Phase 2 Evaluation of Fianlimab, Cemiplimab, and Chemotherapy Versus Cemiplimab and Chemotherapy in Resectable Stage II-IIIB (N2) Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the **pathological complete response (pCR)** by blinded independent pathological review (BIPR) of the combination of fianlimab plus cemiplimab plus chemotherapy versus cemiplimab plus chemotherapy in patients with resectable stage II to IIIB (N2) non-small cell lung cancer (NSCLC). This is clinically relevant as achieving a pCR is associated with improved long-term outcomes and survival rates in patients undergoing treatment for resectable NSCLC.

Secondary objectives include:

• Assessing the efficacy of the treatment combinations as measured by event-free survival (EFS), major pathological response (MPR), tumor response, and pathologic response by local pathology review.
• Evaluating the safety and tolerability of each treatment arm.
• Characterizing the pharmacokinetics (PK) of fianlimab and cemiplimab.
• Assessing the immunogenicity of fianlimab and cemiplimab.
• Evaluating the feasibility of surgery and the rate of peri-operative complications within 90 days post-surgery.
• Assessing the impact on patient-reported outcomes, including health-related quality of life (HRQoL), functioning, lung cancer symptoms, and general health status.

The clinical trial involves a total of **99 participants** diagnosed with **resectable non-small cell lung cancer** (NSCLC), specifically at stage II to IIIB (N2) as per the American Joint Committee on Cancer (AJCC) version 8. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their newly diagnosed, histologically confirmed, fully resectable NSCLC, with no evidence of distant metastases, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not include a vulnerable population. All participants are required to have adequate bone marrow, hepatic, and kidney function, and an evaluable Programmed cell death ligand-1 (PD-L1) immunohistochemistry (IHC) result. The selection process ensures that participants meet these criteria, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **fianlimab** and **cemiplimab** in combination with chemotherapy compared to **cemiplimab** with chemotherapy in patients with resectable early-stage non-small cell lung cancer (NSCLC). This is a Phase 2, randomized, double-blind, controlled trial. The trial aims to assess the pathological complete response (pCR) by blinded independent pathological review (BIPR) in patients with stage II to IIIB (N2) NSCLC. The trial is expected to commence recruitment on December 20, 2024, and conclude by May 22, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed resectable NSCLC, no evidence of distant metastases, and adequate organ function. Following randomization, participants will receive treatment over a maximum period of 54 weeks, with regular follow-up visits to monitor response and safety. The end-of-study visit will evaluate the primary and secondary endpoints, including event-free survival and the occurrence of adverse events.

The expected length of participant involvement is up to 54 weeks, with conditions for early termination including the occurrence of severe adverse events or disease progression. The trial will utilize intravenous infusion as the route of administration for all investigational products, including **cisplatin**, **carboplatin**, **paclitaxel**, and **pemetrexed**. The study will ensure rigorous monitoring of safety and efficacy through predefined criteria and assessments, maintaining the integrity and scientific validity of the trial outcomes.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Cisplatin** is utilized as a solution for infusion, with a maximum daily and total dose of 75 mg/m². It is administered via **intravenous infusion** over a treatment period of up to 12 weeks. This medication is a chemical substance used in chemotherapy protocols.

**Carboplatin** is also administered as a solution for infusion, with a maximum daily and total dose of 6 mg/mL. The route of administration is intravenous infusion, and the treatment period extends up to 12 weeks. Like cisplatin, carboplatin is a chemical substance used in chemotherapy.

**Paclitaxel** is provided as a solution for infusion, with a maximum daily and total dose of 200 mg/m². It is administered intravenously over a 12-week period. Paclitaxel is a chemical substance included in chemotherapy regimens.

**Pemetrexed** is administered as a solution for infusion, with a maximum daily and total dose of 500 mg/m². The administration route is intravenous infusion, and the treatment duration is up to 12 weeks. Pemetrexed is a chemical substance used in chemotherapy.

The trial also includes the administration of **Cemiplimab and Fianlimab** as a combination therapy. This biologic treatment is provided as a solution for infusion, with a treatment period of up to 54 weeks. The administration is via intravenous infusion. Cemiplimab and Fianlimab are proteins of other origin, and their combination is used to assess the pathological complete response in patients.

**LIBTAYO** (cemiplimab) is administered as a concentrate for solution for infusion, with a maximum daily and total dose of 350 mg. The administration route is intravenous infusion, and the treatment period extends up to 54 weeks. Cemiplimab is a protein of other origin, used in the trial as a biologic treatment.

A **placebo** is also utilized in the trial, serving as a comparator treatment. The placebo is not associated with any active substance and is used to evaluate the efficacy of the experimental treatments. The administration details for the placebo are not specified.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **pathological complete response (pCR)** by blinded independent pathological review (BIPR) in post-treatment resected tumor samples. This primary endpoint is crucial for determining the effectiveness of the treatment regimen involving fianlimab plus cemiplimab combined with chemotherapy versus cemiplimab with chemotherapy in patients with resectable stage II to IIIB (N2) non-small cell lung cancer (NSCLC).

Secondary endpoints will include a comprehensive range of measures to further assess efficacy and safety. These include Event-Free Survival (EFS), major pathological response (MPR) by both BIPR and local pathology review, and tumor response to neoadjuvant therapy as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria by investigator assessment. Additionally, the trial will monitor the occurrence of adverse events (AEs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and other specific adverse events categories. The trial will also evaluate the concentrations of cemiplimab and fianlimab in serum, as well as the presence of anti-drug antibodies (ADA) to these agents over time.

Patient-reported outcomes will be assessed using validated instruments such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Lung Cancer 13 (EORTC QLQ-LC13), along with the EuroQoL 5-Dimensional 5-Level Scale (EQ-5D-5L). These tools will measure changes in global health status, physical and role functioning, and specific symptoms like chest pain, dyspnea, and cough. The trial will also track the time until definitive deterioration in these patient-reported outcomes.