A Platform Study of Novel Immunotherapy Combinations in Participants With Previously Untreated, Advanced/Metastatic Non-Small-Cell Lung Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PDy) of novel immunotherapy combinations compared with immunotherapy monotherapy in participants with Programmed death ligand-1 (PD L-1) high (Tumor cells [TC]/ Tumor proportion score [TPS] ≥ 50%), previously untreated, unresectable, locally advanced or metastatic NSCLC. Drug name mentioned as Belrestotug, GSK4428859A, and EOS884448 are all interchangeable for the same compound. In the rest of the document, the drug will be referred to as Belrestotug.

Official Title
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A Phase 2, Randomized, Open-label, Platform Study Utilizing a Master Protocol to Evaluate Novel Immunotherapy Combinations in Participants With Previously Untreated, Locally Advanced/Metastatic, Programmed Death Ligand 1-Selected Non-Small-Cell Lung Cancer

Conditions
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Lung Cancer, Non-Small Cell

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Dostarlimab
* Drug: Belrestotug
* Drug: GSK6097608


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of locally advanced unresectable NSCLC not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy or metastatic NSCLC (squamous or non squamous) No prior systemic therapy for their locally advanced or metastatic NSCLC Provides a fresh tumor tissue sample or recent archival sample collected within 2 years prior to screening PD-L1-high (TC/TPS ≥ 50%) tumor Measurable disease based on RECIST 1.1, as determined by the investigator Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 Adequate baseline organ function Female participants of childbearing potential must use adequate contraception Exclusion Criteria: Presence of Epidermal growth factor receptor (EGFR) mutations, Anaplastic lymphoma kinase (ALK) translocations, or other known genomic aberrations or oncogenic driver mutations for which a locally approved therapy is available. All participants with non squamous histology must have been tested for EGFR mutation and ALK translocation status Had major surgery within 4 weeks or lung radiation of >30 grays (Gy) therapy within 6 months prior to the first dose of study intervention Received prior therapy with any immune checkpoint inhibitors Never smoker, defined as smoking <100 tobacco cigarettes in a lifetime Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years (clinical exceptions apply as per protocol) Symptomatic, untreated, or actively progressing brain metastases and/or leptomeningeal disease (regardless of symptomatology, treatment status, or stability) Autoimmune disease or syndrome that required systemic treatment within the past 2 years Receiving any form of immunosuppressive medication Received any live vaccine ≤ 30 days prior to first dose of study intervention Any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis History or evidence of cardiac abnormalities ≤6 months prior to enrollment Current unstable liver or biliary disease Severe infection within 4 weeks prior to randomization Positive for tuberculosis, human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C Has advanced, symptomatic, or visceral spread and is considered to be at imminent risk of life-threatening complications (including, but not limited to, massive uncontrolled effusions [e.g., pleural, pericardial, peritoneal]) Is currently participating in or has participated in a study of an investigational therapy within 4 weeks prior to the first dose of study intervention Has a history of allogeneic tissue/stem cell transplant or solid organ transplant

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pembrolizumab Monotherapy<br>Participants will be administered an intravenous (IV) infusion of pembrolizumab as monotherapy in a fixed dose. | Drug: Pembrolizumab<br>* Pembrolizumab will be administered as an IV infusion.<br>|
| Experimental: Dostarlimab Monotherapy<br>Participants will be administered an IV infusion of dostarlimab as monotherapy in a fixed dose. | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>|
| Experimental: Substudy 1A<br>Participants will be administered an IV infusion of dostarlimab in a fixed dose followed by an IV infusion of belrestotug in a fixed dose (Dose A). | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: GSK4428859A;|
| Experimental: Substudy 1B<br>Participants will be administered an IV infusion of dostarlimab in a fixed dose followed by an IV infusion of belrestotug in a fixed dose (Dose B). | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: GSK4428859A;|
| Experimental: Substudy 1C<br>Participants will be administered an IV infusion of dostarlimab in a fixed dose followed by an IV infusion of belrestotug in a fixed dose (Dose C). | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: GSK4428859A;|
| Experimental: Substudy 2<br>Participants will be administered an IV infusion of dostarlimab in a fixed dose followed by an IV infusion of belrestotug along with IV infusion of GSK6097608 in a fixed dose. | Drug: Dostarlimab<br>* Dostarlimab will be administered as an IV infusion.<br>Drug: Belrestotug<br>* Belrestotug will be administered as an IV infusion.<br>* Other names: GSK4428859A;Drug: GSK6097608<br>* GSK6097608 will be administered as an IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR, defined as the percentage of participants with complete response (CR) or partial response (PR) per RECIST 1.1 by investigator assessment. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR for comparison between experimental arms | ORR, defined as the percentage of participants with CR or PR per RECIST 1.1 by Investigator assessment. | Up to 24 months | 
| Progression free survival (PFS) | PFS is defined as the time taken from the date of randomization to the date of first documented progressive disease (PD) per RECIST 1.1 by investigator assessment or death due to any cause, whichever comes first. | Up to 24 months | 
| Overall survival (OS) | OS is defined as the time from the date of randomization to the date of death due to any cause. | Up to 5 years | 
| Duration of response (DOR) | DOR is defined as the time from the date of first documented objective response (CR or PR) to the date of first documented PD per RECIST 1.1 by investigator assessment or death due to any cause, whichever comes first. | Up to 5 years | 
| Number of participants with Treatment Emergent adverse events (TEAEs) and Adverse events of Special Interest (AESIs) | A TEAE is any event that was not present prior to the initiation of study intervention administration, or any event already present that worsens in intensity or frequency following exposure to study intervention. AESI are any AE (serious or non-serious) that is of scientific and medical concern specific to the study treatment and include infusion related reaction and immune-related adverse event (irAEs) from the date of enrollment to 90 days after last dose of study treatment. | Up to 5 years | 
| Number of participants with Serious adverse events (SAEs) | SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment assessed by the investigator based on CTCAE v5.0 from the date of enrollment to 90 days after last dose of study treatment. | Up to 5 years | 
| Number of participants with TEAEs or SAEs leading to dose modifications (including dose delay and study intervention discontinuation) |  | Up to 5 years | 
| Number of participants with positive antidrug antibodies (ADA) against belrestotug | Serum samples will be collected for the analysis of the presence of ADAs using validated immunoassays. | Up to 24 months | 
| Number of participants with positive antidrug antibodies (ADA) against dostarlimab | Serum samples will be collected for the analysis of the presence of ADAs using validated immunoassays. | Up to 24 months | 
| Number of participants with positive antidrug antibodies (ADA) against GSK6097608 | Serum samples will be collected for the analysis of the presence of ADAs using validated immunoassays. | Up to 24 months | 
| Maximum Observed Serum Concentration (Cmax) for belrestotug | Blood samples were collected for PK analysis of belrestotug. | Up to 24 months | 
| Maximum Observed Serum Concentration (Cmax) for dostarlimab | Blood samples were collected for PK analysis of dostarlimab. | Up to 24 months | 
| Maximum Observed Serum Concentration (Cmax) for GSK6097608 | Blood samples were collected for PK analysis of GSK6097608. | Up to 24 months | 
| Minimum Observed Serum Concentration (Cmin) for belrestotug | Blood samples were collected for PK analysis of belrestotug. | Up to 24 months | 
| Minimum Observed Serum Concentration (Cmin) for dostarlimab | Blood samples were collected for PK analysis of dostarlimab. | Up to 24 months | 
| Minimum Observed Serum Concentration (Cmin) for GSK6097608 | Blood samples were collected for PK analysis of GSK6097608. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small cell lung cancer, Dostarlimab, Pembrolizumab, PD-L1, GSK4428859A, EOS884448, PD-1 Inhibitor, Immunotherapy, Belrestotug, GSK6097608