A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects with Advanced Solid Tumors (KEYNOTE-158)

The primary objective of this clinical trial is to evaluate the **Objective Response Rate (ORR)** to pembrolizumab, based on RECIST 1.1 criteria as assessed by independent central radiologic review, in subjects with advanced (metastatic and/or unresectable) solid tumors. This evaluation is conducted across various groups: biomarker unselected subjects (Groups A-J), biomarker selected subjects (Groups A-K), subjects from mainland China with dMMR/MSI-H tumors (Group L), and subjects with TMB-H tumors excluding dMMR/MSI-H tumors (Group M). The primary biomarkers under investigation include tumor expression of PD-L1, tumor Gene Expression Profile (GEP), and tumor Microsatellite Instability-High (MSI-H) status. The clinical relevance of this objective lies in determining the efficacy of pembrolizumab across different tumor types and biomarker profiles, which could inform personalized treatment strategies.

Secondary objectives include:

• Evaluating the **Duration of Response (DOR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)** in subjects receiving pembrolizumab, and their relationship with tumor PD-L1 expression, GEP score, and MSI-H status across various groups (Groups A-J, A-K, L, and M).
• Determining the safety and tolerability of pembrolizumab in different subject groups (Groups A-K, L, and M).
• Specifically for Group M, evaluating DOR, PFS, and OS in subjects with advanced solid tumors that have failed at least one line of therapy and are TMB-H, excluding dMMR/MSI-H tumors.

The clinical trial involves a total of **1029 participants** who are diagnosed with various types of advanced solid tumors, including but not limited to **Anal Squamous Cell Carcinoma**, Biliary Adenocarcinoma, Neuroendocrine Tumors, Endometrial Carcinoma, Cervical Squamous Cell Carcinoma, Vulvar Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Mesothelioma, Thyroid Carcinoma, and Salivary Gland Carcinoma. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on the presence of histologically or cytologically documented advanced solid tumors, progression of the tumor, or intolerance to therapies known to provide clinical benefit. The trial includes individuals with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale, a life expectancy of at least three months, and adequate organ function. The trial population is diverse, including vulnerable populations, and requires participants to have radiologically measurable disease. Female participants of childbearing potential are required to use adequate contraception during the study period. The selection criteria ensure that participants have failed at least one line of standard care systemic therapy, with specific requirements for those with colorectal carcinoma. The trial does not include participants with melanoma or non-small cell lung cancer (NSCLC).

The clinical trial is designed to evaluate the **objective response rate (ORR)** to **pembrolizumab** in subjects with advanced solid tumors. This trial is a Phase II, randomized, double-blind, controlled study, focusing on both biomarker unselected and selected subjects. The trial aims to assess the efficacy of pembrolizumab based on RECIST 1.1 criteria, as evaluated by an independent central radiologic review. The study will include subjects with various types of advanced solid tumors, including but not limited to anal squamous cell carcinoma, biliary adenocarcinoma, neuroendocrine tumors, endometrial carcinoma, cervical squamous cell carcinoma, and small cell lung carcinoma. The trial is expected to run from December 23, 2015, to July 18, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histologically or cytologically documented advanced solid tumors and other criteria such as measurable disease and adequate organ function. Following the screening, participants will receive pembrolizumab via **intravenous infusion**. Regular follow-up visits will be scheduled to monitor the participants' response to the treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will conclude the trial for each participant, where final assessments will be conducted to evaluate the overall treatment outcomes.

The expected length of participant involvement in the trial is up to 24 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The primary endpoint of the study is the ORR, while secondary endpoints include duration of response, progression-free survival, overall survival, and the percentage of participants experiencing adverse events or discontinuing the study due to adverse events.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name **KEYTRUDA**. This experimental medication is provided as a **25 mg/mL concentrate for solution for infusion**. The pharmaceutical form is a **solution for infusion**, and it is administered via **intravenous infusion**. The maximum daily dose is set at **400 mg**, with a total maximum dose of **7200 mg** over the course of the treatment. The treatment period is capped at **24 months**. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code **L01FF02**. The medication is produced by **Merck Sharp & Dohme BV** and is not formulated for pediatric use.

In this clinical trial, pembrolizumab is the sole investigational product, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study focuses on evaluating the objective response rate (ORR) to pembrolizumab in subjects with advanced solid tumors, with assessments based on RECIST 1.1 criteria by independent central radiologic review. The trial includes biomarker-selected and unselected subjects, with specific attention to tumor expression of PD-L1, tumor gene expression profile (GEP), and tumor microsatellite instability-high (MSI-H) status. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed primarily through the **Objective Response Rate (ORR)** to pembrolizumab, evaluated based on RECIST 1.1 criteria as determined by an independent central radiologic review. This assessment will be conducted in both biomarker unselected and selected subjects with advanced solid tumors. The primary biomarkers under evaluation include tumor expression of PD-L1 by immunohistochemistry (IHC), tumor gene expression profile (GEP) by RNA analysis, and tumor microsatellite instability-high (MSI-H) status.

Secondary efficacy endpoints include the **Duration of Response (DOR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**. Additionally, the trial will monitor the percentage of participants experiencing adverse events and those who discontinue the study intervention due to adverse events. These parameters will be measured and analyzed at various timepoints throughout the trial to provide a comprehensive evaluation of pembrolizumab's efficacy in the target population.