A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone and in Combination with Pembrolizumab in Subjects with Locally Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2

The primary objective of this study is to evaluate the **efficacy** of disitamab vedotin, both as a monotherapy and in combination with pembrolizumab, in subjects with locally advanced unresectable or metastatic urothelial carcinoma (LA/mUC) that expresses HER2. The efficacy will be measured by the confirmed objective response rate (cORR) assessed by blinded independent central review (BICR). This is clinically relevant as it aims to determine the potential of disitamab vedotin, alone or with pembrolizumab, to provide therapeutic benefits in a population with limited treatment options.

Secondary objectives include:

• Evaluating efficacy as measured by cORR assessed by investigators, duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and overall survival (OS) for disitamab vedotin monotherapy and in combination with pembrolizumab in treatment-naive and previously treated subjects with LA/mUC expressing HER2.
• Assessing the safety and tolerability of disitamab vedotin monotherapy and its combination with pembrolizumab.
• Investigating the pharmacokinetic (PK) characteristics of disitamab vedotin, free MMAE, and total antibody (TAb) when administered alone and in combination with pembrolizumab, as well as the PK characteristics of pembrolizumab in combination with disitamab vedotin.
• Evaluating the immunogenicity of disitamab vedotin and pembrolizumab when administered alone and in combination.

The clinical trial involves a total of **162 participants** diagnosed with **urothelial carcinoma**, specifically targeting those with locally advanced or metastatic forms of the disease. The study population includes both male and female subjects, with an age range corresponding to adults and older adults. Participants were selected based on their **HER2-expression status**, as determined by a central laboratory, and must have histologically confirmed, locally advanced, unresectable, or metastatic urothelial cancer. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2, depending on the cohort. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the efficacy of disitamab vedotin, both as a monotherapy and in combination with pembrolizumab, in subjects with HER2-positive and HER2-low expressions. Key inclusion criteria include an expected survival of at least 12 weeks and the ability to provide archived tumor tissue or a baseline biopsy prior to treatment initiation.

The clinical trial is a **Phase 2**, multi-cohort, open-label, multi-center study designed to evaluate the efficacy and safety of **Disitamab Vedotin** alone and in combination with **Pembrolizumab** in subjects with locally advanced unresectable or metastatic **urothelial carcinoma** that expresses HER2. The trial employs a non-randomized design, focusing on the confirmed overall response rate (cORR) as assessed by blinded independent central review (BICR) according to RECIST version 1.1 criteria. The study is expected to conclude by May 30, 2024, with recruitment having commenced on December 1, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as expected survival of at least 12 weeks, ECOG performance status, and HER2-expression status. Following the screening, eligible participants will receive treatment with Disitamab Vedotin, either as monotherapy or in combination with Pembrolizumab, administered via intravenous infusion. The trial includes follow-up visits to monitor treatment efficacy and safety, with assessments of primary and secondary endpoints such as progression-free survival (PFS), disease control rate (DCR), and overall survival (OS).

The expected length of participant involvement varies, with the maximum treatment period for Disitamab Vedotin being extensive, while Pembrolizumab is limited to a maximum of 24 weeks. Participants may be subject to early termination from the study due to conditions such as disease progression, unacceptable toxicity, or withdrawal of consent. The end-of-study visit will involve final assessments to evaluate the long-term effects and outcomes of the treatment regimen. Throughout the trial, data on adverse events, laboratory abnormalities, and pharmacokinetic parameters will be collected to ensure comprehensive safety monitoring.

The clinical trial involves the administration of **Disitamab Vedotin**, a **powder for solution for infusion**. This investigational medication is provided by Seattle Genetics Inc. and is identified by the sponsor product code SGN-DV. The active substance, **disitamab vedotin**, is a protein-based compound. The medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 2 mg/kg, with a total maximum dose not exceeding 200 mg. The treatment period is extensive, with a maximum duration set at 9999999 days, allowing for long-term administration as required by the study protocol.

In addition to Disitamab Vedotin, the trial also includes the administration of **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, which contains the active substance **pembrolizumab**. This medication is provided by Merck Sharp & Dohme BV and is administered as a **solution for infusion**. Pembrolizumab is also a protein-based compound and is administered via **intravenous infusion**. The dosing schedule for pembrolizumab allows for a maximum daily dose of 400 mg, with the total dose also capped at 400 mg. The treatment period for pembrolizumab is limited to 24 days, aligning with the study's objectives and design.

The efficacy of the clinical trial will be assessed primarily through the **cORR** (confirmed Objective Response Rate) as evaluated by BICR (Blinded Independent Central Review) using RECIST version 1.1 criteria. This primary endpoint will measure the confirmed complete response (CR) and confirmed partial response (PR) in subjects with locally advanced unresectable or metastatic urothelial carcinoma expressing HER2. Secondary endpoints include cORR as assessed by the investigator, confirmed Duration of Response (DOR), Progression-Free Survival (PFS), Disease Control Rate (DCR), and Overall Survival (OS). These will also be evaluated using RECIST v1.1 criteria by both BICR and the investigator.

Additional secondary endpoints will assess the type, incidence, relatedness, severity, and seriousness of adverse events (AEs), as well as treatment discontinuations, dose reductions, or delays due to AEs. Laboratory abnormalities, ECG changes including QTc interval, and effects on Left Ventricular Ejection Fraction (LVEF) will also be monitored. Pharmacokinetic (PK) parameters of disitamab vedotin, free MMAE, TAb, and pembrolizumab will be analyzed, along with the incidence of anti-drug antibodies (ADA) against disitamab vedotin and pembrolizumab. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment's efficacy and safety.