Study Comparing the Combination Domvanalimab and Zimberelimab With Pembrolizumab in Untreated Locally Advanced or Metastatic PD-L1-High Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a phase 3 study to evaluate zimberelimab (AB122) combined with domvanalimab (AB154) compared to pembrolizumab in front-line, PD-L1-high, locally advanced or metastatic NSCLC.

Official Title
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A Phase 3 Study to Evaluate Zimberelimab (AB122) Combined With AB154 in Front-Line, PD-L1-High, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Non Small Cell Lung Cancer, Nonsquamous Non Small Cell Lung Cancer, Squamous Non Small Cell Lung Cancer, Lung Cancer

Intervention / Treatment
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* Drug: Domvanalimab
* Drug: Zimberelimab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Pemetrexed
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, treatment naïve, locally advanced or metastatic (stage IIIB IV per AJCC version 8), squamous or non-squamous NSCLC with documented high PD L1 expression (TC ≥ 50%) as determined by the VENTANA SP263 IHC assay, as assessed by central laboratories). Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Must have at least 1 measurable lesion per RECIST v1.1 Adequate organ and marrow function If a participant has brain or meningeal metastases, the participant must meet the following criteria: Have no evidence of progression by neurologic symptoms or signs for at least 4 weeks prior to the first dose. Participants with previously treated brain metastases may participate provided they have stable central nervous system (CNS) disease for at least 4 weeks prior to enrollment. Stable CNS disease is defined as resolution of all neurologic symptoms to baseline, having no evidence of new or enlarging brain metastases, and not requiring use of corticosteroids for CNS disease for at least 14 days prior to the start of study treatment. Participants who have had brain metastases resected or have received whole brain radiotherapy ending at least 4 weeks (or stereotactic radiotherapy ending at least 2 weeks) prior to initiation of study treatment are permitted. Carcinomatous meningitis is excluded regardless of clinical stability. Exclusion Criteria: Presence of any tumor genomic aberration or driver mutation for which a targeted therapy is approved by local health authority and available Use of any live vaccines against infectious diseases within 28 days of first dose Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer Prior treatment with any anti-PD-1, anti-PD-L1 or any other antibody targeting an immune checkpoint. Other protocol defined Inclusion/Exclusion criteria may 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - Study Part 1 (Platinum-based Chemotherapy)<br>Participants will receive carboplatin, pemetrexed, and paclitaxel by intravenous (IV) infusion. | Drug: Carboplatin<br>* Participants receive carboplatin, pemetrexed, and paclitaxel at a target area under the curve.<br>Drug: Paclitaxel<br>* Participants receive carboplatin, pemetrexed, and paclitaxel at a target area under the curve.<br>Drug: Pemetrexed<br>* Participants receive carboplatin, pemetrexed, and paclitaxel at a target area under the curve.<br>|
| Experimental: Arm B - Study Part 1 (Zimberelimab Monotherapy)<br>Participants will receive zimberelimab monotherapy by IV infusion. | Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|
| Active Comparator: Arm C - Study Part 1 (Domvanalimab + Zimberelimab Combination Therapy)<br>Participants will receive zimberelimab in combination with AB154 by IV infusion. | Drug: Domvanalimab<br>* Domvanalimab is a humanized monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|
| Experimental: Arm D - Study Part 2 (Domvanalimab + Zimberelimab Combination Therapy)<br>Participants will receive domvanalimab in combination with zimberelimab by IV infusion. | Drug: Domvanalimab<br>* Domvanalimab is a humanized monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|
| Experimental: Arm E - Study Part 2 (Pembrolizumab)<br>Participants will receive pembrolizumab by IV infusion. | Drug: Pembrolizumab<br>* Pembrolizumab is a humanized Immunoglobulin G4 monoclonal antibody targeting the PD-1 receptor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Arm D vs. Arm E | From randomization until death from any cause (up to approximately 7 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Arm D vs. Arm E - PFS as assessed by RECIST v1.1 by blinded independent central review | From randomization until death from any cause (up to approximately 7 years) | 
| Confirmed Overall Response Rate (ORR) | Arm D vs. Arm E - ORR as assessed by RECIST v1.1 by blinded independent central review | From randomization until death from any cause (up to approximately 7 years) | 
| Number of Participants With treatment-emergent adverse events | Arm D vs. Arm E | From randomization until death from any cause (up to approximately 7 years) | 
| Time to first symptom deterioration in Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) total score | Arm D vs. Arm E | From randomization until death from any cause (up to approximately 7 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Small Cell Lung Cancer, Lung Cancer, NSCLC