Neoadjuvant Toripalimab for Clinically Stage II-IIIB Resectable Non-small Cell Lung Cancer with EGFR Mutation and PD-L1 Positive Expression

Neoadjuvant Toripalimab for Clinically Stage II-IIIB Resectable Non-small Cell Lung Cancer with EGFR Mutation and PD-L1 Positive Expression: a Prospective, Open-label, Multicenter, Single-arm Phase II Clinical Study

The study is a prospective, open label, multicenter, single arm Phase II clinical trial, aiming to explore the use of neoadjuvant Toripalimab for clinically stage II-IIIB NSCLC patients with EGFR mutations and PD-L1 positive expression, providing a novel perspective for further improving the prognosis of NSCLC patients. This study will provide valuable information for further clinical trials of neoadjuvant Toripalimab and other immune checkpoint inhibitors in NSCLC patients with EGFR mutations and PD-L1 positive expression.

For resectable locally advanced non-small cell lung cancer (NSCLC), the combination of neoadjuvant therapy and surgery has benefited the patients and has become a clinical routine and guideline recommended treatment. Among the East Asian NSCLC population, about 30% are positive for EGFR driver gene mutations. The efficacy of this population receiving neoadjuvant chemotherapy and EGFR inhibitors is limited, and their optimal neoadjuvant treatment strategy is still unclear. The neoadjuvant immunotherapy has achieved good therapeutic effects in driver-negative NSCLC patients, and is superior in PD-L1 expression positive patients.

Based on the above evidence, the investigators plan to conduct a prospective, open label, multicenter, single arm Phase II clinical study to explore the use of neoadjuvant Toripalimab for clinically stage II-IIIB NSCLC patients with EGFR mutations and PD-L1 positive expression, providing a novel perspective for further improving the prognosis of NSCLC patients.

Inclusion Criteria:

1. Men and women aged ≥ 18 years old.
2. Baseline tumor tissues have to be obtained through biopsy (percutaneous or transbronchial) or surgery at study center.
3. Histologically confirmed diagnosis of primary non-small lung cancer on non-squamous histology.
4. Pre-treatment stage as clinical II-IIIB (AJCC/UICC 8th Edition) (stage IIIB excludes N3 disease); curative resectability has to be explicitly verified by the experienced surgical investigator.
5. Confirmation by the central laboratory that the tumor harbors EGFR mutations either sensitive mutations, uncommon mutations or complex mutations.
6. Have a PD-L1 tumor proportion score (TPS) ≥ 1% determined by IHC at the central laboratory. In order to balance patients with high PD-L1 expression (≥50%) and low PD-L1 expression (1-49%), we planned to enroll PD-L1 high and low patients at a ratio of 1:1.
7. Have not received prior systemic treatment for NSCLC.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
9. Expected survival ≥ 3 months.
10. Adequate blood and organ function.

Exclusion Criteria:

1. Patients with histologically confirmed squamous cell carcinoma, combined small cell carcinoma and large cell carcinoma.
2. Molecular testing confirmed ALK translocation.
3. Treatment with prior systemic cancer therapy for the current lung cancer at any time (chemotherapy, radiotherapy, target therapy, ablation, and any other local or systemic therapy).
4. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colorectal, endometrial, cervical, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.
5. Any active or history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma/atopy, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
6. Subjects with a history of interstitial lung disease, pneumonitis, or poorly controlled lung disease (including pulmonary fibrosis, acute lung diseases).
7. Severe chronic or active infections that require systemic antimicrobial, antifungal, or antiviral treatment, including tuberculosis infections.
8. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA ≥ 500 IU/mL [2500 copies/mL] should be excluded.
9. Has known active hepatitis C virus (HCV). Active HCV is defined by positive tests for HCV Ab and quantitative HCV RNA.
10. Known positive history or positive test for Human Immunodeficiency Virus (HIV).
11. The investigator believes that there is a high risk of bleeding (such as esophageal varices with bleeding risk, local active ulcer lesions) or active hemoptysis.
12. History of allergy to study drug components.
13. Pregnant and lactating women are excluded.
14. Fertile men or their female partners (women of childbearing potential, WOCBP) who are not willing to use contraception.
15. Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information.
16. The investigator believes that there are factors that can increase medication risk or confuse outcome judgment.