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.

Phase 3

Recruiting

• Conditions: Non-Small Cell Lung Cancer; Carcinoma, Non-Small-Cell Lung; Carcinoma, Non-Small-Cell Lung (NSCLC)
• Interventions: Drug: Sigvotatug Vedotin; Drug: Pembrolizumab

• Registration Number: NCT06758401
• Lead Sponsor: Pfizer

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-12-26
• Study First Submitted QC: 2024-12-26
• Study First Posted: 2025-01-03
• Status Verified: 2025-05
• Study Start: 2025-05-04
• Last Update Submitted: 2025-05-09
• Last Update Posted: 2025-05-14
• Primary Completion: 2028-09-05
• Study Completion: 2029-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 714

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sigvotatug Vedotin with Pembrolizumab	Sigvotatug Vedotin	Participants will receive Sigvotatug Vedotin, administered as an IV infusion and pembrolizumab, administered as an IV infusion.
Sigvotatug Vedotin with Pembrolizumab	Pembrolizumab	Participants will receive Sigvotatug Vedotin, administered as an IV infusion and pembrolizumab, administered as an IV infusion.
Pembrolizumab Monotherapy	Pembrolizumab	Participants will receive pembrolizumab, administered as an IV infusion.

Primary Outcome Measures

Name	Time	Method
Overall Survival	Baseline to date of death from any cause (Approximately 2 years)	Overall survival defined as the duration from enrollment to death.
Progression Free Survival (PFS) assessed by blinded independent central review (BICR)	From Baseline to to date of first documentation of progression OR death (Approximately 2 year)	Progression-free survival is defined as the time interval from the date of randomization to the date of first documented tumor progression determined by blinded independent central review (BICR) assessment as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or death due to any cause, whichever come first.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival as assessed by Investigator	From Baseline to date of first progression or death (Approximately 4 Years)	Progression Free Survival (PFS) is defined as the time from the date of first dose of study interventions to the date of first documentation of PD or death due to any cause, whichever occurs first.
Objective Response Rate as assessed by BICR	From Baseline to to the date of progression OR death (approximately to 4 years)	Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as best overall response assessed by BICR as per RECIST 1.1, from the date of randomization to the date of disease progression, death due to any cause, whichever occurs first.
Objective Response Rate as assessed by Investigator	From Baseline to to the date of progression OR death (approximately to 4 years)	defined as the proportion of participants who achieve a best response of complete response (CR) or partial response (PR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Investigator.
Duration of Response as assessed by BICR	From the date of the first objective response to the date of disease progression or death (approximately to 4 years)	Duration of response is defined as the time from first documented evidence of CR or PR until progressive disease (PD) as determined by BICR assessment as per RECIST 1.1 or death due to any cause, whichever occurs first.
Duration of Response as assessed by Investigator	From the date of the first objective response to the date of disease progression or death (approximately to 4 years)	defined time from the initial response (CR or PR) until documented tumor progression or death from any cause and based on Investigator assessment.
Number of participants with adverse events (AEs)	From Baseline to end of treatment (up to 4 years)	Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to \[study drug\] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
Pharmacokinetics (PK) of antibody-conjugated monomethyl auristatin E (ac-MMAE) in plasma: Plasma concentration at end of infusion (CEOI)	Cycle 1 (up to Day 29), Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15 and Cycle 11 Day 1	To characterize the pharmacokinetics (PK) of sigvotatug vedotin when administered in combination with pembrolizumab
PK of ac-MMAE in plasma: Plasma predose concentration (Cpredose)	Cycle 1 (up to Day 29), Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15 and Cycle 11 Day 1	To characterize the pharmacokinetics (PK) of sigvotatug vedotin when administered in combination with pembrolizumab
PK of unconjugated monomethyl auristatin E (MMAE) in plasma: Plasma concentration at end of infusion (CEOI)	Cycle 1 (up to Day 29), Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15 and Cycle 11 Day 1	To characterize the pharmacokinetics (PK) of sigvotatug vedotin when administered in combination with pembrolizumab
PK of MMAE in plasma: Plasma predose concentration (Cpredose)	Cycle 1 (up to Day 29), Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15 and Cycle 11 Day 1	To characterize the pharmacokinetics (PK) of sigvotatug vedotin when administered in combination with pembrolizumab
Number of participants with antidrug antibodies (ADAs)	Cycle 1 (up to Day 29), Cycle 3 Day 1, Cycle 5 Day 29, Cycle 8 Day 15 and Cycle 11 Day 1	To characterize the immunogenicity of sigvotatug vedotin when administered in combination with pembrolizumab

Trial Locations

Locations (6)

Mid Florida Hematology and Oncology Center; 🇺🇸 Orange City, Florida, United States

BRCR Global; 🇺🇸 Plantation, Florida, United States

Hope and Healing Cancer Services; 🇺🇸 New Lenox, Illinois, United States

Hematology Oncology Associates of Rockland; 🇺🇸 Nyack, New York, United States

Hope and Healing Cancer Services; 🇺🇸 New Lenox, Illinois, United States

Hematology Oncology Associates of Rockland; 🇺🇸 Nyack, New York, United States