Stage I-III Unresectable NSCLC

Cohort A only: Have documented disease progression or be refractory to an anti-PD-1/PD-L1 antibody and a platinum-based chemotherapy regimen approved for NSCLC, either in combination or sequentially.

Cohort B only: Have not received prior systemic treatment for locally advanced or metastatic NSCLC and have PD-L1 ≥ 50% by local testing using an FDA-approved assay or in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. Note: Prior adjuvant and neoadjuvant therapy are allowed prior to the development of metastatic disease, but adjuvant treatment must have been completed at least 6 months prior to Cycle 1 Day 1 (C1D1) and neoadjuvant treatment must have been completed at least 3 months prior to C1D1. Participants must have recovered from any prior AEs to Grade 1 or lower. 3.

Cohort A only: Last dose of previous anticancer therapy (including investigational agents) ≥ 28 days, radiotherapy ≥ 14 days (targeted palliative radiotherapy is allowed for lesions not planned for injections), or surgical intervention ≥ 21 days prior to C1D1

Cohort A only: Thyroid-stimulating hormone (TSH) within normal limits. If TSH is not within normal limits at baseline, total T3 or free T3 and free T4 must be within normal limits.

Inclusion:
Have systemic treatment naïve, histologically or cytologically confirmed diagnosis of Stage IIIB or IIIC (who are not amenable to curative surgery or radiotherapy) or Stage IV NSCLC
• Participants with non-squamous NSCLC will be enrolled to Substudy A. − Participants must be tested for EGFR mutations and ALK rearrangements; those with actionable results should not be enrolled. − If locally approved targeted first-line therapies are available, participants with known actionable mutations (other than EGFR and ALK alterations) should not be enrolled. Note: Testing for other genomic mutations is not mandated if not done as part of standard local practice.
• Participants with squamous NSCLC will be enrolled to Substudy B. Mixed tumors which involve squamous tumor cells will be categorized as squamous cell NSCLC; if small cell elements are present, the participant is ineligible. − If the participant is 15 years ago then they should be tested for EGFR mutations and ALK rearrangements; those with actionable results should not be enrolled

Exclusion:

Have received any of the following therapies or drugs within the noted time intervals prior to trial treatment:
• Previous chemotherapy (platinum-based) or PD(L)-1 for treating NSCLC in either neoadjuvant/adjuvant or locally advanced/metastatic setting.
• Receipt of an investigational drug or device within 30 days of screening or within five half-lives of the investigational drug (whichever is shorter).
• Participants who received prior treatment with anti-VEGF monoclonal antibody, or PD(L)-1/VEGF bispecific antibody.
• Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 7 days prior to the initiation of trial treatment. Note: local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens) are allowed.
• Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to initiation of the trial treatment.
• Received broad-spectrum intravenous antibiotics therapy within 2 weeks prior to initiation of trial treatment.