This is a Study to Learn About How the Combination of the Study Medicines Sigvotatug Vedotin Plus Pembrolizumab Works in People With Non-small Cell Lung Cancer With High Levels of PD-L1.

Eligibility Criteria

• 1. Participants must meet the following criteria:
• 1. Have pathologically confirmed Stage IIIB or IIIC NSCLC and not be a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC per the AJCC Staging Manual (Version 8.0) and the UICC Staging System (Eighth edition).
• 2. Participants with non-squamous histology must have documented negative test results for EGFR, ALK, and ROS1 AGAs and no known AGAs in NTRK, BRAF, RET, MET, or other AGAs with approved front-line therapies per local standard of care.
• 3. Large cell neuroendocrine carcinoma is excluded.
• 4. Candidate for treatment with pembrolizumab monotherapy per local guidelines.
• 2. Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing
• 3. Measurable disease based on RECIST v1.1 per investigator.
• 4. Resolution of acute effects of any prior therapy to either baseline severity or NCI CTCAE Grade 1 or less (except for AEs not constituting a safety risk in the investigator's judgment), unless otherwise excluded.
• 1. Life expectancy of \<3 months in the opinion of the investigator.
• 2. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.
• 3. 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.
• 4. Known or suspected hypersensitivity, intolerance, or contraindication to any excipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.
• 5. Participants with any of the following respiratory conditions:
• 1. Evidence of noninfectious or drug-induced ILD or pneumonitis
• 2. Known DLCO (adjusted for hemoglobin) \<50% predicted.
• 3. Grade ≥3 pulmonary disease unrelated to underlying malignancy
• 6. 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 \<0.5 cm are permitted.
• 7. Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery within 7 days prior to first dose of study intervention.
• 8. Receipt of a live vaccine within 30 days prior to first dose of study intervention.
• 9. Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.
• 10. Uncontrolled diabetes mellitus, defined as HbA1c ≥8.0% or HbA1c between 7.0% and 8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
• 11. Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, required a high-dose steroid taper (≥0.5 mg/kg prednisone or equivalent per day) for \>2 weeks, or required treatment with systemic immunosuppressive therapy.
• 12. History of autoimmune disease that has required systemic treatment in the past 2 years
• 13. Participants with prior solid organ or bone marrow transplantation.
• 14. Currently receiving a high-dose steroid (\>10 mg prednisone or equivalent per day) or other immune suppressant or has a condition requiring a chronic high-dose steroid or immune suppressant.
• 15. Prior and concomitant therapy:
• 1. Any prior treatment with MMAE-derived drugs or IB6 targeting agents.
• 2. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.
• * (Neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred ≥9 months after the last dose.
• * Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose.
• 3. Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received.
• 4. Chemotherapy, biologics, and/or other antitumor treatment with immunotherapy not specifically prohibited that is completed less than 4 weeks prior to first dose of study intervention, or 2 weeks for palliative radiotherapy.
• 5. Any prior therapy with an immune-oncology agent directed to a stimulatory or co-inhibitory T-cell receptor
• 16. History of or current ongoing infection, including participants positive for active HIV, HBV, or HCV.
• 17. Severe uncontrolled cardiac or cerebrovascular condition within the previous 6 months