1L Stage IV or Recurrent Metastatic NSCLC

Key Eligibility:

1. ECOG 0-2
2. No prior systemic therapy for advanced/metastatic NSCLC (prior adjuvant chemotherapy following
complete resection of early-stage NSCLC I-II is allowed)
3. Participants with 5 or fewer brain metastases are eligible if intracranial sites can be treated with
surgery and/or stereotactic radiosurgery, prior to initiation of chemo-immunotherapy
4. Visits: SOC Chemoimmunotherapy plus radiation to oligometastatic sites (frequency of radiation
visits determined on case by case basis)

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.

Key Eligibility Criteria
Inclusion
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
• Expected life expectancy ≥ 3 months
• Metastatic (Stage IV) NSCLC
• Histologically or cytologically confirmed squamous or non-squamous NSCLC
• Tumor demonstrates high PD-L1 expression based on an IHC pharmDx 22C3 (TPS ≥50%) or SP263 (TC ≥50%) IHC clinical assay approved/cleared by local health authorities and in a laboratory compliant with national provisions; this can be obtained from available results, or from archival or fresh tumor tissue for measurement of PD-L1 expression at a local or central laboratory.
• At least one measurable noncerebral lesion according to RECIST v1.1. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions since radiotherapy.
• No prior systemic treatment for metastatic NSCLC. Patients receiving adjuvant or neoadjuvant chemotherapy or curative-intent chemoradiotherapy and/or PD-1/L1 inhibitors are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease

Exclusion
• Histologic or cytopathologic evidence of the presence of small cell lung carcinoma.
• Known actionable genomic alterations (EGFR, ALK, ROS1, and BRAF V600E) for which first-line approved therapies are indicated. For patients with non-squamous histology, actionable driver mutation testing results are required before randomization.
• Has received any prior therapy for NSCLC in the metastatic setting
• Radiologically documented evidence of major blood vessel invasion (central pulmonary artery, central pulmonary veins, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava) or tumor invading organs (heart, trachea, esophagus, central bronchi [not including segmental bronchi]) or if there is a risk of esophagotracheal or esophagopleural fistula in the opinion of the investigator. b. Radiographic evidence of major blood vessel encasement with narrowing of the vessel or intratumor lung cavitation or necrosis that the investigator determines will pose a significantly increased risk of bleeding
• Symptomatic CNS metastases, CNS metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease