A Biomarker-Directed, Multi-Centre Phase II/III Study of ctDNA Response Adaptive Immuno-Chemotherapy in Lung Cancer - BR.36

This biomarker-directed Phase II/III study evaluates circulating tumor DNA (ctDNA) response-adaptive immunochemotherapy in patients with metastatic non-small cell lung cancer (NSCLC). The primary objective in Phase II is to assess progression-free survival (PFS), while the Phase III primary objective is to evaluate overall survival (OS). These endpoints are clinically relevant for determining whether ctDNA-guided treatment adaptation can improve survival outcomes in this patient population.

The secondary objectives include:

• Phase II: Feasibility assessment including screening success rate (greater than 30% of screened patients demonstrating persistent ctDNA following 6 weeks of pembrolizumab), accrual targets (achieving 50% enrollment by month 18 post-randomization), and randomization acceptance rate (≥80% of consenting patients). Additional Phase II secondary objectives comprise evaluation of best overall RECIST response rate post-randomization and assessment of safety and tolerability.

• Phase III: Evaluation of best overall RECIST response rate post-randomization, response duration, progression-free survival, and safety/tolerability assessed using CTCAE version 5. These endpoints provide comprehensive assessment of treatment efficacy and adverse event profiles in the context of biomarker-directed therapy selection.

This clinical trial enrolled a total of **194 participants** diagnosed with **metastatic non-small cell lung cancer (NSCLC)**. The study population included both **male and female** subjects aged **18 years and older**, comprising **adults** and **elderly** patients. Participants were required to have histologically or cytologically confirmed metastatic NSCLC with **EGFR** and **ALK mutation negative** disease. A key selection criterion was the presence of **PD-L1 expression** with a Tumour Proportion Score (TPS) of at least 50%, confirmed by a certified laboratory. Eligible participants had received limited prior treatment, specifically at least one but not more than two cycles of **pembrolizumab** as first-line systemic immunotherapy for advanced metastatic disease. Patients were required to be clinically stable without evidence of clinical progression or symptomatic deterioration, with an **ECOG performance status** of 0 to 2. Prior chemotherapy or immunotherapy for non-metastatic disease was permitted if at least six months had elapsed before starting pembrolizumab for metastatic disease. The presence of detectable **circulating tumor DNA (ctDNA)** at screening was mandatory for enrollment and randomization. Patients with Large Cell Neuroendocrine Carcinoma were excluded from participation. The trial population represented a vulnerable group requiring specialized clinical consideration.

This is an international, multi-centre, open-label, biomarker-directed, phase II/III clinical trial evaluating circulating tumor DNA (**ctDNA**) response adaptive immuno-chemotherapy in patients with **metastatic non-small cell lung cancer** (NSCLC) who have programmed death-ligand 1 (**PD-L1**) tumor proportion score expression of at least 50%. The trial is designed to assess whether adding **chemotherapy** to **pembrolizumab** for patients with persistent ctDNA detected at 6 weeks of treatment results in improved **progression-free survival** (PFS) and **overall survival** (OS) compared to patients who continue pembrolizumab monotherapy until clinical progression. The study employs a **randomized** design and is conducted in two stages, with the second stage specifically testing the clinical benefit of tailoring treatment based on molecular response. The trial is categorized as phase II/III, with the primary objective being PFS in the phase II component and OS in the phase III component. Secondary endpoints include feasibility of the biomarker-directed approach.

Eligible participants must have histologically or cytologically confirmed metastatic NSCLC with **EGFR** and **ALK** mutation-negative disease and PD-L1 TPS of at least 50%. Patients must have received at least one but not more than two cycles of pembrolizumab 200 mg or 2 mg/kg intravenously every 3 weeks, or at least one but not more than one cycle of 400 mg or 4 mg/kg intravenously every 6 weeks as first-line systemic immunotherapy for advanced metastatic disease at the time of screening. Prior chemotherapy or immunotherapy for non-metastatic disease is permitted if at least 6 months have elapsed between completion of prior therapy and initiation of pembrolizumab for metastatic disease. Patients must have an **ECOG** performance status of 0 to 2, be at least 18 years of age, and have clinically and/or radiologically documented evaluable disease. Detectable ctDNA on screening is required for subsequent enrollment and randomization. Patients must be clinically stable without evidence of clinical progression or symptomatic deterioration that requires change in cancer treatment.

The investigational medicinal products include **paclitaxel albumin-bound** (Abraxane) administered as a powder for dispersion for infusion, **cisplatin**, **carboplatin**, paclitaxel, and **pemetrexed disodium**, all administered as solution for infusion. Pembrolizumab is utilized as both a test product and comparator depending on the treatment arm. Maximum daily doses are 100 mg/m² for paclitaxel albumin-bound, 75 mg/m² for cisplatin, 200 mg for pembrolizumab, 400 mg/m² for carboplatin, 200 mg/m² for paclitaxel, and 500 mg/m² for pemetrexed disodium. The maximum treatment period for chemotherapy agents is 12 weeks, while pembrolizumab may be administered for up to 24 months. Maximum total doses over the treatment period are 1200 mg/m² for paclitaxel albumin-bound, 300 mg/m² for cisplatin, 6800 mg for pembrolizumab, 1600 mg/m² for carboplatin, 800 mg/m² for paclitaxel, and 2000 mg/m² for pemetrexed disodium.

The trial protocol includes a screening visit during which ctDNA testing is performed to determine eligibility for randomization. Imaging investigations including **computed tomography** (CT) of the chest, abdomen, and pelvis, as well as magnetic resonance imaging (MRI) or CT of the brain if brain metastases are known, must be completed within 14 days prior to randomization to ensure patients do not have clinical progression requiring change in systemic treatment. Follow-up visits are scheduled according to the protocol to monitor treatment response, assess toxicity, and perform additional ctDNA measurements. The end-of-study visit occurs upon completion of the treatment phase or upon early termination from the study. Conditions that may lead to early termination include disease progression as defined by **RECIST** criteria, unacceptable toxicity, patient withdrawal of consent, or clinical deterioration requiring change in cancer treatment. The estimated recruitment start date is January 2026, with an estimated trial completion date of January 2031. Total participant involvement varies depending on treatment assignment and response but may extend up to 24 months for those receiving pembrolizumab maintenance therapy.

**Abraxane** (paclitaxel albumin-bound) is administered as a powder for dispersion for infusion, reconstituted to a 5 mg/ml dispersion for infusion and delivered via intravenous route as a solution for infusion. The maximum daily dose is 100 mg/m² with a maximum total dose of 1200 mg/m² over a treatment period of up to 12 months. This medicinal product contains paclitaxel in an albumin-bound formulation and is manufactured by Bristol-Myers Squibb Pharma EEIG.

**Cisplatin** is administered as a solution for infusion via the intravenous route. The maximum daily dose is 75 mg/m² with a maximum total dose of 300 mg/m² over a treatment period of up to 12 months. Cisplatin is a platinum-based chemotherapeutic agent used as an experimental treatment in this trial.

**Paclitaxel** is administered as a solution for infusion via the intravenous route. The maximum daily dose is 200 mg/m² with a maximum total dose of 800 mg/m² over a treatment period of up to 12 months. This formulation represents the conventional paclitaxel preparation and serves as an experimental treatment in the study.

**Pemetrexed disodium** is administered as a solution for infusion via the intravenous route. The maximum daily dose is 500 mg/m² with a maximum total dose of 2000 mg/m² over a treatment period of up to 12 months. Pemetrexed is an antifolate chemotherapeutic agent used as an experimental treatment.

**Carboplatin** is administered as a solution for infusion via the intravenous route. The maximum daily dose is 400 mg/m² with a maximum total dose of 1600 mg/m² over a treatment period of up to 12 months. Carboplatin is a platinum-based chemotherapeutic agent utilized as an experimental treatment in this clinical trial.

**Pembrolizumab** is administered as a solution for infusion via the intravenous route and serves as a comparator treatment in this study. The maximum daily dose is 200 mg with a maximum total dose of 6800 mg over a treatment period of up to 24 months. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody classified as a protein-based therapeutic agent.

Efficacy will be assessed using progression-free survival (PFS) as the primary endpoint in Phase II and overall survival (OS) as the primary endpoint in Phase III. PFS and OS serve as key parameters to evaluate the clinical benefit of tailoring treatment based on molecular response in patients with advanced non-small cell lung cancer with PD-L1 Tumour Proportion Score (TPS) ≥ 50% and persistent circulating tumor DNA (ctDNA) detected at 6 weeks of treatment. Feasibility will be evaluated as a secondary endpoint. Imaging investigations including CT of the chest, abdomen, and pelvis, as well as MRI or CT of the brain for patients with known brain metastases or other scans as necessary to document all sites of disease, must be performed within 14 days prior to randomization to ensure patients do not have clinical progression requiring a change in systemic treatment. Patients must have RECIST non-progressive disease or clinically stable progressive disease documented prior to enrollment. Detectable ctDNA on screening is required for subsequent enrollment and randomization. Patients should be clinically stable without evidence of clinical progression or symptomatic deterioration that requires a change in cancer treatment at the time of assessment.