Phase III Study of Toripalimab Versus Placebo Plus Chemotherapy in Resectable NSCLC

This is a randomized, double-blind, placebo-controlled, multi-center, phase III clinical study to evaluate the efficacy and safety of Toripalimab injection (JS001) combined with platinum-based doublet drug chemotherapy versus placebo combined with platinum-based doublet drug chemotherapy for subjects with resectable, stage II-III NSCLC.

Subjects who meet all the inclusion criteria but do not meet any exclusion criteria are randomized into two groups at a ratio of 1:1: according to the stratification factors as below:

* Disease stage: II vs IIIA vs IIIB
* PD-L1 status: PD-L1 expression ≥1% vs. PD-L1 \<1% or not evaluable
* Planned surgical operation: pneumonectomy vs. lobectomy
* Pathological type: non-squamous cell carcinoma vs. squamous cell carcinoma Neoadjuvant therapy should be started within 3 days after randomization. Toripalimab IV 240 mg Q3W /plaecbo will be given combined with platinum-based doublet drug chemotherapy for three cycles in the preoperative neoadjuvant therapy period for trial group; Every 3 weeks of treatment is regarded as one cycle, in which combined therapy is given in the first day of every cycle.

All the subjects will receive preoperative radiological and surgical evaluation 3-5 weeks after neoadjuvant therapy.

After 3 cycles of preoperative neoadjuvant therapy, all the subjects who still have surgical indications will receive radical excision based on the surgical operation criteria of the World Association for Lung Cancer Research within 4-6 weeks after 3 cycles of preoperative neoadjuvant therapy. The pTNM will be staged in accordance with AJCC Cancer Staging Manual (version 8). All the specimens taken during the operation will be evaluated by local pathologists for the surgical margin. The tumor tissue samples collected from subjects during the study will be submitted to the authorized central laboratory for blinded evaluation of pathological response and translational research.

All the subjects who have completed the radical operation will receive one cycle of postoperative adjuvant therapy, i.e., Toripalimab IV 240 mg/placebo + platinum-based doublet drug chemotherapy in 30 days after the operation. If there is no adjuvant radiotherapy plan, it will proceed to consolidation treatment period three weeks after adjuvant therapy; if adjuvant radiotherapy is planned then the consolidation treatment period will start 30 days after adjuvant radiotherapy. In the consolidation treatment period, Toripalimab IV 240 mg/placebo is given in each cycle of every 3 weeks for a total of 13 cycles . Adverse events (AEs) will be monitored throughout the study, and the severity will be graded to the guidelines listed in National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 5.0 or above. The safety will be followed up in the subjects who have received study treatment and discontinued the drug prematurely. All the subjects will be followed up for overall survival, until death, withdrawal of informed consent or end of study.

Eligibility Criteria:
Inclusion criteria：

1. Having sufficient understanding of this study and being willing to sign the informed consent form (ICF);
2. Aged 18-70 years, male or female;
3. Treatment-naive, histologically confirmed resectable, stage II, IIIA, IIIB (N2) (AJCC staging system, version 8) NSCLC; cTNM stage can be confirmed through PET-CT or pathological biopsy; resectable stage II non-small cell lung cancer is defined as eligible for radical resection evaluated by a qualified thoracic surgeon; resectable stage III is defined as the resectable and potential resectable according to the Chinese expert consensus on the multidisciplinary diagnosis and treatment for stage III non-small cell lung cancer (2019)in which resectable includes IIIA(N0-1), partial N2 with single-station mediastinal lymph node metastasis and the short diameter of lymph node\<2 cm， partial T4 (satellite nodules in the adjacent lobe) N1 and potential resectable includes partial stage IIIA and IIIB with the short diameter of single-station N2 mediastinal lymph node\<3 cm, other potentially resectable T3 or T4 central tumor ; Any suspected lesions which could change the TNM stage, such as contralateral mediastinal lymph node, supraclavicular lymph mode, solid/sub-solid pulmonary node and non-isolated ground glass opacity (GGO), pathological confirmation is strongly recommended.
4. Measurable lesions based on the response evaluation criteria in solid tumors version 1.1;
5. Tumor tissue specimens available for pathological diagnosis, detection of PD-L1 expression and biomarkers prior to randomization (the tumor tissue specimens must be freshly obtained or archived samples within 3 months prior to enrollment; tumor tissue specimens must be the samples of histological category, including but not limited to the tissue punctured by core needle and hollow needle, tissue acquired by bronchoscopic clamp, surgically resected samples; the samples acquired by fine needle puncture and bronchial brushing are not acceptable);
6. ECOG score 0-1;
7. Good organ function:
8. Being willing and able to comply with the visits, treatment plan, laboratory examinations and other study procedures scheduled in the study;
9. pulmonary function test being able to withstand the planned pneumonectomy evaluated by surgeons; Women of childbearing potential must undergo serum pregnancy test within 3 hours prior to the first dose and the result must be negative. Female subjects of childbearing potential and male subjects whose partners are women of childbearing potential must agree to use highly effective contraceptive methods during the study period and within 180 days after the last dose of study drug.
10. Women of childbearing potential must undergo serum pregnancy test within 3 days prior to the first dose and the result must be negative. Female subjects of childbearing potential and male subjects whose partners are women of childbearing potential must agree to use highly effective contraceptive methods during the study period and within 180 days after the last dose of study drug

Exclusion criteria：

1. Presence of locally advanced, unresectable or metastatic disease; unresectable includes the unresectable defined in the Chinese expert consensus on the multidisciplinary diagnosis and treatment for stage III non-small cell lung cancer (2019), including partial stage IIIA and IIIB and all the stage IIIC; N2: single station mediastinal lymph node metastasis with short diameter ≥3cm; N2: multiple station mediastinal lymph node metastasis with lymph node fusion and the short diameter of lymph node ≥2cm on CT; ALL the N3; T4: invading esophagus, heart, aorta;
2. NSCLC involving superior sulcus, large cell neuroendocrine carcinoma (LCNEC), sarcomatoid tumor;
3. Participants with known EGFR sensitive mutations or ALK translocation, EGFR and ALK mutation status needs to be identified for the subjects with non-squamous cell carcinoma;
4. Previous treatment with systemic antitumor therapy for early NSCLC, including investigational product;
5. History of (non-infectious) pneumonitis/interstitial lung disease requiring steroid treatment, or ongoing pneumonitis/interstitial lung disease requiring steroid treatment;
6. Active tuberculosis;
7. Active infection requiring systemic treatment;
8. Subjects with any known or suspected autoimmune disorder or immunodeficiency, with the following exceptions: hypothyroidism, hormone therapy is not needed, or well controlled at physiological dose; controlled type I diabetes;
9. Uncontrolled active hepatitis B (defined as positive hepatitis B surface antigen \[HBsAg\] in screening period with HBV-DNA detected higher than the upper limit of normal at the clinical laboratory of the study center); (the subjects with HBV-DNA assay \<500 IU/mL within 28 days prior to randomization who have received local standard antiviral therapy for at least 14 days and are willing to receive antiviral therapy continuously during the study can be enrolled); active hepatitis C (defined as positive hepatitis C surface antibody \[HCsAb\] in screening period and positive HCV-RNA);
10. Known human immunodeficiency virus (HIV) infection (known positive HIV antibody);
11. Vaccination of live vaccine within 30 days prior to the first dose. Including but not limited to the following: parotitis, rubella, measles, varicella/ herpes zoster (varicella), yellow fever, Rabies, Bacille Calmette-Guérin (BCG) and typhoid vaccine (inactivated virus vaccine allowed);
12. ≥ Grade 2 peripheral neuropathy;
13. Previous use of PD-1/PD-L1 agent or the drug acting on another targeted T cell receptor (e.g., CTLA-4, OX-40);
14. Severe allergic reaction to other monoclonal antibodies;
15. History of serious allergy to Pemetrexed, paclitaxel or docetaxel, cisplatin, carboplatin or its preventive medications;
16. Known serious or uncontrolled pre-existing diseases; including but not limited to cardiovascular events with hemodynamic instability, symptomatic cerebrovascular events, and hepatic cirrhosis above Child-Pugh A within 6 months;
17. History or current evidence of any disease, therapy or abnormal laboratory examination that may confuse the study results, interfere with subject's participation in the full course of the study or not meet the best interest of subject's participation in the study, as judged by investigators;
18. Other malignant tumors within 5 years prior to the first dose, except non-small cell lung cancer. The malignant tumors with negligible risk of metastasis or death (e.g., expected disease-free survival \> 5 years) and expected to achieve radical outcomes after treatment (e.g., sufficiently treated carcinoma in situ of cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated for radical surgery) can be excluded.