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);

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