Neoadjuvant Immunotherapy in Rare Mutations Localized NSCLC

Neoadjuvant Toripalimab Combined With Chemotherapy in Rare Mutations Stage IIB-IIIB NSCLC

Phase II, single-arm, open-label single center study that assess clinical feasibility and safety of 3 cycles neoadjuvant Toripalimab plus chemotherapy in rare mutations stage IIB-IIIB NSCLC followed by optional adjuvant treatment upon investigators' decisions.

Study Overview

• Status: Recruiting
• Conditions: Non-Small Cell Lung Cancer; BRAF V600 Mutation; MET Amplification; MET Exon 14 Skipping Mutation; RET Driver Mutation; Erb-B2 Receptor Tyrosine Kinase Exon 20 Mutation
• Intervention / Treatment: Biological: Toripalimab; Drug: Nab paclitaxel; Drug: Pemetrexed; Drug: Carboplatin

Detailed Description

30 eligible patients will be enrolled and 3 cycles of Toripalimab 240mg + chemotherapy (Nab-paclitaxel + carboplatin, or pemetrexed + carboplatin) will be administered. Rare mutations include RET fusions, BRAF (V600E or non-V600E but confirmed driver mutations), ERBB2 exon20 insertion, MET amplification (FISH confirmed) or exon 14 skipping. Dynamic blood samples before, during or after neoadjuvant treatment will be obtained for exploratory analysis. Patients who showed inferior response to neoadjuvant treatment leading to unresectable disease will be scheduled for local radiation or other potential subsequent treatment regarding multidisciplinary discussion. After completion of local treatment (surgery or radiation), patients will be provided with optional adjuvant treatment including chemotherapy or/and rare mutations TKI upon investigators' consideration. The primary objective of the study is pathological complete response (pCR) defined as no residue tumor found in both primary lung cancer and metastatic lymph nodes.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Wen-Zhao Zhong, Ph.D; Phone Number: +86 02083827812; Email: syzhongwenzhao@scut.edu.cn
• Study Contact Backup: Name: Rui Fu, Ph.D; Phone Number: +86 02083827812; Email: ruifu66@foxmail.com

Study Locations

• China
  • Guangdong
    • Guanzhou, Guangdong, China, 510080
      • Recruiting
      • Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences
      • Contact: Wen-Zhao Zhong, Ph.D; Phone Number: +86 02083827812; Email: syzhongwenzhao@scut.edu.cn
      • Contact: Rui Fu, Ph.D; Phone Number: +86 02083827812; Email: ruifu66@foxmail.com
      • Principal Investigator: Wen-Zhao Zhong, Ph.D
      • Sub-Investigator: Rui Fu, Ph.D
      • Principal Investigator: Chao Zhang, Ph.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: 18 Years and older
2. ECOG physical score 0-1 points; expected survival time ≥ 3 months;
3. Pathologically confirmed diagnosis with Stage IIB-IIIB NSCLC which harbored rare driver alteration including RET fusions, BRAF (V600E or non-V600E but confirmed driver mutations), ERBB2 exon20 insertion, MET amplification (FISH confirmed) or exon 14 skipping. Suspected N2 disease should be confirmed by either mediastinoscopy or EBUS. N1 disease could be determined through PET/CT but biopsy of primary lung cancer is needed;
4. Lung function capacity capable of tolerating the proposed lung surgery
5. Available tissue of tumor for PD-L1 test
6. Subjects voluntarily joined the study and signed informed consent, with good compliance to follow-up.

Exclusion Criteria:

1. Stage I and stage IV NSCLC;
2. Patients who have previously used any other anti-tumor drugs or radiotherapy;
3. Large panel NGS indicated sensitive EGFR alteration, ALK fusion, ROS1 fusion or any other driver mutations combined with MDM2/MDM4 amplification;
4. Histologically confirmed small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer);
5. A history of active bleeding within the 6 months before enrollment, or receiving thrombolysis or anticoagulant therapy, or the investigator believes that there is a clear tendency to gastrointestinal bleeding (such as esophageal varices with bleeding risk, local activity) Ulcer lesions, etc.) or active hemoptysis;
6. Patients with any underlying disease that investigators consider it may affect patient's prognosis including sever cardiovascular, pulmonary disease or serious infections; Clinically obvious gastrointestinal abnormalities, which may affect the intake, transport or absorption of drugs (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.), or patients with total gastrectomy;
7. Known or suspected autoimmune disease with activity. Participants may be enrolled if they have type 1 diabetes, hypothyroidism that requires only hormone replacement therapy, skin diseases that require no systemic treatment (such as purpura, psoriasis, or hair loss), or other conditions that are not expected to return without external trigger.
8. Patients with active hepatitis B (positive for HBsAg) or hepatitis C (positive for HCV RNA).
9. Patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
10. Patients with other active malignancies within five years
11. Pregnant or lactating women; those who have fertility are unwilling or unable to take effective contraceptive measures;
12. Patients with low compliance or willingness to take the drugs and surveillance.

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 plus chemotherapy; 3 cycles of neoadjuvant Toripalimab (240mg every 3 weeks) with nab-paclitaxel + carboplatin, or pemetrexed + carboplatin (decided by investigators; nab-paclitaxel 135 mg/m2, d1, 8 and carboplatin AUC 5, d1 every 3 weeks; pemetrexed, 500mg/m2 d1 every 3 weeks) will be administered before surgery, followed by optional adjuvant treatment including chemotherapy for 3-4 cycles or rare mutations-TKIs for up to 2 years or till disease progression or unacceptable toxicity.

Biological: Toripalimab; 240mg Q3W; Drug: Nab paclitaxel; 135 mg/m2, d1, 8 Q3W; Drug: Pemetrexed; 500mg/m2, d1 Q3W; Drug: Carboplatin; AUC 5, d1 Q3W

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR)	Evaluation of the pathological complete response: The pathological complete response is defined as the absence of residual tumor in both lung and lymph nodes after neoadjuvant treatment.	pCR will be assessed within 2 weeks after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR)	Percentage of Participants with Major Pathologic Response. MPR was defined as percentage of tumor cells within tumor bed less than 10% for both primary lung lesions and metastatic lymph nodes.	MPR will be assessed within 2 weeks after surgery
Event-Free Survival (EFS)	Event-free survival (EFS) is defined as the length of time from initiation of neoadjuvant treatment to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause.	From date of initiation of neoadjuvant treatment to disease progression, reoccurrence, or death due to any cause, up to 36 months.
Overall Survival (OS)	Overall survival (OS) is defined as the time between the date of initiation of neoadjuvant treatment and the date of death.	From date of initiation of neoadjuvant treatment to the date of all-cause death, assessed up to 60 months.
Adverse Events (AEs)	Incidence of all grade AE which has been confirmed to be correlated with neoadjuvant treatment or surgery.	From date of initiation of neoadjuvant treatment till treatment discontinuation, assessed up to 14 weeks.

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Collaborators: Shanghai Junshi Bioscience Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: March 21, 2023
• First Submitted That Met QC Criteria: April 4, 2023
• First Posted (Actual): April 5, 2023

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 4, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Non-small Cell Lung Cancer; Neoadjuvant immunotherapy; Rare Mutations
• 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; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Folic Acid Antagonists; Carboplatin; Paclitaxel; Pemetrexed
• Other Study ID Numbers: NEORM

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No