Phase III Randomized Study of Immunotherapy and Local Ablative Treatments in Oligometastatic NSCLC: Evaluating Carboplatin, Ipilimumab, and Drug Combination

The primary objective of this study is to demonstrate the **survival benefit** of adding a radical local treatment (RLT) to a maximum of five secondary lesions in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) who are receiving standard of care (SoC)-based immunotherapy. This is clinically relevant as it aims to improve overall survival rates in this patient population, potentially offering a more effective treatment strategy for managing oligometastatic NSCLC.

Secondary objectives include:

• Comparing progression-free survival (PFS), immune progression-free survival (iPFS), cancer-specific survival, and patterns of relapse between the two arms.
• Comparing the frequency and severity of adverse events between the two arms.
• Comparing patient-reported outcomes (PROs) and quality of life (QoL).
• Assessing the clearance of circulating tumor DNA.
• Evaluating the cost-utility (cost per QALY) of RLT combined with immunotherapy-based SoC compared to immunotherapy-based SoC alone.
• Exploring the effect of RLT modality (minimally invasive surgery vs. stereotactic body radiation therapy (SBRT) vs. interventional radiology) on overall survival and local control.

The clinical trial involves participants diagnosed with **synchronous oligometastatic non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who are eligible for first-line immunotherapy-based standard of care according to the European Marketing Authorization. Participants must have a maximum of five metastases in three organs, with each metastasis measuring no more than 5 cm, as determined by CT scan, brain MRI, and FDG-PET. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have acceptable organ function for radical local treatment (RLT) and must be affiliated with the social security system. The trial population was selected based on specific inclusion criteria, including histologically proven advanced synchronous oligometastatic stage IV NSCLC and the availability of PDL1 status. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the survival benefit of adding radical local treatment (RLT) to standard of care (SoC) immunotherapy in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC). This is a **randomized**, multicentre, open-label phase III study. The trial is expected to commence on March 6, 2025, and conclude by November 1, 2026. Participants will be involved in the study for a maximum treatment period of 17 months, depending on the specific treatment regimen assigned.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven advanced NSCLC, acceptable organ function, and ECOG performance status of 0-1. Following the screening, participants will undergo randomization to receive either the SoC immunotherapy alone or in combination with RLT. The study will involve regular follow-up visits to monitor treatment efficacy and safety, assess overall survival, and evaluate secondary endpoints such as progression-free survival and quality of life. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, fail to comply with the study protocol, or withdraw consent. The primary endpoint of the trial is overall survival, with secondary endpoints including progression-free survival, cancer-specific survival, and quality of life assessments. The trial will also evaluate the clearance rate of circulating tumor DNA and conduct an economic evaluation based on quality-adjusted life years. The investigational medicinal products used in the trial, such as **carboplatin**, **ipilimumab**, and **pembrolizumab**, are administered via intravenous infusion and are authorized for use in accordance with their marketing authorizations.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Carboplatin**, marketed as CARBOPLATINE KABI 10 mg/ml, is provided as a solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 6 mg and a total dose of 300 mg over a treatment period of 4 weeks. The active substance is of chemical origin.

**Ipilimumab**, under the brand name YERVOY 5 mg/ml, is a concentrate for solution for infusion. It is delivered through intravenous infusion at a maximum daily dose of 1 mg/kg, with a total dose of 60 mg/kg over a 17-week period. The active substance is a protein of other origin.

**Paclitaxel**, available as PACLITAXEL SANDOZ 6 mg/ml, is a solution for infusion administered intravenously. The maximum daily dose is 200 mg/m², with a total dose of 800 mg/m² over 4 weeks. The active substance is of chemical origin.

**Cemiplimab**, marketed as LIBTAYO 350 mg, is a concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 350 mg and a total dose of 21,000 mg over 17 weeks. The active substance is a protein of other origin.

**Atezolizumab**, under the brand name Tecentriq 840 mg, is a concentrate for solution for infusion. It is delivered intravenously with a maximum daily dose of 1,200 mg and a total dose of 72,000 mg over 17 weeks. The active substance is a protein of other origin.

**Pembrolizumab**, marketed as KEYTRUDA 25 mg/mL, is a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 400 mg and a total dose of 24,000 mg over 17 weeks. The active substance is a protein of other origin.

**Pemetrexed**, available as Pemetrexed Accord 25 mg/ml, is a concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 500 mg/m² and a total dose of 2,000 mg/m² over 4 weeks. The active substance is of chemical origin.

**Cisplatin**, marketed as Cisplatine Accord 1 mg/ml, is a concentrate for solution for infusion. It is delivered intravenously with a maximum daily dose of 6 mg and a total dose of 2,760 mg over 4 weeks. The active substance is of chemical origin.

**Nivolumab**, under the brand name OPDIVO 10 mg/mL, is a concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 360 mg and a total dose of 21,600 mg over 17 weeks. The active substance is a protein of other origin.

All medications are administered as part of the study protocol, with compliance monitored through standard clinical trial procedures. No non-experimental treatments, such as placebos or comparator treatments, are specified in the trial data provided.

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is overall survival (OS), which will be measured to determine the survival benefit of adding a radical local treatment (RLT) to the standard of care (SoC) in patients with non-small cell lung cancer (NSCLC). Secondary endpoints include progression-free survival (PFS) or immune-related PFS (iPFS) according to RECIST 1.1 and iRECIST criteria, cancer-specific survival, and the type of relapses, as well as local and distant control rates in both treatment arms.

Additional secondary endpoints involve the evaluation of acute and late adverse events graded by CTCAE v5, including toxic death and serious adverse events. Quality of life (QoL) will be assessed using the EORTC QLQ-C30, QLQ-LC-13, and EQ-5D-5L instruments. The clearance rate of circulating tumor DNA in plasma will be measured at 6 weeks and 4 months (before maintenance therapy) compared to baseline values in both arms. An economic evaluation will also be conducted, focusing on the incremental cost per Quality-adjusted life year (QALY) based on EQ-5D-5L measures and the incremental net monetary benefit.