A Phase 3 Randomized, Open-label Clinical Study to Evaluate the Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Coformulated With Hyaluronidase (MK-3475A) Versus Intravenous Pembrolizumab, Administered With Chemotherapy, in the First-line Treatment of Participants With Metastatic Non-small Cell Lung Cancer

The primary objective of this study is to compare the **pharmacokinetics** of subcutaneous pembrolizumab coformulated with hyaluronidase (MK-3475A SC) to intravenous pembrolizumab (IV) in terms of area under the curve (AUC) and steady-state trough concentration (Ctrough). This comparison is clinically relevant as it may provide insights into the efficacy and dosing regimen of pembrolizumab in the first-line treatment of metastatic non-small cell lung cancer, potentially offering a more convenient administration route for patients.

Secondary objectives include: - Evaluating pembrolizumab exposure for MK-3475A SC relative to pembrolizumab IV. - Assessing the development of circulating anti-pembrolizumab antibodies for both MK-3475A SC and pembrolizumab IV. - Comparing pembrolizumab Ctrough for MK-3475A SC relative to pembrolizumab IV. - Evaluating MK-3475A SC and pembrolizumab IV with respect to objective response rate (ORR) per RECIST 1.1 as assessed by blinded independent central review (BICR). - Assessing progression-free survival (PFS) per RECIST 1.1 as evaluated by BICR. - Evaluating overall survival (OS). - Assessing duration of response (DOR) per RECIST 1.1 as evaluated by BICR. - Evaluating the safety and tolerability of MK-3475A SC and pembrolizumab IV. - Assessing the change from baseline in global health status/quality of life (QoL) for both MK-3475A SC and pembrolizumab IV.

The clinical trial involves a total of **293 participants** diagnosed with **metastatic non-small cell lung cancer** (NSCLC), including both squamous and non-squamous types. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of NSCLC and a life expectancy of at least three months. The trial population includes individuals who are considered vulnerable. Participants are required to provide either an archival tumor tissue sample or a newly obtained biopsy from a tumor lesion that has not been previously irradiated. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures a diverse representation of the affected population, focusing on those who meet the inclusion criteria for this first-line treatment study.

The clinical trial is designed as a **randomized**, open-label study to evaluate the pharmacokinetics and safety of subcutaneous pembrolizumab coformulated with hyaluronidase (MK-3475A) compared to intravenous pembrolizumab, administered with chemotherapy, in the first-line treatment of participants with metastatic non-small cell lung cancer. The trial aims to compare the area under the curve (AUC) and steady-state trough concentration (Ctrough) of pembrolizumab between the two administration routes. The study is expected to run until May 22, 2028, with recruitment having commenced on February 13, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of non-small cell lung cancer and a life expectancy of at least three months. Following the screening, participants will be randomized to receive either the subcutaneous or intravenous formulation of pembrolizumab, alongside chemotherapy. Regular follow-up visits will be conducted to monitor pharmacokinetic parameters, safety, and efficacy outcomes, including primary endpoints like the AUC and Ctrough of pembrolizumab, and secondary endpoints such as maximum serum concentration (Cmax), objective response rate, progression-free survival, and overall survival.

The expected length of participant involvement in the trial is contingent upon the treatment regimen, with a maximum treatment period of 150 weeks for some participants. Conditions that may lead to early termination from the study include the occurrence of adverse events, disease progression, or withdrawal of consent. The trial will conclude with an end-of-study visit to assess final outcomes and gather data on any long-term effects of the treatment. Throughout the trial, the safety and well-being of participants will be closely monitored, with any adverse events being documented and addressed promptly.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Paclitaxel** is provided as a concentrate for solution for infusion, with a concentration of 6 mg/mL. It is administered intravenously with a maximum daily dose of 200 mg/m² and a total treatment period of up to 12 weeks. The pharmaceutical form is a solution for infusion, and the product is manufactured by EVER VALINJECT GMBH.

**Pembrolizumab**, marketed as KEYTRUDA, is used as a concentrate for solution for infusion with a concentration of 25 mg/mL. It is administered intravenously, with the dosing schedule determined by the study protocol. The product is manufactured by MERCK SHARP & DOHME BV and is used as a comparator in the study.

**Cisplatin** is provided as a concentrate for solution for infusion with a concentration of 1 mg/mL. It is administered intravenously with a maximum daily dose of 75 mg/m² over a treatment period of up to 12 weeks. The product is manufactured by TEVA GMBH.

**Filgrastim** is administered as an intravenous infusion. It is a biological product used to support the treatment regimen, with dosing and administration details specified in the study protocol. The product is not a pediatric formulation and is used as an auxiliary treatment.

**Carboplatin** is provided as a concentrate for solution for infusion with a concentration of 10 mg/mL. It is administered intravenously with a maximum daily dose of 6 mg/m² over a treatment period of up to 12 weeks. The product is manufactured by FRESENIUS KABI DEUTSCHLAND GMBH.

**Pemetrexed**, marketed as ALIMTA, is provided as a powder for concentrate for solution for infusion with a dose of 500 mg. It is administered intravenously with a maximum daily dose of 500 mg/m² over a treatment period of up to 150 weeks. The product is manufactured by ELI LILLY NEDERLAND B.V.

**Paclitaxel albumin-bound**, marketed as Pazenir, is provided as a powder for dispersion for infusion with a concentration of 5 mg/mL. It is administered intravenously with a maximum daily dose of 100 mg/m² over a treatment period of up to 12 weeks. The product is manufactured by RATIOPHARM GMBH.

**MK-3475A**, a formulation of pembrolizumab coformulated with hyaluronidase, is administered subcutaneously. It is used as the test product in the study, with dosing and administration details specified in the study protocol. The product is manufactured by MERCK & CO. INC.

**Glatiramer acetate** is administered as an intravenous infusion. It is a biological product used as an auxiliary treatment, with dosing and administration details specified in the study protocol. The product is not a pediatric formulation.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The study aims to evaluate the pharmacokinetics and safety of the treatments in participants with metastatic non-small cell lung cancer.

The efficacy of the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the **Area Under the Curve (AUC)** of Pembrolizumab measured after the first dose and the **Trough Concentration (Ctrough)** of Pembrolizumab measured at steady state. These pharmacokinetic parameters will provide insights into the drug's absorption and concentration levels over time.

Secondary endpoints will further evaluate the efficacy and safety profile of the treatment. These include the **Maximum Serum Concentration (Cmax)** of Pembrolizumab measured after the first dose and at steady state, the number of participants who test positive for anti-drug antibodies (ADAs) for Pembrolizumab, and various clinical outcomes such as Objective Response Rate (ORR), Progression-free Survival (PFS), Overall Survival (OS), and Duration of Response (DOR) as per the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1).

Additionally, patient-reported outcomes will be assessed through changes from baseline in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) scores, including Global Health Status/Quality of Life (GHS/QoL), Physical Functioning, and Role Functioning scores. The number of participants experiencing adverse events and those who discontinue treatment due to adverse events will also be recorded to evaluate the treatment's safety profile.