Phase 3 Randomized Study of Nivolumab and Ipilimumab with Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

The primary objective of this study is to compare **progression-free survival (PFS)** for Arm A versus Arm C in patients with previously untreated, locally advanced non-small cell lung cancer (LA NSCLC). This objective is clinically relevant as PFS is a critical endpoint in oncology trials, providing insights into the efficacy of treatment regimens in delaying disease progression.

Secondary objectives include:

• Comparing overall survival (OS) for Arm A versus Arm C.
• Evaluating PFS and OS for Arm B versus Arm C and Arm A versus Arm B.
• Assessing tumor response for Arm A versus Arm C, Arm B versus Arm C, and Arm A versus Arm B according to blinded independent central review (BICR) assessment.
• Evaluating PFS and tumor response for Arm A versus Arm C, Arm B versus Arm C, and Arm A versus Arm B according to investigator assessment of tumor imaging.
• Evaluating time to death or distant metastases (TTDM) for Arm A versus Arm C, Arm B versus Arm C, and Arm A versus Arm B according to investigator assessment of tumor imaging.
• Assessing safety and tolerability of study treatments.
• Evaluating symptom deterioration for Arm A versus Arm C, Arm B versus Arm C, and Arm A versus Arm B.

The clinical trial involves a total of **699 participants** diagnosed with **previously untreated locally advanced non-small cell lung cancer (LA NSCLC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a diagnosis of locally advanced stage IIIA, IIIB, or IIIC NSCLC, as per the 8th TNM classification. All participants are newly diagnosed and treatment-naïve, having received no prior local or systemic anticancer therapy for their condition. The trial also includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy of **nivolumab** in combination with concurrent chemoradiotherapy (CCRT) followed by either nivolumab plus **ipilimumab** or nivolumab alone, compared to CCRT followed by **durvalumab** in patients with previously untreated, locally advanced non-small cell lung cancer (LA NSCLC). The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), and duration of response (DoR) among others. The trial is expected to conclude by December 3, 2026, with recruitment having started on August 20, 2019.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and a diagnosis of stage IIIA, IIIB, or IIIC NSCLC. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of 61 weeks for those receiving nivolumab. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial involves intravenous administration of the investigational products, with dosing and administration schedules tailored to each treatment arm. The study is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Carbomedac® 10 mg/ml** is a **solution for infusion** containing the active substance **carboplatin**. It is administered via **intravenous use** with a maximum daily dose of 6 units and a total dose of 18 units over a treatment period of 9 cycles. The pharmaceutical form is a concentrate for solution for infusion, and it is of chemical origin.

**Durvalumab** is another experimental treatment used in the trial. It is a **concentrate for solution for infusion** with the active substance **durvalumab**, administered intravenously. The dosing regimen includes a maximum daily dose of 10 mg/kg and a total dose of 240 mg/kg over 12 cycles. This treatment is of biological/biotechnological origin.

**Carboplatin Bendalis 10mg/ml** is also utilized in the study. It is a **solution for infusion** with the active substance **carboplatin**, administered intravenously. The dosing schedule is similar to Carbomedac®, with a maximum daily dose of 6 units and a total dose of 18 units over 9 cycles. It is of chemical origin.

**Cisplatin-Ebewe, 1 mg/ml** is a **solution for infusion** containing **cisplatin**. It is administered intravenously with a maximum daily dose of 80 mg/m² and a total dose of 240 mg/m² over 9 cycles. This treatment is of chemical origin.

**ETO-cell® 20 mg/ml** is a **solution for infusion** with the active substance **etoposide**, administered intravenously. The dosing regimen includes a maximum daily dose of 100 mg/m² and a total dose of 900 mg/m² over 9 cycles. It is of chemical origin.

**Bendatax 6 mg/ml** is a **solution for infusion** containing **paclitaxel**, administered intravenously. The dosing schedule includes a maximum daily dose of 200 mg/m² and a total dose of 500 mg/m² over 9 cycles. It is of chemical origin.

**OPDIVO 10 mg/mL** is a **solution for infusion** with the active substance **nivolumab**, administered intravenously. The dosing regimen includes a maximum daily dose of 480 mg and a total dose of 7320 mg over 61 cycles. This treatment is of biological/biotechnological origin.

**Paclitaxel Aurobindo 6 mg/ml** is a **solution for infusion** containing **paclitaxel**, administered intravenously. The dosing schedule includes a maximum daily dose of 200 mg/m² and a total dose of 500 mg/m² over 9 cycles. It is of chemical origin.

**Cisplatin Teva® 1 mg/ml** is a **solution for infusion** with the active substance **cisplatin**, administered intravenously. The dosing regimen includes a maximum daily dose of 80 mg/m² and a total dose of 240 mg/m² over 9 cycles. It is of chemical origin.

**CARBO-cell® 10 mg/ml** is a **solution for infusion** containing **carboplatin**, administered intravenously. The dosing schedule is similar to Carbomedac®, with a maximum daily dose of 6 units and a total dose of 18 units over 9 cycles. It is of chemical origin.

**CISPLATIN** is a **concentrate for solution for infusion** with the active substance **cisplatin**, administered intravenously. The dosing regimen includes a maximum daily dose of 80 mg/m² and a total dose of 240 mg/m² over 9 cycles. It is of chemical origin.

**PACLITAXEL** is a **concentrate for solution for infusion** containing **paclitaxel**, administered intravenously. The dosing schedule includes a maximum daily dose of 200 mg/m² and a total dose of 500 mg/m² over 9 cycles. It is of chemical origin.

**CARBOPLATIN** is a **concentrate for solution for infusion** with the active substance **carboplatin**, administered intravenously. The dosing schedule is similar to Carbomedac®, with a maximum daily dose of 6 units and a total dose of 18 units over 9 cycles. It is of chemical origin.

**PEMETREXED DISODIUM** is a **powder for concentrate for solution for infusion** with the active substance **pemetrexed disodium**, administered intravenously. The dosing regimen includes a maximum daily dose of 500 mg/m² and a total dose of 1500 mg/m² over 9 cycles. It is of chemical origin.

**ETOPOSIDE** is a **concentrate for solution for infusion** with the active substance **etoposide**, administered intravenously. The dosing regimen includes a maximum daily dose of 100 mg/m² and a total dose of 900 mg/m² over 9 cycles. It is of chemical origin.

**ALIMTA 500 mg** is a **powder for concentrate for solution for infusion** containing **pemetrexed**, administered intravenously. The dosing schedule includes a maximum daily dose of 500 mg/m² and a total dose of 1500 mg/m² over 9 cycles. It is of chemical origin.

**Cisplatin NeoCorp 1 mg/ml** is a **solution for infusion** with the active substance **cisplatin**, administered intravenously. The dosing regimen includes a maximum daily dose of 80 mg/m² and a total dose of 240 mg/m² over 9 cycles. It is of chemical origin.

**Ipilimumab** is a **concentrate for solution for infusion** with the active substance **ipilimumab**, administered intravenously. The dosing regimen includes a maximum daily dose of 1 mg/kg and a total dose of 8.67 mg/kg over 12 cycles. This treatment is of biological/biotechnological origin.

**IMFINZI 50 mg/mL** is a **concentrate for solution for infusion** with the active substance **durvalumab**, administered intravenously. The dosing regimen includes a maximum daily dose of 10 mg/kg and a total dose of 240 mg/kg over 12 cycles. This treatment is of biological/biotechnological origin.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will be evaluated using the RECIST 1.1 criteria as assessed by a Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS) for different treatment arms, Objective Response Rate (ORR), Duration of Response (DoR), Time to Response (TTR), and Time to Death or Distant Metastases (TTDM), all assessed by RECIST 1.1 criteria either by BICR or investigator assessment. Additionally, the incidence of adverse events (AEs) and serious adverse events (SAEs) will be monitored, along with the proportion of participants without symptom deterioration based on the NSCLC-SAQ.

The efficacy parameters will be measured and collected at various timepoints throughout the trial. The assessments will be conducted using validated scales and criteria, such as RECIST 1.1, to ensure consistency and reliability in the evaluation of treatment outcomes. The schedule for these assessments will align with the trial's protocol, ensuring that data collection is systematic and comprehensive.