Evaluation of Pembrolizumab Monotherapy Versus Pembrolizumab Combined with Chemotherapy in First-Line Treatment of Advanced Stage Non-Small Cell Lung Cancer

The primary objective of this study is to assess the effect of chemotherapy administered concurrently with **pembrolizumab** on the overall response rate (ORR) in patients with advanced stage non-small cell lung cancer (NSCLC) who exhibit high PD-L1 expression and high tumor burden. This evaluation is clinically relevant as it aims to determine whether the combination therapy can enhance the therapeutic response compared to standard treatment approaches, potentially leading to improved patient outcomes in this specific patient population.

Secondary objectives include:

• Examining the effect of concurrent chemotherapy and pembrolizumab on progression-free survival (PFS) and overall survival (OS) in patients with high PD-L1 and high tumor burden, compared to pembrolizumab monotherapy followed by chemotherapy at progression.
• Comparing the PFS of concurrent chemo-pembrolizumab with sequential pembrolizumab followed by chemotherapy at progression, specifically evaluating PFS-1 plus PFS-2.

The clinical trial involves participants diagnosed with **advanced stage non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of NSCLC, with negative results for EGFR mutations and ALK fusions, although molecular testing is not mandatory for those with squamous NSCLC. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Scale score between 0 and 2, indicating a range from fully active to capable of all self-care but unable to carry out any work activities. They must also have measurable disease based on RECIST v1.1 criteria and provide tissue from a non-irradiated histological tumor biopsy. High tumor PD-L1 expression (≥50% TPS) and a high tumor burden, characterized by metastases (M1) not suitable for local consolidative therapies, are required. Adequate hematologic and organ function is necessary for inclusion. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in combination with chemotherapy compared to pembrolizumab alone in patients with advanced stage non-small cell lung cancer (NSCLC). This is a randomized, double-blind, controlled trial with an estimated duration from January 2020 to December 2025. The primary objective is to assess the overall response rate (ORR) in NSCLC patients with high PD-L1 expression and high tumor burden. The trial will also evaluate secondary endpoints such as progression-free survival (PFS), overall survival (OS), and safety as defined by the Common Terminology Criteria for Adverse Events (CTCAE).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed NSCLC, ECOG Performance Scale 0-2, and high tumor PD-L1 expression. Following successful screening, participants will be randomized into one of the study arms. The trial includes regular follow-up visits to monitor treatment response and adverse events, with assessments conducted at specified intervals, including a primary endpoint evaluation at week 6. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant meets criteria for early termination, such as disease progression or unacceptable toxicity.

The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or any medical condition that, in the opinion of the investigator, warrants discontinuation. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the treatment of advanced stage NSCLC.

The clinical trial involves the administration of several **experimental medications**. **Pemetrexed Baxter** is provided as a 500 mg powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 500 mg/m². The treatment period for this medication is up to 3 cycles, with each cycle lasting 21 days. The active substance, **pemetrexed**, is of chemical origin and is manufactured by Baxter Holding B.V.

**Carboplatin Medac** is supplied as a 10 mg/mL solution to be diluted for infusion. This medication is also administered intravenously, with a maximum daily dose of 75 mg/m². The treatment period extends up to 12 cycles, with each cycle lasting 21 days. The active substance, **carboplatin**, is chemically derived and produced by Medac Gesellschaft für klinische Spezialpräparate mbH (Wedel).

**Keytruda** is available as a 25 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 200 mg. The treatment period for Keytruda is up to 24 cycles, with each cycle lasting 21 days. The active substance, **pembrolizumab**, is a protein of other origin, manufactured by Merck Sharp & Dohme B.V.

**Paclitaxel Kabi** is provided as a 6 mg/mL concentrate for solution for infusion. This medication is administered intravenously with a maximum daily dose of 200 mg/m². The treatment period is up to 3 cycles, with each cycle lasting 21 days. The active substance, **paclitaxel**, is of chemical origin and is produced by Fresenius Kabi Hungary Kft.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to assess the effect of chemotherapy given concurrently with pembrolizumab on the overall response rate in patients with non-small cell lung cancer (NSCLC) exhibiting high PD-L1 expression and high tumor burden. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial.

The efficacy of the clinical trial titled "Pembrolizumab Alone versUs pembrolizumab-chemotherapy in first LInE NSCLC (PAULIEN)" will be assessed using several primary and secondary endpoints. The primary endpoints include the **Overall Response Rate (ORR)**, defined by partial response (PR) and complete response (CR) at week 6, and the Disease Control Rate (DCR), defined by stable disease (SD), PR, and CR at week 6. These endpoints will be measured to evaluate the effect of chemotherapy given concurrently with pembrolizumab on patients with non-small cell lung cancer (NSCLC) who have high PD-L1 expression and high tumor burden.

Secondary endpoints include Progression-Free Survival (PFS), determined using the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and defined as the time to the development of new lesions, progression of existing lesions, or death, whichever occurs first. Additional secondary endpoints are PFS-2, defined by the PFS on second-line chemotherapy in arm 1, ORR-2, defined by the ORR on second-line chemotherapy in arm 1, and Overall Survival (OS), measured from baseline until death. Safety will also be assessed, defined as the percentage of patients experiencing adverse events, categorized according to the Common Terminology Criteria for Adverse Events (CTCAE).