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.

Prior treatment

• Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Up to 5 clinically asymptomatic brain metastases of longest diameter \<1.0 cm are permitted without definitive surgery and/or radiotherapy.
• Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery (excluding peripherally inserted central catheter placement and implantable central venous port placement) within 3 days prior to first dose of study intervention.
• Receipt of a live vaccine within 30 days prior to first dose of study intervention.
• 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.
• Participants with prior solid organ or bone marrow transplantation.
• 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.
• Prior and concomitant therapy:
  • Any prior treatment with MMAE-derived drugs or IB6 targeting agents.
  • 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.
  • Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received. This includes both curative and palliative radiotherapy.
  • 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.
  • Any prior therapy with an immune-oncology agent directed to a stimulatory or co-inhibitory T-cell receptor
• Severe uncontrolled cardiac or cerebrovascular condition within the previous 6 months

Other illness

• 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.
• Known or suspected hypersensitivity, intolerance, or contraindication to any excipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.
• History of autoimmune disease that has required systemic treatment in the past 2 years
• History of or current ongoing infection, including participants positive for active HIV, HBV, or HCV.

Lab values

• 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.
• Participants with any of the following respiratory conditions:
  • Evidence of noninfectious or drug-induced ILD or pneumonitis
  • Known DLCO (adjusted for hemoglobin) \<50% predicted.
  • Grade ≥3 pulmonary disease unrelated to underlying malignancy
• 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.

Other

• Life expectancy of \<3 months in the opinion of the investigator.
• Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.

• Participants must meet the following criteria:
  • 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).
  • Participants with known AGAs including EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET, for which there are approved and available first-line therapies per local SOC are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.
  • Participants with large cell neuroendocrine carcinoma are excluded.
  • Must be an appropriate candidate for treatment with pembrolizumab monotherapy per local guidelines.
• Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing.
• Measurable disease based on RECIST v1.1 per investigator.
• 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.