A Randomized, Double-Blind Phase 2/3 Study of Fianlimab (Anti-LAG-3 antibody) in Combination with Cemiplimab (Anti-PD-1 antibody) versus Cemiplimab Monotherapy in First-Line Treatment of Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with Tumors Expressing PD-L1 ≥50%
- Trial ID
- 2022-501483-18-00
- Protocol
- R3767-ONC-2235
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **objective response rate (ORR)** of the combination of cemiplimab and fianlimab compared to 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 assessment is conducted through a blinded independent central review committee (BICR) in Phase 2. In Phase 3, the primary objective shifts to comparing the overall survival (OS) between the combination therapy and monotherapy. These objectives are clinically relevant as they aim to determine the efficacy of the combination therapy in improving response rates and survival outcomes in a specific patient population, potentially offering a more effective treatment option for advanced NSCLC.
Secondary objectives include:
- Assessing the safety and tolerability of the combination therapy compared to monotherapy in both Phase 2 and Phase 3.
- Evaluating other anti-tumor activities such as disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), and progression-free survival (PFS) by BICR and investigator assessment.
- Assessing patient-reported outcomes using the EORTC-QLQ-C30, LC13, and EQ-5D-5L questionnaires, and evaluating patient-reported fatigue using the PRO CTCAE criteria.
- Characterizing the pharmacokinetics (PK) and immunogenicity of fianlimab and cemiplimab.
Participants
The clinical trial involves a total of **150 participants** diagnosed with **Advanced Non-Small Cell Lung Cancer**. 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 includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ and bone marrow function is required. The trial population is characterized by the inclusion of a vulnerable population, and both genders are represented. Participants' lifestyle factors such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of a combination therapy involving **Fianlimab** and **Cemiplimab** compared to Cemiplimab monotherapy in patients with **Advanced Non-Small Cell Lung Cancer** (NSCLC) expressing PD-L1 ≥50%. The trial is structured in two phases: Phase 2 focuses on assessing the objective response rate (ORR) as evaluated by a blinded independent central review committee, while Phase 3 aims to compare overall survival (OS) between the combination therapy and monotherapy groups. The trial is expected to commence recruitment on June 7, 2024, and conclude by February 5, 2032, with a maximum treatment period of 108 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological confirmation of NSCLC, PD-L1 expression levels, and adequate organ function. Following successful screening, participants will be randomized to receive either the combination therapy or monotherapy. Study visits will include regular follow-up assessments to monitor treatment efficacy and safety, including imaging studies to evaluate tumor response per RECIST 1.1 criteria and laboratory tests to assess organ function and detect any treatment-emergent adverse events (TEAEs).
The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent by the participant. Throughout the trial, secondary endpoints such as the incidence of serious adverse events (SAEs), disease control rate (DCR), and patient-reported outcomes will be evaluated to provide a comprehensive assessment of the treatment's impact on patient health and quality of life.
Treatment
The clinical trial involves the administration of **Fianlimab**, a solution for injection, as the experimental medication. Fianlimab is a monoclonal antibody targeting LAG-3, with the active substance name being Fianlimab. It is of biological/biotechnological origin and is produced by Regeneron Pharmaceuticals, Inc. The pharmaceutical form is a solution for injection, and it is administered via intravenous use. The maximum daily dose is 1600 mg, with a total maximum dose of 57600 mg over a treatment period of 108 weeks. Participant compliance will be monitored through regular assessments and adherence checks.
**Cemiplimab**, marketed as LIBTAYO, serves as the comparator treatment in this study. It is a concentrate for solution for infusion, with the active substance being Cemiplimab, also of biological/biotechnological origin. Manufactured by Regeneron Ireland D.A.C., it is administered intravenously. The maximum daily dose is 350 mg, with a total maximum dose of 12600 mg over a treatment period of 108 weeks. The administration schedule and participant adherence will be closely monitored to ensure protocol compliance.
The study also includes a **placebo** for Fianlimab, which is a saline/dextrose formulation sourced locally by investigational sites. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased results. It is administered intravenously, mirroring the administration route of Fianlimab. The placebo is crucial for evaluating the efficacy and safety of the experimental treatment in comparison to standard care.
Efficacy
Efficacy in this clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** as assessed by a blinded independent central review (BICR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for Phase 2, and **Overall Survival (OS)** for Phase 3. Secondary endpoints encompass a range of measures, including the incidence of treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), and adverse events of special interest (AESIs) across both phases. Additionally, the trial will evaluate the disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), and progression-free survival (PFS) by both BICR and investigator assessment. Patient-reported outcomes will also be measured, such as changes from baseline in global health status, physical functioning, and specific symptoms like chest pain, dyspnea, and cough, using validated instruments like the EORTC QLQ-C30 and QLQ-LC13. The trial will further assess the concentrations of cemiplimab and fianlimab in serum, as well as immunogenicity through anti-drug antibodies (ADA) and neutralizing antibodies (NAb) to both drugs. These efficacy parameters will be collected and analyzed at various timepoints throughout the study, ensuring a comprehensive evaluation of the treatment's impact on patients with advanced non-small cell lung cancer (NSCLC) expressing PD-L1 ≥50%.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with non-squamous or squamous histology NSCLC with stage IIIB or stage IIIC disease who are not candidates for surgical resection or definitive chemoradiation per investigator assessment or stage IV (metastatic disease), who received no prior systemic treatment for recurrent or metastatic NSCLC.
- Availability of an archival or on-study formalin-fixed, paraffin-embedded tumor tissue sample, without intervening therapy between biopsy collection and screening as described in the protocol
- For enrollment in phase 2, patients should have PD-L1 levels ≥ 50%, as determined by a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA) (or equivalently licensed, according to local regulations) accredited laboratory, as described in the protocol. For enrollment in phase 3, patients should have expression of programmed cell death ligand-1 (PD-L1) in ≥50% of tumor cells stained using an assay performed by a central laboratory, as described in the protocol.
- At least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria. Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
- Adequate organ and bone marrow function
- Additional protocol defined inclusion criteria apply
Exclusion Criteria
- Patients who have never smoked, defined as smoking ≤100 cigarettes in a lifetime
- Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. Patients must be off (immunosuppressive doses of) corticosteroid therapy
- Patients with tumors tested positive for actionable epidermal growth factor receptor (EGFR) gene mutations, anaplastic lymphoma kinase (ALK) gene translocations, or c-ros oncogene 1 (ROS1) fusions, as described in the protocol.
- Encephalitis, meningitis, or uncontrolled seizures in the year prior to enrollment
- History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6 months prior to enrollment.
- Known primary immunodeficiencies, either cellular (eg, DiGeorge syndrome, T-cell-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (eg, T- and B-cell negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency)
- Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk of immune-mediated treatment-emergent adverse events (imTEAEs). Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are excluded. The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment
- Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 14 days of randomization. Physiologic replacement doses are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Patients with clinically relevant systemic immune suppression within the last 3 months before trial enrollment are excluded. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder
- Patients who have received prior systemic therapies are excluded with the exception of the following: a. Adjuvant or neoadjuvant platinum-based doublet chemotherapy (after surgery and/or radiation therapy) if recurrent or metastatic disease develops more than 6 months after completing therapy as long as toxicities have resolved to CTCAE grade ≤1 or baseline with the exception of alopecia and peripheral neuropathy. b. Anti-PD-L1 with or without LAG-3 as an adjuvant or neoadjuvant therapy as long as the last dose is >12 months prior to enrollment. c. Prior exposure to other immunomodulatory or vaccine therapies such as anti-CTLA-4 antibodies as long as the last dose is >3 months prior to enrollment. Immune-mediated AEs must be resolved to CTCAE grade ≤1 or baseline by the time of enrollment. Endocrine immunemediated AEs controlled with hormonal or other nonimmunosuppressive therapies without resolution prior to enrollment are allowed
- Additional protocol defined exclusion criteria apply
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 07 Jun 2024 | 8 |
 Greece | Not Recruiting | 07 Jun 2024 | 30 |
 Romania | Not Recruiting | 07 Jun 2024 | 30 |
 Spain | Not Recruiting | 07 Jun 2024 | 34 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fianlimab | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 00 | 9999 | PRD10082279 |
LIBTAYO 350 mg concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 9999 | PRD7478447 |
Placebo for Fianlimab | Placebo | N/A | — | — | — | N/A |