Overview

The purpose of the study is to compare how the new combination treatment (Sigvotatug Vedotin plus pembrolizumab) works compared to pembrolizumab alone in patients with non-small cell lung cancer (NSCLC) with high levels of PD-L1. This is a protein that acts as a kind of "brake" to keep the body's immune responses under control.

The study is seeking for participants who:

• Are confirmed to have NSCLC (Stage 3 or 4).
• Have PD-L1 levels in more than 50% of the cancer cells.

All participants in this study will receive pembrolizumab at the study clinic once every 6 weeks as an intravenous (IV) infusion (give directly into a vein). In addition, half of the participants will also receive Sigvotatug Vedotin once every 2 weeks as an IV infusion in addition to receiving pembrolizumab.

Participants may receive pembrolizumab for up to about two years. Those participants taking Sigvotatug Vedotin can continue until their NSCLC is no longer responding. The study team will monitorsee how each participant is doing with the study treatment during regular visits at the clinic.

Eligibility

Inclusion 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.

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