• The subject provides written informed consent.

• Adults ≥ 18 years of age on day of signing informed consent.

• Disease must be measurable per RECIST 1.1, as assessed by the Site(s) Investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in these lesions.

• Subject has histologically or cytologically documented, locally advanced (Stage IIIB or IIIC) disease (not candidate for surgical resection, local therapies with curative intent, or definitive chemoradiation) or the subject has metastatic NSCLC (Stage IV). Staging will be based on the American Joint Committee on Cancer, Eighth Edition. Subjects with adenocarcinoma, large cell carcinoma, undifferentiated carcinoma, squamous carcinoma, or mixed histology are eligible. Subjects with a small cell component are not eligible.

• Phase 1b Subjects additional eligibility criteria:

∙ Subjects must have received a minimum of one prior systemic treatment for advanced unresectable or metastatic NSCLC and progressed following prior SOC.

‣ Maximum of up to 4 prior lines of therapy in an advanced or metastatic setting is allowed.

‣ Subjects who had disease recurrence or progression following neoadjuvant or adjuvant therapy or definitive chemoradiation therapy are eligible.

‣ Subjects who received treatment with an approved/available targeted therapy for an actionable genomic alteration (including but not limited to EGFR, ALK, ROS1, KRAS, etc.) can participate if they have documented disease progression or were unable to tolerate the approved targeted therapy.

• Phase 1b Notes:

• Targeted therapy for advanced setting is counted as a prior line of therapy.

• Prior use of a PD(L)-1, anti-CTLA-4 (Cytotoxic T-lymphocyte associated protein 4) antibody, or any other antibody or drug that specifically targets immune checkpoint pathway is allowed and is counted as a prior line of therapy.

• Neoadjuvant and adjuvant therapies initiated \< 12 months prior to the first dose of study drug(s) will be counted as one prior line of therapy for advanced setting.

• Neoadjuvant and adjuvant therapies initiated ≥ 12 months prior to the first dose of study drug(s) are not counted as prior lines of therapy.

• Maintenance therapy is not counted as a prior line of therapy.

• Phase 2a Subjects additional eligibility criteria:

• Cohort 1:

⁃ Tumors must have PD-L1 expression (TPS ≥ 1% as determined by SOC).

⁃ Subjects are eligible to participate if they did not receive any prior therapy (SOC or investigational) or prior immunotherapy of any kind for advanced or metastatic disease. See Exclusion Criteria 1.0.

⁃ Subjects with disease recurrence or progression following neoadjuvant or adjuvant therapy or definitive chemoradiation therapy are eligible.

⁃ Prior adjuvant or neoadjuvant immunotherapy is allowed if completed more than 12 months before documented relapse.

• Cohort 2:

⁃ Subjects should have received at least 2 doses of an approved anti PD(L) 1 monoclonal antibody (mAb) in an advanced or metastatic setting.

⁃ Progressive disease should be documented during treatment or within 12 weeks from the last dose of anti-PD(L)-1 mAb.

⁃ Up to a maximum of 2 prior lines of approved cancer therapy in an advanced or metastatic setting, including an anti-PD(L)-1 mAb administered either as monotherapy or in combination with other therapies, is allowed.

⁃ Subjects who received treatment with an approved/available targeted therapy for an actionable genomic alteration (including but not limited to EGFR, ALK, ROS1, KRAS, etc.) can participate if they have documented disease progression or were unable to tolerate the approved targeted therapy. Only these subjects are allowed to receive up to a maximum of 3 prior lines of cancer therapy in an advanced or metastatic setting.

⁃ Subjects with disease recurrence or progression following neoadjuvant or adjuvant therapy or definitive chemoradiation therapy are eligible.

• Cohort 2 Notes:

• Targeted therapy for advanced setting is counted as a prior line of therapy.

• Maintenance therapy is not counted as a prior line of therapy.

• Neoadjuvant and adjuvant therapies initiated \< 12 months prior to first dose of study drug(s) will be counted as one prior line of therapy for advanced setting.

• Neoadjuvant and adjuvant therapies initiated ≥ 12 months prior to first dose of study drug(s) are not counted as prior lines of therapy.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Life expectancy of at least 3 months.

• An archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated must exist to participate in the study (Mandatory in Phase 2a but subjects in Phase 1b may be enrolled in the absence of a tumor tissue sample). Only core needle and/or excisional biopsy samples, from archival or fresh tissue, will be accepted in this study.

• Adequate organ function as defined below must be met for subjects to participate in the study. Clinical laboratory specimens must be collected within 10 days prior to first dose of study drug(s):

∙ Absolute neutrophil count (ANC) ≥ 1500/µL or ≥ 1.5 × 109/L (in the absence of growth factor support).

‣ Platelets ≥ 100,000/µL or 100 × 109/L (in the absence of transfusion or growth factor support).

‣ Hemoglobin ≥ 9 g/dL or ≥ 90 g/L (in the absence of transfusion). Note: Criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin (≥ approximately 3 months).

‣ Creatinine Clearance (CCr) ≥ 50 mL/minute using the Cockcroft and Gault formula.

∙ Note: The Cockcroft and Gault formula (1973): CCr = (\[{140 - age} × weight\]/\[72 × SCr\]) × 0.85 (if female); where CCr = mL/minute; age = years; weight = kg; SCr (serum creatinine) = mg/dL.

‣ Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (unless a diagnosis of Gilbert's syndrome in which case ≤ 3 × ULN) OR direct bilirubin ≤ 1 × ULN for participants with total bilirubin \>1.5 × ULN.

‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5× ULN for subjects with liver metastases).

‣ International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy PT or INR should be within the therapeutic range of the intended use of anticoagulants.

‣ Activated partial thromboplastin time/partial thromboplastin time (aPTT/PTT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy PTT should be within the therapeutic range of intended use of anticoagulants.

• Note: Low molecular weight heparin, warfarin (INR monitoring required), direct oral anticoagulants, and drugs in the anticoagulant class (e.g., Lovenox \[enoxaparin\]) administered for deep vein thrombosis are permitted.

• Women who are not of childbearing potential must be documented and will not be tested for pregnancy or required to utilize contraception if they meet one or more of the following definitions of non-childbearing potential:

∙ Amenorrheic for \> 2 years without a hysterectomy and oophorectomy, and a follicle stimulating hormone (FSH) value in the postmenopausal range upon screening evaluation.

‣ Post-hysterectomy, bilateral oophorectomy, or tubal ligation. Tubal ligation should be confirmed with medical records of the actual procedure.

• 12\. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum) within 72 hours prior to first dose of study drug(s) and meet the following criteria throughout the study, starting with the screening visit through 120 days after the last dose of study drug(s) (or 30 days if new cancer therapy is initiated):

∙ Agrees to follow contraceptive guidance throughout the study as per protocol.

‣ Willing to use 2 highly effective birth control methods throughout the study. The 2 birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Refer to Appendix 4 for complete list of acceptable birth control methods.

‣ Refrain from egg donation. Note: If there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be enrolled.

• Male subjects must agree to use an acceptable method of contraception and refrain from sperm donation throughout the study: from screening, during the treatment period, and for at least 120 days after the last dose of study drug(s) (or 30 days if new cancer therapy is initiated).

• Willing and able to participate in blood sampling and all other required study procedures.