Phase 2 Evaluation of Cemiplimab and BNT116 Combination Versus Cemiplimab Monotherapy in Advanced NSCLC with PD-L1 Expression ≥50%

The primary objective of this Phase 2 study is to assess the **objective response rate (ORR)** per blinded independent review committee (BIRC) of the combination of **cemiplimab** and **BNT116** versus cemiplimab monotherapy in the first-line treatment of patients with advanced **non-small cell lung cancer (NSCLC)** whose tumors express **PD-L1** in ≥50% of tumor cells. This evaluation is clinically relevant as it aims to determine the efficacy of the combination therapy compared to monotherapy, potentially offering improved treatment options for patients with this specific cancer profile.

Secondary objectives include:

• Assessing other anti-tumor activities of the combination of cemiplimab and BNT116 and cemiplimab monotherapy, as measured by ORR per investigator assessment, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
• Further examining the safety and tolerability of the combination of cemiplimab and BNT116 and cemiplimab monotherapy.

The clinical trial involves a total of **65 participants** diagnosed with **Advanced Non-Small Cell Lung Cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including those with non-squamous or squamous histology NSCLC at stage IIIB, IIIC, or IV, who are not candidates for surgical resection or definitive chemoradiation, and have not received prior systemic treatment for recurrent or metastatic NSCLC. The trial population is characterized by the expression of Programmed cell death ligand-1 (PD-L1) in ≥50% of tumor cells, and participants must have at least one radiographically measurable lesion. The general health status of participants is assessed with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **cemiplimab** in combination with BNT116 compared to cemiplimab monotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells. This is a Phase 2, randomized, double-blind, controlled study. The trial aims to assess the objective response rate (ORR) as the primary endpoint, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), and the incidence of treatment-emergent adverse events (TEAEs).

The trial is expected to commence recruitment on November 14, 2023, and conclude by June 7, 2027. Participants will be involved in the study for a maximum treatment period of 108 weeks. The study will include an initial screening visit to confirm eligibility based on criteria such as histology type, disease stage, and PD-L1 expression. Participants must have at least one measurable lesion and an ECOG performance status of ≤1. Following the screening, eligible participants will be randomized to receive either the combination therapy or monotherapy.

Study visits will be scheduled at regular intervals to monitor the participants' response to treatment and assess any adverse events. These visits will include imaging assessments using CT or MRI to evaluate tumor response according to RECIST 1.1 criteria. Follow-up visits will continue until disease progression, unacceptable toxicity, or withdrawal of consent. An end-of-study visit will be conducted to gather final data on the participants' health status and treatment outcomes.

Participants may be withdrawn from the study early if they experience significant adverse events, disease progression, or if they choose to withdraw consent. The trial will adhere to strict ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **BNT116**, a **concentrate for dispersion for injection**. BNT116 is composed of multiple active substances, including **enomimeran** and several nucleic acid-based components: RBL005.3, RBL007.2, RBL012.2, RBL027.2, and RBL035.2. The pharmaceutical form of BNT116 is designed for intravenous administration. The maximum daily dose is 90 micrograms, with a total treatment period extending up to 108 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to BNT116, the trial also includes the administration of **LIBTAYO**, a **concentrate for solution for infusion**. LIBTAYO contains the active substance **cemiplimab**, a protein-based therapeutic agent. The pharmaceutical form is intended for intravenous use, with a maximum daily dose of 350 milligrams. The treatment period for LIBTAYO is also set at 108 days. The trial aims to evaluate the efficacy of cemiplimab both as a monotherapy and in combination with BNT116 in patients with advanced non-small cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells.

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as evaluated by a blinded independent review committee (BIRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This primary endpoint will measure the proportion of patients with advanced non-small cell lung cancer (NSCLC) whose tumors express PD-L1 ≥50% and who achieve a complete or partial response to the treatment regimen. Secondary endpoints include ORR by investigator assessment, Duration of Response (DOR) as assessed by both BIRC and investigator, Progression-Free Survival (PFS) as assessed by both BIRC and investigator, Overall Survival (OS), and the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, and laboratory abnormalities.

The trial will involve the administration of cemiplimab, an anti-PD-1 antibody, in combination with BNT116, a FIXVAC lung cancer vaccine, versus cemiplimab monotherapy. The efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, with assessments conducted using validated imaging techniques such as computerized tomography (CT) or magnetic resonance imaging (MRI) to identify radiographically measurable lesions. The trial is designed to provide a comprehensive evaluation of the treatment's impact on disease progression and patient outcomes, with the estimated end date set for June 7, 2027.