Toripalimab Plus Pemetrexed+Platinus in Advanced Non-small-cell Lungcancer Patients Previsouly Treated EGFR-TKI

Study Overview
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Brief Summary
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This is a Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with chemotherapy in Advanced Non-small Cell Lung Cancer (NSCLC) Participants with TKI-resistant EGFR-mutated Tumors; and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 440 subjects with advanced non-small cell lung cancer with activated EGFR mutation will be 1:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: The history of the previous lines of EGFR-TKI treament ( 1st or 2nd generation of TKI vs. 3rd generation of TKI vs. 1st or 2nd generation of TKI + 3rd generation of TKI) ; Disease stage (IIIB-C vs. IV);

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of Pemetrexed + Platinum Chemotherapy With or Without Toripalimab (JS001) in Advanced Non-small Cell Lung Cancer (NSCLC) Participants With TKI-resistant EGFR-mutated Tumors

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: TORIPALIMAB INJECTION(JS001 )


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: Fully informed consent and signed ICF; Age of 18-75 years; Histologically and/or cytologically confirmed advanced or recurrent stage III B-C or IV (AJCC Version 8) NSCLC with TKI-resistant EGFR-mutated tumors, which also satisfy following conditions: Without T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.) treatment failure;If with T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.),participants are required to have osimertinib or other 3rd generation EGFR-TKI treatment failure prior to enrollment.Participants with osimertinib treatment failure as 1st line therapy (regardless of their EGFR T790M mutation status);Previous neoadjuvant/adjuvant chemotherapy is allowed, but the time interval between the last dose of chemotherapy and recurrence/metastasis must be at least 6 months. With at least one measurable disease per RECIST 1.1; Agree to provide formalin fixed tumor specimen after EGFR-TKI treatment failure or provide fresh biopsy tissue; ECOG performance status of 0-1; Life expectancy ≥ 3 months; Good organ function; Any adverse event resulting from prior treatment, surgery, or radiotherapy must return to grade 0 or 1 according to NCI-CTCAE v5.0, except for alopecia of any grade; Willing and able to follow protocol visits, treatment plans, laboratory tests and other study procedures; Women of childbearing potential must have negative serum pregnancy test within 3 days prior to the first dose of investigational product: Exclusion Criteria: Exclusion of tumor histology or cytology confirmed the presence of small cell lung cancer components, or squamous cell carcinoma components of more than 10%; Combined with other driver mutations with known therapeutic drug, including but not limited to: ALK rearrangement, ROS1 mutation, BRAF600E mutation; Previous systematic chemotherapy for advanced NSCLC; Subjects with no measurable lesions; Subjects with cancer meningitis and spinal cord compression; Subjects with untreated central nervous system (CNS) tumor metastasis; Subjects were previously treated with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 agent; Subjects with any active, known or suspected autoimmune disease; Subjects who are now participating in other clinical studies or the last dose of prior investigational drug was given in < 4 weeks (or 5 half-lives) from the first investigational product administration of this study; Subjects who were expected to receive any other antitumor therapy (eg, other maintenance therapy for NSCLC, radiotherapy, and/or surgical excision); Subjects who received major surgery within 4 weeks prior to enrollment or were not fully recovered from prior surgery; Subjects with other malignancies requiring concurrent treatment; Subjects with grade II or above myocardial ischemia or myocardial infarction, or subjects with arrhythmia with poor control; Subjects with uncontrolled pleural/pericardial effusion, or with ascites requiring repeated drainage; Subjects with uncontrolled tumor-related pain; Subjects with severe allergic reactions to other monoclonal antibodies and subjects with severe allergic reactions to pemetrexed, platinum or its prophylaxis; Subjects with psychological disorder, alcohol alcoholism, drug abuse or drug dependency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Group TORIPALIMAB combined with standard chemotherapy<br> | Drug: TORIPALIMAB INJECTION(JS001 )<br>* TORIPALIMAB INJECTION(JS001 ) or Placebo, 240mg/6ml/vial, Q3W,up to 2 years of treatment.<br>|
| Placebo Comparator: Group Placebo combined with standard chemotherapy<br> | Drug: TORIPALIMAB INJECTION(JS001 )<br>* TORIPALIMAB INJECTION(JS001 ) or Placebo, 240mg/6ml/vial, Q3W,up to 2 years of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival，It's suitable for all subjects. | Approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS (Progression Free Survival) by investigator | Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1) | Approximately 4 years | 
| ORR (Objective Response Rate) | Objective response rate (ORR) evaluated by investigators based on RECIST1.1; | Approximately 4 years | 
| DOR (Duration of Response) | Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1; | Approximately 4 years | 
| DCR (Disease of Response) | Disease control rate (DCR) evaluated by investigators based on RECIST1.1; | Approximately 4 years | 
| TTR (Time to Response) | Time to response (TTR) evaluated by investigators based on RECIST1.1; | Approximately 4 years | 
| Incidence of AEs/SAEs | Adverse events (AEs) study drug related; serious adverse events (SAEs)study drug related; abnormal value of Lab test according to NCI-CTCAE V5.0 | Approximately 5 years |