 14 days prior to C1D1.

• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study treatment hazardous, including but not limited to:

  • History of interstitial lung disease or noninfectious pneumonitis,
  • Active viral, bacterial or fungal infections requiring parenteral treatment within 14 days of C1D1,
  • Clinically significant cardiovascular disease,
  • A condition that may obscure the interpretation of toxicity determination or AEs,
  • History of prior solid-organ transplantation.

• Concurrent medical condition requiring the use of supra-physiologic doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive medications (absorbable topical corticosteroids are not excluded).

• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.

• Evidence of chronic hepatitis B (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.

• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.

• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy.

  • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
  • Participants with asthma who require intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections will not be excluded from this study.
  • Participants on chronic systemic corticosteroids will be excluded from the study.

• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.

• Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of C1D1.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any agents used in the study, or known hypersensitivity to recombinant proteins, or any excipient contained in the trial formulations.

• Pregnant and/or breastfeeding. People of childbearing potential must have a negative pregnancy test within 7 days of study entry.