A Study of AK104/Tislelizumab With Chemotherapy as First-line Treatment in PD-L1 TPS < 1% Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a randomized, double-blind, phase III clinical study to compare the efficacy and safety of AK104 combined chemotherapy versus Tislelizumab combined chemotherapy in first-line treatment of Locally advanced or metastatic NSCLC with PD-L1 TPS < 1%.

Official Title
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A Randomized, Double-blind, Phase III Trial to Compare the Efficacy and Safety of AK104 Combined With Chemotherapy to Tislelizumab Combined With Chemotherapy as First-line Treatment in PD-L1 TPS < 1% Non-small Cell Lung Cancer (NSCLC)

Conditions
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Locally Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: AK104
* Drug: Tislelizumab
* Drug: carboplatin
* Drug: Pemetrexed
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects voluntarily participated in the study with full informed consent and signed written informed consent form. Aged ≥18 years when the subject signed the informed consent. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy ≥ 3 months. Histologically or cytologically confirmed locally advanced (Stage IIIB/IIIC) that not amenable to complete surgical resection and not amenable to radical concurrent/sequential chemoradiation or metastatic (Stage IV) NSCLC (American Joint Committee on Cancer [AJCC] 8th edition). No prior systemic therapy for advanced or metastatic NSCLC was received. PD-L1 TPS < 1%. No EGFR sensitive mutations or ALK gene translocation alterations. Exclusion Criteria: Histologically confirmed small cell lung cancer (SCLC). NSCLC with driver gene mutations for approved targeted drug indications. Active central nervous system (CNS) metastases were present. Pulmonary radiation therapy > 30 Gy within 6 months prior to first dose. Active malignant tumors within the past 5 years, except for tumors in this study and scured local tumors. Pregnant or lactating women. Clinically significant cardiovascular or cerebrovascular disease. Subjects with a known history of severe hypersensitivity to other monoclonal antibodies. A known history of allergy or hypersensitivity to all investigational drugs or any of their components. Active autoimmune disease requiring systemic treatment within 2 years prior to the start of study treatment, or autoimmune diseases that may relapse or require scheduled treatment as judged by the Investigator. Known active pulmonary tuberculosis. Patients with active hepatitis B or active hepatitis C. Known medical history of immunodeficiency or positive HIV test.

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: AK104 arm<br> | Drug: AK104<br>* AK104 IV, q3w<br>Drug: carboplatin<br>* carboplatin IV, q3w<br>Drug: Pemetrexed<br>* Pemetrexed IV, q3w (for Nonsquamous NSCLC)<br>Drug: Paclitaxel<br>* Paclitaxel IV, q3w (for squamous NSCLC)<br>|
| Active Comparator: Tislelizumab arm<br> | Drug: Tislelizumab<br>* Tislelizumab IV, q3w<br>Drug: carboplatin<br>* carboplatin IV, q3w<br>Drug: Pemetrexed<br>* Pemetrexed IV, q3w (for Nonsquamous NSCLC)<br>Drug: Paclitaxel<br>* Paclitaxel IV, q3w (for squamous NSCLC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival(OS) | OS is defined as the time from randomization to death due to any cause. | Through Database Cutoff Date (Up to approximately 39 months) | 
| Progression-Free Survival(PFS) by investigator(INV) | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1 | Through Database Cutoff Date (Up to approximately 39 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival(PFS) by Blind independent center review(BIRC) | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1 | Through Database Cutoff Date (Up to approximately 39 months) | 
| Objective response rate (ORR) was assessed by INV | ORR is the proportion of subjects with CR or PR based on RECIST v1.1 | Through Database Cutoff Date (Up to approximately 39 months) | 
| Disease control rate (DCR) was assessed by INV | Disease control rate (DCR) was assessed based on RECIST V1.1 criteria | Through Database Cutoff Date (Up to approximately 39 months) | 
| Time to response (TTR) was assessed by INV | The time from the first administration to the date of documented CR or PR | Through Database Cutoff Date (Up to approximately 39 months) | 
| Duration of response (DOR) was assessed by INV | Measured from the date of partial or complete response to therapy until the disease progression per RECIST v1.1 criteria | Through Database Cutoff Date (Up to approximately 39 months) | 
| Objective response rate (ORR) was assessed by BIRC | ORR is the proportion of subjects with CR or PR based on RECIST v1.1 | Through Database Cutoff Date (Up to approximately 39 months) | 
| Disease control rate (DCR) was assessed BIRC | Disease control rate (DCR) was assessed based on RECIST V1.1 criteria | Through Database Cutoff Date (Up to approximately 39 months) | 
| Time to response (TTR) was assessed by BIRC | The time from the first administration to the date of documented CR or PR | Through Database Cutoff Date (Up to approximately 39 months) | 
| Duration of response (DOR) was assessed by BIRC | Measured from the date of partial or complete response to therapy until the disease progression per RECIST v1.1 criteria | Through Database Cutoff Date (Up to approximately 39 months) | 
| The number of subjects experiencing adverse events (AEs) | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results. | Through Database Cutoff Date (Up to approximately 39 months) | 
| Pharmacokinetic | The endpoints for assessment of PK of AK104 include serum concentrations of AK104 at different timepoints after AK104 administration | Through Database Cutoff Date (Up to approximately 39 months) | 
| Antidrug antibodies (ADA) of AK104 | Proportion of subjects who develop detectable anti-drug antibodies (ADAs) | Through Database Cutoff Date (Up to approximately 39 months) | 
| Health-related Quality of Life (HRQoL) assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | EORTC QLQ-C30 measures cancer patients' physical, psychological, and social functions. Scale ranges from: 1, Not at all; 2, A little; 3, Quite a bit; to 4, Very much. Higher score for the functioning scales and global health status denotes a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms. | Through Database Cutoff Date (Up to approximately 39 months) | 
| Health-related Quality of Life (HRQoL) assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 29 module (EORTC QLQ-LC29) | EORTC-QLQ-LC29 measures the quality of life in patients with lung cancer. Symptom scale ranges from: 1, Not at all; 2, A little; 3, Quite a bit; to 4, Very much. For symptoms scales, higher scores indicated greater symptom burden. | Through Database Cutoff Date (Up to approximately 39 months) |