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.

Inclusion Criteria:

1. Participants must meet the following criteria:

2. Have pathologically confirmed Stage IIIB or IIIC NSCLC and not be a candidatefor surgical resection or definitive chemoradiation, or Stage IV NSCLC per theAJCC Staging Manual (Version 8.0) and the UICC Staging System (Eighth edition).

3. Participants with non-squamous histology must have documented negative testresults 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.

4. Large cell neuroendocrine carcinoma is excluded.

5. Candidate for treatment with pembrolizumab monotherapy per local guidelines.

6. Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by localtesting

7. Measurable disease based on RECIST v1.1 per investigator.

8. Resolution of acute effects of any prior therapy to either baseline severity or NCICTCAE Grade 1 or less (except for AEs not constituting a safety risk in theinvestigator's judgment), unless otherwise excluded.

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) oractive suicidal ideation/behavior or laboratory abnormality that may increase therisk of study participation or make the participant inappropriate for the study.

3. Participants with any history of another malignancy within 3 years before the firstdose of study intervention, or any evidence of residual disease from a previouslydiagnosed malignancy.

4. Known or suspected hypersensitivity, intolerance, or contraindication to anyexcipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.

5. Participants with any of the following respiratory conditions:

6. Evidence of noninfectious or drug-induced ILD or pneumonitis

7. Known DLCO (adjusted for hemoglobin) <50% predicted.

8. Grade ≥3 pulmonary disease unrelated to underlying malignancy

9. Known active CNS lesions are excluded. Participants with definitively treated brainmetastases (surgery and/or radiotherapy) may be eligible. Clinically inactive brainmetastases of longest diameter <0.5 cm are permitted.

10. 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 studyintervention.

11. Receipt of a live vaccine within 30 days prior to first dose of study intervention.

12. Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.

13. 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 nototherwise explained.

14. Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, requireda high-dose steroid taper (≥0.5 mg/kg prednisone or equivalent per day) for >2weeks, or required treatment with systemic immunosuppressive therapy.

15. History of autoimmune disease that has required systemic treatment in the past 2years

16. Participants with prior solid organ or bone marrow transplantation.

17. Currently receiving a high-dose steroid (>10 mg prednisone or equivalent per day) orother immune suppressant or has a condition requiring a chronic high-dose steroid orimmune suppressant.

18. Prior and concomitant therapy:

19. Any prior treatment with MMAE-derived drugs or IB6 targeting agents.

20. 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 progressionoccurred ≥9 months after the last dose.
• Other (neo)adjuvant or definitive therapy is allowed if recurrence orprogression occurred ≥6 months after the last dose.

3. Prior radiotherapy to the lung within 6 months of first dose of studyintervention, referencing the last date radiotherapy was received.

4. Chemotherapy, biologics, and/or other antitumor treatment with immunotherapynot specifically prohibited that is completed less than 4 weeks prior to firstdose of study intervention, or 2 weeks for palliative radiotherapy.

5. Any prior therapy with an immune-oncology agent directed to a stimulatory orco-inhibitory T-cell receptor

6. History of or current ongoing infection, including participants positive for activeHIV, HBV, or HCV.

7. Severe uncontrolled cardiac or cerebrovascular condition within the previous 6months