Thoracic Radiotherapy and Inhibition of PD-1 and LAG-3 for Locally Advanced Non-Small Cell Lung Cancer

NCT06865339 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2024-16318
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

Brief Summary

Determine anti-tumor efficacy by characterizing response rates on positron emission tomography (PET) following three cycles of induction immunotherapy with cemiplimab and fianlimab without chemotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Conditions

NSCLC; Locally Advanced

Keywords

Human Immunoglobulin G (IgG) anti-PD-1 monoclonal antibody; Human IgG anti-lymphocyte activation gene; Tumor Proportion Score

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) to induction IO therapy

  ORR to induction therapy will be evaluated by fluorodeoxyglucose (FDG) FDG-PET scan using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. Pre-and post-treatment maximum standardized uptake value (SUV) levels following PERCIST criteria will be assessed. Specifically, the percentage of patients who experience either a complete metabolic response (CMR) or partial metabolic response (PMR) based on changes in FDG uptake will be determined and quantified using the following calculation (PMR+CMR/Sample Size). All participants who initiate study therapy will be analyzed for ORR. Participants who do not undergo response rate evaluation for any reason will be categorized as non-responders. Response rates in each study cohort will be summarized and reported using counts and percentages. 95% Clopper-Pearson confidence intervals will be calculated. ORR based on PET are more accurate predictors of long-term clinical outcomes than computed tomography (CT).

  Following 3 cycles (each cycle is ~3 weeks) of induction IO therapy, approximately 10 weeks overall

Secondary Outcomes (1)

• Dose-limiting toxicity (DLT)

  From initiation of study immunotherapy until 4 weeks following completion of radiotherapy, up to 17 weeks total

Study Arms (2)

Cohort 1: PD-L1 (TPS ≥ 50%)

EXPERIMENTAL

* Fixed-dose combination (FDC) of Cemiplimab 350mg IV + Fianlimab 1600mg IV every 3 weeks x 3 cycles * Radiotherapy * FDC of Cemiplimab + Fianlimab every 3 weeks x 13 cycles, starting 4-6 weeks after completion of RT

Drug: Cemiplimab; Drug: Fianlimab; Radiation: Radiotherapy

Cohort 2: PD-L1 (TPS < 50%)

EXPERIMENTAL

* FDC of Cemiplimab 350mg IV + Fianlimab 1600mg IV and histology-specific platinum-doublet chemotherapy (PDC) every 3 weeks x 3 cycles * Radiotherapy +/- PDC * FDC of Cemiplimab + Fianlimab every 3 weeks x 13 cycles, starting 4-6 weeks after completion of RT Weekly radiosensitizing PDC will be recommended for PD-L1 TPS \<50% patients during RT but is not required

Drug: Cemiplimab; Drug: Fianlimab; Radiation: Radiotherapy; Drug: Platinum Doublet Chemotherapy (PDC)

Interventions

Cemiplimab DRUG

Human IgG anti-PD-1 monoclonal antibody approved for treatment of advanced NSCLC with PD-L1 TPS ≥ 50% as monotherapy and in combination with chemotherapy

Also known as: REGN2810 (PD1)_cemiplimab_LIBTAYO

Cohort 1: PD-L1 (TPS ≥ 50%); Cohort 2: PD-L1 (TPS < 50%)

Fianlimab DRUG

Human IgG anti-lymphocyte activation gene 3 (LAG-3) monoclonal antibody, which is expressed by various immune cells, and regulates effector T-cell activation and responses. LAG-3 inhibition restores the effector function of exhausted T cells, enhancing their ability to attack tumor cells. Fianlimab is currently under investigation in several clinical studies involving NSCLC (NCT05800015, NCT03916627, NCT05785767).

Cohort 1: PD-L1 (TPS ≥ 50%); Cohort 2: PD-L1 (TPS < 50%)

Radiotherapy RADIATION

Thoracic radiotherapy. Conventionally fractionated 1.8-2.0 Gray (Gy) per day. Adaptive radiotherapy will not be performed unless difficulty with patient setup or changes in internal patient anatomy require repeating the CT simulation procedure

Cohort 1: PD-L1 (TPS ≥ 50%); Cohort 2: PD-L1 (TPS < 50%)

Platinum Doublet Chemotherapy (PDC) DRUG

Acceptable histology-specific PDC regimens include carboplatin plus paclitaxel or nab-paclitaxel (any histology), carboplatin/cisplatin plus pemetrexed (nonsquamous), carboplatin/cisplatin plus etoposide (any histology), and carboplatin/cisplatin plus docetaxel or gemcitabine (squamous). Carboplatin can be used instead of cisplatin after cycle 1 in cases of cisplatin-induced neuro-/oto-/nephrotoxicity as long as the patient remains eligible for chemoradiotherapy. Weekly radiosensitizing PDC will be recommended for PD-L1 TPS \<50% patients during RT but is not required.

Cohort 2: PD-L1 (TPS < 50%)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Previously untreated and biopsy-proven NSCLC, with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection or stereotactic radiotherapy for early-stage disease is allowed)
• AJCC version 8 Stage II disease, medically or technically unresectable
• AJCC version 8 Stage III disease, eligible for non-surgical treatment
• Determination of PD-L1 expression on pretreatment tumor specimen using a clinically validated assay
• Eligible for standard nonsurgical treatment for Stage III NSCLC, i.e., chemotherapy and concurrent RT followed by adjuvant durvalumab
• Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic pulmonary lesion(s) and/or thoracic lymph node(s)
• MRI of the brain or head CT with contrast within 42 days prior to study entry
• PFTs within 42 days of study entry
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate end-organ function for study therapy, as per clinician assessment and including:
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3)
• Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
• AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of normal (ULN)

You may not qualify if:

• Not a woman of childbearing potential (WOCBP) as defined in the Appendix
• A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 6 months (180 days) after the last dose of study treatment with cemiplimab and fianlimab
• A WOCBP who agrees to follow the contraceptive guidance in the Appendix and for at least 6 months after the last dose of chemotherapy or as specified in FDA prescribing labels (e.g. 14 months after the last dose of cisplatin)
• A male participant must agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• Presence of known sensitizing epidermal growth factor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion
• o Determination of EGFR/ALK mutation status is required for non-squamous cell carcinoma histologies and recommended for squamous cell carcinoma
• Prior therapy with an anti-PD-1, anti-PD-L1, or LAG-3 inhibitor
• Patient currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
• Active malignancy other than lung cancer that (1) requires active treatment other than hormonal therapy and (2) is deemed by the treating physicians to be likely to affect the patient's life expectancy
• A history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Known history of myocarditis
• Troponin T (TnT) or troponin I (TnI) \> 2x institutional ULN at baseline. Patients with TnT or TnI levels between \> 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \> 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgement in the patient's best interest
• Known active Bacillus Tuberculosis (TB)
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Sponsors & Collaborators

• Regeneron Pharmaceuticals: collaborator
• Henry Ford Health System: collaborator
• Montefiore Medical Center: lead
• NYU Langone Health: collaborator
• University of Michigan: collaborator

Study Sites (1)

Montefiore Einstein Comprehensive Cancer Center (MECCC)

The Bronx, New York, 10461, United States

RECRUITING

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MeSH Terms

Interventions

cemiplimab; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Nitin Ohri, MD, MS

  Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nitin Ohri, MD, MS

CONTACT

718-405-8550; nitin.ohri@einsteinmed.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2025
• First Posted: March 7, 2025
• Study Start: August 7, 2025
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)