Study of PD-1 Inhibitor JTX-4014 Alone and in Combination With Vopratelimab in Biomarker-selected Subjects With Metastatic NSCLC After One Prior Platinum-containing Regimen

Inclusion Criteria: 1. Able and willing to participate and comply with all study requirements and provide signed and dated informed consent prior to initiation of any study procedures; 2. Histologically or cytologically confirmed diagnosis of NSCLC with evaluable or measurable disease according to RECIST v1.1 with at least 1 measurable lesion; 3. Confirmed tumor RNA signature score in accordance with the study protocol; 4. Previously treated for locally advanced or metastatic NSCLC with 1 prior systemic antineoplastic platinum-containing regimen. Regimen should consist of chemotherapy or with bevacizumab; 5. Age of ≥18 years; 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 7. Predicted life expectancy of ≥ 3months; 8. Specified laboratory values in accordance with the study protocol; 9. If with medical history of the following, eligibility should be discussed with the Medical Monitor: 1. Prior biliary tract disorders (based on Medical Dictionary for Regulatory Activities \[MedDRA\] system organ class of Hepatobiliary disorders and MedDRA high-level terms of Obstructive bile duct disorders, Hepatic vascular disorders, and Structural and other bile duct disorders); 2. Portal hypertension and/or hepatic vascular disorders; 10. For women of childbearing potential (WOCBP): negative serum pregnancy test within 72 hours prior to planned Cycle 1, Day 1 (C1D1) and a negative urine or serum pregnancy test on C1D1. In addition, the WOCBP must be willing to complete a urine or serum pregnancy test prior to each dose of either study drug; 11. WOCBP and males whose partners are WOCBP must agree to use a highly effective method of birth control throughout their participation and for 5 months following the last study drug administration. Highly effective methods of birth control are defined as those that, alone or in combination, result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Exclusion Criteria: 1. Concurrent anticancer treatment or subject is expected to require any other form of antineoplastic therapy while on study, either approved or investigational; 2. Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting; 3. Chemotherapy \<28 days prior to planned C1D1 4. Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor monoclonal antibody (mAb) at any time, including pimivalimab; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy; 5. Organ transplantation, including allogenic or autologous stem cell transplantation; 6. Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted therapy, with the exception of bevacizumab if administered in combination with a platinum-based chemotherapy regimen as first line treatment 7. Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q; 8. The following toxicity history: 1. Ongoing toxicity attributed to prior therapy that was Grade \>1 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE); Exceptions: Grade \>1 toxicities that, in the opinion of the Investigator, should not exclude the subject (e.g., alopecia, Grade 2 neuropathy, hypo- or hyperthyroidism, or other endocrinopathies that are well controlled with hormone replacement therapy) and are approved by the Medical Monitor; 2. History of pneumonitis or interstitial lung disease; 3. Symptomatic ascites or pleural effusion (subjects who are clinically stable for \>3 months following treatment for these conditions \[including therapeutic thoraco- or paracentesis\] are eligible); 4. If with medical history of the following, eligibility should be discussed with the Medical Monitor: colitis, hepatitis, nephritis, skin reactions, or encephalitis; 9. Known severe intolerance or life-threatening hypersensitivity reactions to humanized mAbs or IV Ig preparations; any history of anaphylaxis; prior history of human anti-human antibody response; or known allergy to any of the study drugs (including their analogues or excipients \[L-Histidine, mannitol, sodium chloride, or polysorbate 80\]); 10. Major surgery (excluding minor procedures, e.g., placement of vascular access, gastrointestinal/biliary stent, and biopsy) \< 4 weeks prior to planned C1D1; 11. Prior whole brain radiation; 12. Subjects with the following should be reviewed with the Medical Monitor prior to enrollment: 1. Brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation; 2. Radiation (other than whole brain radiation) has been or will be administered \<21 days prior to planned C1D1; 13. Active and clinically relevant bacterial, fungal, or viral infection, including known hepatitis B, C, or human immunodeficiency virus (testing not required); 14. Women who are pregnant, breastfeeding, or who plan to become pregnant/breastfeed while on study; men who plan to father children during the study; 15. Concurrent second malignancy; 16. An active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents at a dose of ≥10 mg/day of prednisone equivalent. Subjects who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Subjects with hypothyroidism who are stable on hormone replacement therapy will not be excluded from the study; 17. Medical or social condition that, in the opinion of the Investigator, might place the subject at an increased risk, adversely affect compliance, or confound safety or other clinical study data interpretation; 18. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.