Phase 3 Clinical Study of AK112 for NSCLC Patients

Study Overview
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Brief Summary
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A Randomized, Double-blind, Multi-center, Phase III Clinical Study of Ivonescimab (SMT112 or AK112) or Placebo Plus Pemetrexed and Carboplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer Who Have Progressed on or Following Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Treatment (HARMONi)

Detailed Description
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The trial will be performed as a randomized, Double-Blind, Multicenter trial to compare Ivonescimab (SMT112 or AK112) Plus Pemetrexed and Carboplatin to Placebo Plus Pemetrexed and Carboplatin in Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Harboring. Approximately 470 subjects will be randomized to two treatment arms at the ratio of 1:1. Each enrolled subject will receive an intravenous infusion of Ivonescimab (SMT112 or AK112) Plus Pemetrexed and Carboplatin or Placebo Plus Pemetrexed and Carboplatin（Q3W, up to 4 cycles) in treatment periods per the randomization schedule. Afterward, Ivonescimab (SMT112 or AK112) Plus Pemetrexed or Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.

Official Title
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A Randomized, Double-blind, Multi-center, Phase III Study of AK112 or Placebo Combined With Pemetrexed and Carboplatin in Patients With EGFR-mutant Locally Advanced or Metastatic Non-squamous NSCLC Who Have Failed to EGFR-TKI Treatment

Conditions
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Non-Squamous Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ivonescimab (SMT112 or AK112) Injection
* Drug: Placebo Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily sign a written informed consent form (ICF), which must be signed before the specified study procedures required for the study are performed. Males or females aged ≥ 18 years at the time of signing informed consent. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. Life expectancy ≥3 months； Locally advanced (stage IIIB/IIIC) or metastatic (stage IV) non-squamous NSCLC confirmed by histology or cytology, inoperable and unable to receive radiotherapy and chemotherapy; The tumor histology, cytology or hematology confirmed the presence of EGFR activating mutations before enrollment Have previously received 3rd generation EGFR-TKI treatment and have progressed on or following Subjects have at least one measurable non-brain tumor lesion per RECIST v1.1 Major organ function prior to treatment meets the following criteria Patients of childbearing potential must agree to use effective contraceptive measures Exclusion Criteria: Histological or cytological pathology confirmed the presence of small cell carcinoma components, or the main component is squamous cell carcinoma There are reports confirming the existence of other driver gene mutations with known drug treatments Subjects who received any prior treatments targeting the mechanism of tumor immunity The subject has received systemic anti-tumor therapy other than EGFR-TKI Currently enrolled in any other clinical study Received EGFR-TKI treatment, palliative local treatment, non-specific immunomodulatory treatment within 2 weeks prior to the first dose. Tumor surrounds important blood vessels or has obvious necrosis, cavitation, or invades surrounding important organs and blood vessels. Symptomatic central nervous system metastases Active malignancies within the past 3 years, with the exception of tumors in this study and cured local tumors Active autoimmune disease requiring systemic treatment within 2 years prior to the start of study treatment There is a history of major diseases 1 year prior to the first dose. .Medical history of gastrointestinal perforation or gastrointestinal fistula within 6 months prior to the first dose Received chest radiation therapy prior to the first dose Presence of clinically symptomatic pleural effusion, pericardial effusion, or ascites requiring frequent drainage. Active or previously documented inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis).

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: Ivonescimab (SMT112 or AK112) in combination with Pemetrexed and Carboplatin<br>Subjects will receive Ivonescimab (SMT112 or AK112) Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles. Afterward, AK112 Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years. | Drug: Ivonescimab (SMT112 or AK112) Injection<br>* Subjects will receive Ivonescimab (SMT112 or AK112) Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles. Afterward, Ivonescimab (SMT112 or AK112) Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.<br>* Other names: Carboplatin;|
| Placebo Comparator: Placebo in combination with Pemetrexed and Carboplatin<br>Subjects will receive Placebo Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles in treatment periods per the randomization schedule. Afterward, Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years. | Drug: Placebo Injection<br>* Subjects will receive Placebo Plus Pemetrexed and Carboplatin via intravenous infusion (IV) Q3W, up to 4 cycles in treatment periods per the randomization schedule. Afterward, Placebo Plus Pemetrexed will be used for maintenance treatment (administered on Day 1 of each cycle, Q3W) up to 2 years.<br>* Other names: Carboplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Progression-free survival (PFS) assessed by IRC per RECIST v1.1 in the ITT population. | Up to 2 years | 
| Overall Survival (OS) | Overall Survival (OS) in the ITT population | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Efficacy measures such as overall response rate (ORR), which is the proportion of subjects with CR or PR by IRRC based on RECIST v1.1 | Up to 2 years | 
| DCR | Disease control rate (DCR), which is defined as the proportion of subjects with CR, PR, or SD, based on RECIST v1.1 | Up to 2 years | 
| DoR | Duration of response (DoR), which is defined as the duration from the first documentation of objective response to the first documented disease progression or death due to any cause, whichever occurs first. | Up to 2 years | 
| TTR | TTR is defined as the time to response base on RECIST v1.1 | Up to 2 years | 
| PFS | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first assessed by investigator Per RECIST 1.1. | Up to 2 years | 
| AE | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results. | From the subject signs the ICF to 30 days (AE) and 90 days (SAE) after the last dose of study treatment or initiation of other anti-tumor therapy, whichever occurs first,up to 2 years | 
| Observed concentrations of AK112 | The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration | through study completion, an average of 2 year | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK112 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs) | From first dose of AK112 through 90 days after last dose of AK112,up to 2 years |