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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Toripalimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hecheng Li, PhD, MD; Phone Number: 00862164370045; Email: lihecheng2000@hotmail.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510180
      • Guangdong Provincial People's Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Toripalimab; Neoadjuvant Toripalimab 240 mg IV on cycle 1 day 1 (C1D1), C2D1 and C3D1 before radical surgery for lung cancer. The participants will attend follow-up visits based on molecular residual disease (MRD) and receive adjuvant treatment including EGFR-TKI or chemotherapy if recommended.	Drug: Toripalimab; 240mg IV, Q3W

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR)	Defined as the incidence rate in postoperative pathology where the percentage of surviving tumor cells in the tumor bed is ≤ 10%, regardless of the presence or absence of live tumor cells in the lymph nodes.	MPR will be assessed within 2 weeks after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR)	Defined as the proportion of patients in postoperative pathology who have no residual live tumor cells in the primary tumor bed or in all excised lymph nodes.	pCR will be assessed within 2 weeks after surgery
Objective Response Rate (ORR)	Based on the solid tumor evaluation criteria (RECIST 1.1), the sum of the proportions of complete and partial remission evaluated by imaging	Tumor response will be evaluated within 30 days after last dose of neoadjuvant treatment
2-year Event Free Survival (EFS)	EFS is defined as the time from the first use of the investigational drug to any of the following events (whichever occurs first): the investigator assessed the disease progression based on imaging according to RECIST 1.1 and therefore was unable to receive curative surgery, local or distant recurrence, or death from any cause. A 2-year EFS is used as a secondary endpoint.	2 years after the date of initiation of neoadjuvant treatment
2-year Overall Survival (OS)	OS is defined as the date from the first use of the investigational drug until death from any cause. A 2-year OS is used as a secondary endpoint.	2 years after the date of initiation of neoadjuvant treatment
Safety (Number of Participants With Grade 3 and Higher-grade Treatment-related Adverse Events)	The safety evaluation will be based on weekly blood routine tests, liver and kidney function, electrolyte analysis, etc., and adverse reactions of level 3 or above will be recorded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0).	From date of neoadjuvant treatment until surgery was applied during study period or up to at least 90 days after last dose.
Feasibility (Number of Participants Who Finished Neoadjuvant therapy and Receive Surgery Within 3-6 Weeks After Neoadjuvant Therapies)	Among patients who have been evaluated as operable after completing neoadjuvant therapy, a surgical period of no more than 42 days from the completion of neoadjuvant therapy is defined as feasible.	6 weeks after last dose of neoadjuvant treatment

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: Guangdong Provincial People's Hospital
• Investigators: Principal Investigator: Hecheng Li, PhD, MD, Ruijin hospitalRuijin Hospital, Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): March 30, 2024
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2030

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 12, 2024
• First Posted (Estimated): February 21, 2024

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: RTS-019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No