This study is being done to find out if a new medicine called PF-08634404, when given with chemotherapy, works better than the present standard treatment (pembrolizumab with chemotherapy) for adults with a type of lung cancer called non-small cell lung cancer (NSCLC) that is either locally advanced (spread to nearby tissues) or has spread to other parts of the body.

To join the study, participants must meet the following conditions:

• Be 18 years or older.
• Have locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) squamous or non-squamous NSCLC.
• Is not a candidate for complete surgical resection or curative chemoradiotherapy.
• Do not have known actionable genomic alterations
• Be treatment naïve for advanced or metastatic disease

Participants in this study will be assigned to two different parts of the study depending on their type of tumor: participants with squamous NSCLC will be assigned to Part 1, while participants with non-squamous NSCLC will be assigned to Part 2.

Each participant will be randomly assigned (like a flip of the coin) to one of two treatment groups in a blinded fashion:

• Part 1 - Arm A or Part 2 - Arm C (Experimental Group): Will receive a new study medicine called PF-08634404 along with a kind of chemotherapy specific to the type of tumor.
• Part 1 - Arm B or Part 2 - Arm D (Control Group): Will receive an approved medicine called pembrolizumab along with a kind of chemotherapy specific to the type of tumor.

Participants will receive their assigned treatment through intravenous (IV) infusions, which means the medicine is given directly into a vein. The treatment will be given in cycles, participants will receive PF-08634404 or Pembrolizumab in combination with chemotherapy followed by maintenance with either PF-08634404 or Pembrolizumab monotherapy (Part 1) or PF-08634404 or Pembrolizumab in combination with a chemotherapeutic drug (Part 2). Participants will continue receiving treatment if it is helping and not experiencing serious side effects.

The study will include regular visits for:

• Treatment and health checks: while participant continues receiving treatment.
• Tests to monitor how cancer responds: every 6 weeks during the first 48 weeks, then every 12 weeks thereafter.

Inclusion Criteria:

• 18 years of age or older at screening.
• Have pathologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV)squamous or non-squamous NSCLC and not be a candidate for complete surgical resection and curative concurrent/sequential chemoradiotherapy (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer Tumor, lymph nodes, metastasis (TNM) staging system).
• Have tumor tissue available, either paraffin block or slides from a core, excisional or fine needle biopsy
• PD-L1 status available based on local testing results
• Measurable disease based on RECIST v1.1 per investigator.
• Eastern Cooperative Oncology Group performance status (ECOG) score of 0 or 1
• Expected survival ≥12 weeks

Exclusion Criteria:

• Participants with known actionable genomic alteration (AGAs), including estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), Repressor of Silencing 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), rearranged during transfection (RET), and mesenchymal-epithelial transition (MET), for which there are available first-line therapies per local standard-of-care (SOC) are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.

• Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Clinically inactive brain metastases of longest diameter < 1 cm are permitted.

• Participants with clinically significant risk of hemorrhage or fistula are excluded.

• Participants with any history of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.

• Unresolved toxicities from prior anti-tumor therapy, that did not recover to NCI CTCAE v5.0 Grade 0 or 1.

• Known to have a history of a severe allergy to any component of the study intervention, or a history of severe allergic reaction to chimeric or humanized antibody.

• History of allogeneic organ / hematopoietic stem cell transplantation.

• Participants with any of the following respiratory conditions:

• Evidence of noninfectious or drug-induced interstitial lung disease (ILD) or pneumonitis

• Grade ≥3 pulmonary disease unrelated to underlying malignancy

• History of uncontrolled comorbidities within 6 months prior to the first dose including uncontrolled cardiac and cerebrovascular conditions, hypertension, diabetes, significant vascular disease or arterial/severe venous thromboembolic events.

• Major surgery < 4 weeks or minor surgery < 3 days prior to first dose of study intervention.

• History of severe bleeding tendency or coagulation dysfunction

• History of esophageal varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to the first dose.

• Participants with acute, chronic or symptomatic infections including participants positive for active HIV, hepatitis B virus (HBV), or Hepatitis C virus (HCV).

• Participants with history of immunodeficiency

• Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior (in the past 5 years) or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.

• Previous systemic anti-tumor therapy including:

  1. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.
  2. Previous treatment with immunotherapy
  3. Prior radiotherapy > 30 Gy to the lung < 6 months of first dose of study intervention
  4. Palliative local therapy < 2 weeks before the first dose of study intervention;
  5. Non-specific immunomodulatory therapy < 2 weeks before the first dose.
  6. Prior systemic anti-angiogenic therapy

• Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, adverse events from prior immunotherapy not improved to Grade 1 before screening, or required treatment with systemic immunosuppressive therapy.

• Prior and concomitant therapy:

  1. therapeutic oral or parenteral anticoagulants or thrombolytic agents < 10 days to the first dose.
  2. chronic antiplatelet therapy <7 days to randomization.
  3. live or attenuated live vaccine < 4 weeks to the first dose.
  4. current high-dose systemic corticosteroids.
  5. prohibited concomitant medication(s) < 21 days to the first dose.

• Breastfeeding participants, participants of childbearing potential, and male participants who are unwilling to follow contraceptive measures.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

This is double-blind study, neither the participants nor the study team will know whether the participants are receiving PF-08634404 or Pembrolizumab.