Evaluation of Pembrolizumab, Chemotherapy, and Radiotherapy in Advanced Non-Small Cell Lung Cancer: A Randomized Controlled Trial

The primary objective of the study is to compare **Overall Survival (OS)** rates between two treatment regimens in patients with advanced non-small cell lung cancer (NSCLC). The comparison is between anti-PD-1 and chemotherapy versus anti-PD-1 and chemotherapy combined with radiotherapy, with a specific focus on the 1-year survival rate. This objective is clinically relevant as it aims to determine the most effective treatment strategy for improving survival outcomes in this patient population.

Secondary objectives include:

• Comparing toxicities between the two treatment arms according to CTCAE v5.
• Evaluating tumor response using RECIST 1.1 and iRECIST criteria.
• Assessing **Overall Survival (OS)** with a report of the 2-year rate.
• Comparing **Progression-Free Survival (PFS)** with a report of the 1-year rate.
• Evaluating **Cancer-Specific Survival (CSS)** with a report of the 1-year rate.
• Assessing local and distant control in irradiated patients, with reports at 6 months and 1 year for irradiated and non-irradiated sites, respectively.
• Comparing quality of life according to QLQ-C30.
• Evaluating the best tumor response between arms, including local and distant control, using RECIST 1.1 and iRECIST on irradiated and non-irradiated sites.
• Comparing the best tumor response between arms.
• Assessing iPFS between arms.

The clinical trial involves a total of **6 participants** diagnosed with **advanced non-small cell lung cancer (NSCLC)**, specifically at stages IIIB, IIIC, or IV. The study population includes both male and female subjects, aged 18 years and older, who are eligible for treatment with a PD-1 antagonist, such as pembrolizumab, in accordance with the European Marketing Authorization. Participants were selected based on their ability to comply with the study protocol, including treatment, scheduled visits, and examinations. The trial population is characterized by a good general health status, as indicated by an ECOG performance status of 0 to 1 and a life expectancy of more than 3 months. Additionally, participants must have adequate organ function and measurable lesions as assessed by RECIST version 1.1. The study also considers lifestyle factors, requiring participants to agree to use adequate contraception during the study and for 6 months after completing treatment. The trial includes a vulnerable population, ensuring that all participants are affiliated with a social security system or equivalent. The selection criteria ensure that participants are suitable for the study's objective of comparing overall survival rates between different treatment combinations involving anti-PD-1 therapy, chemotherapy, and radiotherapy.

The clinical trial is designed to evaluate the **overall survival** (OS) rate in patients with advanced non-small cell lung cancer (NSCLC) treated with a combination of anti-PD-1 therapy and chemotherapy, with or without concurrent radiotherapy. This is a randomized, double-blind, controlled trial, aiming to compare the efficacy of these treatment regimens. The trial is expected to run until September 2026, with recruitment having commenced in March 2019. Participants will be involved in the study for a maximum treatment period of 21 days per cycle, with the possibility of multiple cycles depending on individual response and tolerance.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as histologically confirmed advanced NSCLC, ECOG performance status of 0-1, and adequate organ function. Following randomization, participants will undergo regular follow-up visits to assess treatment response, monitor for **acute or late toxicity**, and evaluate overall health status. These visits will include clinical assessments, laboratory tests, and imaging studies as per the protocol. The end-of-study visit will occur after the final treatment cycle or upon early termination, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participants are expected to remain in the study for the duration of their treatment cycles, with follow-up assessments continuing until the end of the study period. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. The trial's primary endpoint is the OS rate at one year, while secondary endpoints include progression-free survival, cancer-specific survival, and quality of life assessments. The trial will utilize **intravenous** administration of the investigational products, including paclitaxel albumin-bound, pemetrexed, pembrolizumab, cisplatin, carboplatin, and paclitaxel, each with specified dosing regimens and maximum daily doses.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Paclitaxel albumin-bound** is provided as a dispersion for infusion. The maximum daily dose is 100 mg/m², with a total dose not exceeding 300 mg/m² over a 21-day treatment period. The administration route is intravenous, and the formulation is not pediatric.

**Pemetrexed** is administered as a concentrate for solution for infusion. The maximum daily and total dose is 500 mg/m², administered intravenously over a 21-day treatment cycle. This formulation is also not intended for pediatric use.

**Pembrolizumab** is supplied as a powder and solvent for solution for injection. The maximum daily and total dose is 200 mg, administered intravenously within a 21-day treatment period. This formulation is not pediatric.

**Cisplatin** is provided as a solution for infusion. The maximum daily and total dose is 75 mg/m², administered intravenously over a 21-day treatment cycle. This formulation is not intended for pediatric use.

**Carboplatin** is administered as a solution for infusion. The maximum daily and total dose is 400 mg/m², with intravenous administration over a 21-day treatment period. This formulation is not pediatric.

**Paclitaxel** is provided as a concentrate for solution for infusion. The maximum daily and total dose is 200 mg/m², administered intravenously over a 21-day treatment cycle. This formulation is not intended for pediatric use.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Each medication is classified as a chemical substance, except for pembrolizumab, which is a protein-based substance. The trial aims to evaluate the efficacy of these treatments in advanced non-small cell lung cancer.

The efficacy of the clinical trial titled "NIRVANA-Lung: PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumour sites in advanced Non-small cell lung cAncer" will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from randomization to the date of documented death from any cause or last follow-up, with the OS rate reported at 1 year. Secondary endpoints include acute and late toxicity graded by CTCAE v5, tumor response rates according to RECIST 1.1 and iRECIST, and progression-free survival (PFS) or iPFS, which will be reported at 1 year. Cancer-specific survival (CSS) and local and distant control rates in irradiated patients will also be evaluated, with control rates reported at 6 months and 1 year. Quality of life will be assessed using self-administered EORTC QLQ-C30 questionnaires.