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.

Exclusion Criteria

• •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