A Phase 3 Randomized Open-Label Study Comparing Sigvotatug Vedotin and Docetaxel in Adults with Previously Treated Non-Small Cell Lung Cancer

The primary objective of this study is to compare the **overall survival** (OS) between the experimental arm, which involves the administration of sigvotatug vedotin, and the control arm, which uses docetaxel, in patients with previously treated **non-small cell lung cancer** (NSCLC). This comparison is clinically relevant as it aims to determine the efficacy of sigvotatug vedotin in extending the lifespan of patients compared to the standard treatment with docetaxel. Additionally, the study seeks to compare the **objective response rate** (ORR) as assessed by blinded independent central review (BICR) between the two arms, providing insights into the treatment's effectiveness in reducing tumor size or extent.

Secondary objectives include:

• Comparing progression-free survival (PFS) as assessed by BICR and by investigator between the experimental and control arms.
• Comparing the ORR as assessed by investigator between the experimental and control arms.
• Estimating the duration of response (DOR) for both arms.
• Characterizing the safety and tolerability profile of sigvotatug vedotin.
• Comparing changes in quality of life (QoL), functioning, and lung cancer symptom response between the arms.
• Comparing time to deterioration (TTD) in QoL, functioning, and lung cancer symptoms between the arms.

The clinical trial involves a total of **325 participants** diagnosed with **Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, including a histologically or cytologically confirmed diagnosis of locally advanced, unresectable, or metastatic NSCLC, with nonsquamous histology. The trial excludes individuals with tumors of squamous or small cell elements. Participants must have received prior therapies, including platinum-based chemotherapy and PD-(L)1 monoclonal antibodies, and have measurable disease based on RECIST v1.1 criteria. The trial does not include vulnerable populations, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is a **randomized**, phase 3, open-label study designed to evaluate the efficacy of **sigvotatug vedotin** compared to **docetaxel** in adult participants with previously treated **non-small cell lung cancer (NSCLC)**. The primary objectives are to compare the overall survival (OS) and the objective response rate (ORR) between the experimental arm (sigvotatug vedotin) and the control arm (docetaxel), as assessed by blinded independent central review (BICR). The trial is expected to commence recruitment on February 9, 2024, and conclude by November 1, 2028.

Participants will be involved in the study for a maximum treatment period of 60 days, with the trial duration extending over several years to accommodate follow-up assessments. The study visits will include an initial screening visit to confirm eligibility based on histologically or cytologically confirmed diagnosis of locally advanced, unresectable, or metastatic NSCLC, among other criteria. Participants must have received prior therapies and shown disease progression or relapse. The inclusion visit will be followed by regular follow-up visits to monitor treatment response and adverse events, with assessments based on RECIST v1.1 criteria. The end-of-study visit will evaluate the primary and secondary endpoints, including progression-free survival (PFS), duration of response (DOR), and quality of life measures.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will employ intravenous infusion as the route of administration for both investigational products, with sigvotatug vedotin administered as a **powder for injection** and docetaxel as a concentrate for solution for infusion. The study will not include pediatric formulations, and the trial is not classified as a low-intervention study. The trial's secondary endpoints will assess various aspects of treatment efficacy and safety, including adverse events and quality of life changes, using validated questionnaires such as the EORTC QLQ-C30 and QLQ-LC13.

The clinical trial involves the administration of **sigvotatug vedotin**, an experimental medication, which is a **powder for injection**. This investigational drug is an **antibody-drug conjugate** composed of a humanized IgG1 monoclonal antibody against integrin beta-6, conjugated to monomethyl auristatin E via a valine-citrulline linker. The pharmaceutical form is specifically designed for **intravenous infusion**. The dosing regimen for sigvotatug vedotin is set at a maximum daily dose of 1.8 mg/kg, with a total maximum dose of 181.9 mg over a treatment period of 60 days. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.

The comparator treatment in this study is **docetaxel**, a well-established chemotherapeutic agent classified under **taxanes**. Docetaxel is provided as a **concentrate for solution for infusion** and is also administered via **intravenous infusion**. The dosing for docetaxel is determined based on body surface area, with a maximum daily dose of 75 mg/m² and a total maximum dose of 375 mg over the same 60-day treatment period. As with the experimental treatment, compliance with the dosing schedule is rigorously monitored to maintain the integrity of the trial data.

Efficacy in this clinical trial will be assessed by comparing the **overall survival (OS)** and **objective response rate (ORR)** between the experimental arm, which involves the administration of sigvotatug vedotin, and the control arm, which involves the administration of docetaxel. The ORR will be evaluated using the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), as assessed by a blinded independent central review (BICR). The primary endpoints include OS and confirmed ORR using RECIST v1.1 as assessed by BICR.

Secondary endpoints will include progression-free survival (PFS) and duration of response (DOR), both assessed using RECIST v1.1 by BICR and investigators. Additionally, the trial will evaluate the type, incidence, severity, seriousness, and relatedness of adverse events (AEs). Patient-reported outcomes will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Lung Cancer 13 (EORTC QLQ-LC13), focusing on global health status, quality of life, physical functioning, role functioning, and symptoms such as dyspnea, cough, and chest pain. The mean scores and changes from baseline, as well as time to deterioration (TTD) in these scores, will be analyzed.