A Study to Learn if a Combination of Fianlimab and Cemiplimab Versus Cemiplimab Alone is More Effective for Adult Participants With Advanced Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This study is researching an experimental drug called fianlimab (also called REGN3767), combined with a medication called cemiplimab (also called REGN2810), individually called a study drug or collectively called study drugs . The study is focused on patients who have advanced non-small cell lung cancer (NSCLC). The aim of the study is to see how effective the combination of fianlimab and cemiplimab is in treating advanced NSCLC, in comparison with cemiplimab by itself. The study is looking at several other research questions, including: What side effects may happen from taking the study drugs How much study drug is in your blood at different times Whether the body makes antibodies against the study drugs (which could make the drug less effective or could lead to side effects) How administering the study drugs might improve your quality of life

Official Title
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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%

Conditions
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Advanced Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: fianlimab
* Drug: cemiplimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key 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 non-small cell lung cancer (NSCLC). Availability of an archival or on-study formalin-fixed, paraffin-embedded (FFPE) 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, as described in the protocol. Key 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: 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. Anti-PD-(L) 1 with or without LAG-3 as an adjuvant or neoadjuvant therapy as long as the last dose is >12 months prior to enrollment. Prior exposure to other immunomodulatory or vaccine therapies as an adjuvant or neoadjuvant therapy, Cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibodies as long as the last dose is >6 months prior to enrollment. Immune-mediated AEs must be resolved to CTCAE grade ≤1 or baseline by the time of enrollment. Endocrine immune-mediated AEs controlled with hormonal or other non-immunosuppressive therapies without resolution prior to enrollment are allowed. Note: Other protocol-defined Inclusion/ Exclusion Criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: fianlimab+cemiplimab<br>Phase 2: fianlimab (HD) Phase 3: fianlimab (chosen dose) | Drug: fianlimab<br>* Every three weeks (Q3W) as intravenous (IV) co-infusion<br>* Other names: REGN3767;Drug: cemiplimab<br>* Q3W as IV co-infusion<br>* Other names: Libtayo;|
| Experimental: B: fianlimab+cemiplimab<br>Phase 2: fianlimab (LD) Phase 3: fianlimab (chosen dose) | Drug: fianlimab<br>* Every three weeks (Q3W) as intravenous (IV) co-infusion<br>* Other names: REGN3767;Drug: cemiplimab<br>* Q3W as IV co-infusion<br>* Other names: Libtayo;|
| Experimental: C: cemiplimab monotherapy+placebo<br>Phase 2 and Phase 3 | Drug: cemiplimab<br>* Q3W as IV co-infusion<br>* Other names: Libtayo;Drug: Placebo<br>* Q3W as IV co-infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) as assessed by blinded independent central review (BICR), using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) | Phase 2 and Phase 3 Proportion of patients with a best overall response of confirmed complete response (CR) or partial response (PR) | Up to 136 weeks | 
| Overall survival (OS) | Phase 3 The time from randomization to the date of death due to any cause | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) | Phase 2 and Phase 3 A TEAE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment | Up to 136 weeks | 
| Incidence of treatment-related TEAEs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Incidence of serious adverse events (SAEs) | Phase 2 and Phase 3 Any untoward medical occurrence that at any dose: Results in death - includes all deaths, even those that appear to be completely unrelated to study drug (eg, a car accident in which a patient is a passenger) Is life-threatening Requires in-patient hospitalization or prolongation of existing hospitalization • Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is an important medical event | Up to 136 weeks | 
| Incidence of adverse events of special interest (AESIs) | Phase 2 and Phase 3 Serious or non-serious; is one of scientific and medical concern specific to the sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it. | Up to 136 weeks | 
| Incidence of immune-mediated adverse events (imAEs) | Phase 2 and Phase 3 Immune-mediated AEs are thought to be caused by unrestrained cellular immune responses directed at normal host tissues. An imAE can occur shortly after the first dose or several months after the last dose of treatment. Early detection and management reduces the risk of severe drug induced toxicity | Up to 136 weeks | 
| Occurrence of interruption of study drug(s) due to TEAEs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Occurrence of discontinuation of study drug(s) due to TEAEs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Occurrence of interruption of study drug(s) due to AESIs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Occurrence of discontinuation of study drug(s) due to AESIs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Occurrence of interruption of study drug(s) due to imAEs | Phase 2 and Phase 3 | Up to 136 weeks | 
| Occurrence of discontinuation of study drug(s) due to imAEs | Phase 2 and Phase 3 A unique set of toxicities thought to be caused by unrestrained cellular immune responses | Up to 136 weeks | 
| Incidence of deaths due to TEAE | Phase 2 and Phase 3 | Up to 136 weeks | 
| Incidence of grade 3 to 4 laboratory abnormalities | Phase 2 and Phase 3 ≥ grade 3 per National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v5.0] | Up to 136 weeks | 
| ORR by investigator assessment, using RECIST 1.1 | Phase 2 | Up to 136 weeks | 
| Disease control rate (DCR) by BICR | Phase 2 and Phase 3 The proportion of patients with best overall response of complete response (CR), partial response (PR), or stable disease (SD) | Up to 136 weeks | 
| DCR by investigator assessment | Phase 2 and Phase 3 | Up to 136 weeks | 
| Time to tumor response (TTR) by BICR | Phase 2 and Phase 3 The time from randomization to the date of the first response of CR or PR (whichever is first recorded) for patients with confirmed CR or PR. | Up to 136 weeks | 
| TTR by investigator assessment | Phase 2 and Phase 3 | Up to 136 weeks | 
| Duration of response (DOR) by BICR | Phase 2 and Phase 3 The time from first response of CR or PR to first radiographic progression or death due to any cause for patients with confirmed CR or PR. | Up to 5 years | 
| DOR by investigator assessment | Phase 2 and Phase 3 | Up to 5 years | 
| Progression free survival (PFS) by BICR | Phase 2 and Phase 3 | Up to 5 years | 
| PFS by investigator assessment | Phase 2 and Phase 3 | Up to 5 years | 
| Overall survival (OS) | Phase 2 The time from randomization to the date of death due to any cause | Up to 5 years | 
| Change from baseline in patient-reported global health status/quality of life (GHS/QoL) per European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) | Phase 2 and Phase 3 EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a GHS/QoL scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Up to 5 years | 
| Change from baseline in patient-reported physical functioning per EORTC QLQ-C30 | Phase 2 and Phase 3 | Up to 5 years | 
| Change from baseline in patient-reported chest pain per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer (EORTC QLQ-LC13) | Phase 2 and Phase 3 EORTC QLQ-LC 13 is a lung cancer specific module developed to assess lung cancer-associated symptoms and treatment-related side effects among lung cancer patients | Up to 5 years | 
| Change from baseline in patient-reported dyspnea per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Change from baseline in patient-reported cough per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported physical functioning per EORTC QLQ-C30 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported chest pain per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported dyspnea per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported cough per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Time until definitive deterioration in patient-reported composite of chest pain, dyspnea and cough per EORTC QLQ-LC13 | Phase 2 and Phase 3 | Up to 5 years | 
| Change from baseline in patient-reported general health status per EuroQoL-5 Dimensions, 5-level Questionnaire-Visual Analogue Score (EQ-5D-5L VAS) | Phase 2 and Phase 3 The EQ-5D-5L VAS records the respondent's self-rated health on a 10 centimeter (cm) vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being the worst health you can imagine and 100 being the best health you can imagine. | Up to 5 years | 
| Change from baseline in patient-reported severity with usual or daily activities due to fatigue per the Patient Reported Outcomes for Common Terminology Criteria for Adverse Events (PRO-CTCAE). | Phase 2 and Phase 3 PRO-CTCAE questionnaire assesses side effect symptoms in cancer clinical trials using a PRO-CTCAE score. The PRO-CTCAE includes an item library of 124 items representing 78 symptomatic toxicities drawn from the CTCAE. | Up to 5 years | 
| Change from baseline in patient-reported interference with usual or daily activities due to fatigue per the Patient Reported Outcomes for Common Terminology Criteria for Adverse Events (PRO-CTCAE). | Phase 2 and Phase 3 | Up to 5 years | 
| Concentrations of cemiplimab in serum | Phase 2 and Phase 3 | Up to 136 weeks | 
| Concentrations of fianlimab in serum | Phase 2 and Phase 3 | Up to 136 weeks | 
| Immunogenicity, as measured by anti-drug antibodies (ADA) to fianlimab | Phase 2 and Phase 3 | Up to 136 weeks | 
| Immunogenicity, as measured by ADA to cemiplimab | Phase 2 and Phase 3 | Up to 136 weeks | 
| Immunogenicity, as measured by neutralizing antibodies (NAb) to fianlimab | Phase 2 and Phase 3 | Up to 136 weeks | 
| Immunogenicity, as measured by NAb to cemiplimab | Phase 2 and Phase 3 | Up to 136 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment naïve, NSCLC