Phase 3 Study of Sigvotatug Vedotin and Pembrolizumab Versus Pembrolizumab Monotherapy in PD-L1 High Non-Small Cell Lung Cancer

The primary objective of this study is to demonstrate that **sigvotatug vedotin** in combination with **pembrolizumab** is superior to pembrolizumab monotherapy in prolonging overall survival (OS) and progression-free survival (PFS) in patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. This is clinically relevant as it may offer a more effective first-line treatment option for this patient population, potentially improving survival outcomes.

Secondary objectives include:

• Comparing the objective response rate (ORR) by blinded independent central review (BICR) between the experimental and control arms.
• Evaluating additional measures of efficacy for both treatment arms.
• Characterizing the safety and tolerability profile of both treatment arms.
• Characterizing the pharmacokinetics (PK) of sigvotatug vedotin when administered in combination with pembrolizumab.
• Characterizing the immunogenicity of sigvotatug vedotin when administered in combination with pembrolizumab.

The clinical trial involves a total of **484 participants** diagnosed with **non-small cell lung cancer**. The study population includes both male and female subjects, aged **18 years or older**, who have been selected based on specific health criteria. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. They must also have adequate baseline hematologic, hepatic, and renal function. The trial excludes individuals with small cell elements or large cell neuroendocrine carcinoma. Participants must not have actionable genomic alterations for which approved front-line therapies exist, and they must be suitable candidates for pembrolizumab monotherapy. The study does not involve a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to assess the efficacy of sigvotatug vedotin in combination with pembrolizumab compared to pembrolizumab alone in prolonging overall survival and progression-free survival.

The clinical trial is designed as an **open-label**, **randomized**, **controlled** Phase 3 study to evaluate the efficacy of **sigvotatug vedotin** in combination with **pembrolizumab** compared to pembrolizumab monotherapy in participants with **non-small cell lung cancer** (NSCLC) exhibiting high levels of PD-L1 expression. The primary objective is to demonstrate the superiority of the combination therapy in prolonging overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review (BICR). The trial is expected to commence recruitment on August 25, 2025, and conclude by February 17, 2029.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. The inclusion criteria require participants to have pathologically confirmed Stage IIIB, IIIC, or IV NSCLC, with PD-L1 expression in ≥50% of tumor cells. Exclusion criteria are not specified in the provided data. Following the screening, eligible participants will be randomized to receive either the combination therapy or pembrolizumab alone. The treatment period for sigvotatug vedotin is up to 60 weeks, while pembrolizumab is administered for a maximum of 27 weeks.

Study visits will include regular assessments to monitor the safety and efficacy of the treatment, with endpoints such as confirmed objective response rate (ORR), duration of response (DOR), and incidence of adverse events (AEs) being evaluated. Participants will also have their plasma concentrations measured for pharmacokinetic analysis. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent. The expected length of participant involvement is contingent on individual response and tolerance to the treatment, with the possibility of early termination based on the aforementioned conditions.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose of pembrolizumab is 400 mg, with a total maximum dose of 7200 mg over a treatment period of up to 27 weeks. Pembrolizumab is a biologic product, specifically a protein of other origin, and is manufactured by Merck Sharp & Dohme B.V. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to pembrolizumab, the trial also includes the experimental medication **sigvotatug vedotin**, which is provided as a powder for concentrate for solution for infusion. This medication is also administered via **intravenous infusion**. The dosing for sigvotatug vedotin is calculated based on body weight, with a maximum daily dose of 1.8 mg/kg and a total maximum dose of 1.8 mg/kg over a treatment period of up to 60 weeks. Sigvotatug vedotin is a biologic product, classified as a protein of other origin, and is produced by Pfizer Inc. The trial aims to evaluate the efficacy of sigvotatug vedotin in combination with pembrolizumab compared to pembrolizumab monotherapy in participants with PD-L1 high, locally advanced, unresectable, or metastatic non-small cell lung cancer.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include overall survival (OS) and progression-free survival (PFS) as evaluated by blinded independent central review (BICR) using the **Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)**. Secondary endpoints encompass confirmed objective response rate (ORR) and duration of response (DOR), both assessed by BICR and investigators using RECIST v1.1. Additionally, the trial will evaluate the type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as plasma concentrations of antibody-conjugated monomethyl auristatin E (ac-MMAE) and unconjugated monomethyl auristatin E (MMAE) at the end of infusion and predose. The incidence of antidrug antibodies (ADAs) will also be measured.