Tislelizumab Combined With Chemotherapy With or Without Bevacizumab in TKI-Resistant EGFR-Mutated Non-squamous NSCLC

A Phase II Two Cohorts Prospective Study to Evaluate the Efficacy and Safety of Tislelizumab Combined With Chemotherapy With or Without Bevacizumab in Non-squamous NSCLC With EGFR Sensitizing Mutation Who Failed EGFR TKI Therapy

A phase II, open-label, multicenter, two cohorts, prospective clinical study to investigate the efficacy and safety of tislelizumab (anti-pd1 antibody) combined with chemotherapy with or without bevacizumab in non-squamous non-small cell lung cancer patients with EGFR sensitizing mutation who failed EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) therapy.

Study Overview

• Status: Recruiting
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Tislelizumab; Drug: Carboplatin; Drug: Pemetrexed; Drug: Nab paclitaxel; Drug: Bevacizumab

Detailed Description

Although EGFR tyrosine kinase inhibitors (TKI) have improved the survival of EGFR mutated NSCLC pts, drug resistance inevitably develops in almost all pts. Tislelizumab (tis), an anti-PD-1 mAb, has shown improved efficacy when combined with chemotherapy in pts with advanced EGFR-wt NSCLC with a tolerable safety profile. This study aims to evaluate the efficacy and safety of tislelizumab plus carboplatin and Nab-paclitaxel（cohort 1）or tislelizumab plus Nab-paclitaxel and bevacizumab （cohort 2） in EGFR-mut nsq-NSCLC pts failed to EGFR TKI therapies.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200000
      • Recruiting
      • Shanghai Chest Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed, locally advanced (Stage IIIB/C) not amenable to curative surgery or radiotherapy, or metastatic (Stage IV) non-squamous NSCLC according to American Joint Committee on Cancer, 8th Edition.
2. Documentation of tumor EGFR sensitizing mutation before EGFR TKI treatment, including 19del, L858R, G719X, S786I and L861Q.
3. Disease progression after treatment with an EGFR TKI therapy: 1) Patients previously treated with 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib/icotinib) are required to provide specimens after PD to confirmed absence of EGFR T790M mutation; 2) Patients with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib/icotinib) are required to have 3rd generation EGFR TKI (e.g. osimertinib) treatment failure prior to enrollment; 3) Patients previously failed from 3rd generation EGFR TKI (e.g. osimertinib) treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status.
4. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1.
5. Life expectancy ≥ 3 months.
6. Adequate organ function
7. Able to provide written informed consent by the patient or by the patient's legally acceptable representative and can understand and agree to comply with the requirements of the study.
8. 18 to 75 years old on the day of signing the ICF (Informed Consent Form).

Exclusion Criteria:

1. Received prior therapies targeting PD-1, PD-L1, CTLA-4 or other immune checkpoints.
2. Received prior platinum-based chemotherapy for advanced disease.
3. Patients who have received prior systemic anti-vascular therapy (e.g., bevacizumab and small molecule VEGFR inhibitors) for advanced disease (Cohort 2)
4. Received EGFR TKI treatment within 2 weeks
5. Treatment with any approved systemic anti-cancer therapy or systemic immune-stimulatory agents (including but not limited to interferons, interleukin IL-2, and tumor necrosis factor) within 28 days prior to initiation of study treatment.
6. Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or abdominal tapping for drainage within 2 weeks prior to initiation of study treatment.
7. Active leptomeningeal disease or uncontrolled brain metastasis.
8. History of allergic reactions to any study drugs.
9. CrCl < 45 mL/min
10. Patients with active viral hepatitis that requires treatment.
11. Active autoimmune diseases that requires treatment and may affect study treatment estimated by investigator.
12. Any condition that required systemic treatment with either corticosteroids or any other immunosuppressive medication that may affect study treatment estimated by investigator.
13. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy.
14. History of hemoptysis, i.e., coughing up at least one-half teaspoon of fresh blood, within 3 months prior to enrollment. (Cohort 2)
15. Imaging shows tumor invasion of a large vessel (e.g., pulmonary artery or superior vena cava) that the investigator determines is at risk for bleeding. (Cohort 2)
16. Had minor surgical procedures, such as tube placement, within 48 hours prior to first bevacizumab treatment. (Cohort 2)
17. Recently treated with a full dose oral or parenteral anticoagulant or thrombolytic agent. Prophylactic using anticoagulants is allowed. (Cohort 2)
18. History or test results indicating an inherited bleeding tendency or coagulation disorder that may increase the risk of bleeding (cohort 2)
19. uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg) (cohort 2)
20. Clinically meaningful (e.g., active) cardiovascular disease that, in the judgment of the investigator, is intolerant to bevacizumab therapy (cohort 2)
21. Non-cured wound, peptic ulcer in active phase, or fracture (cohort 2)
22. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or thrombotic disease within 6 months judged by the investigator to be intolerant to bevacizumab treatment (Cohort 2)
23. With a history of interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.
24. Have known human immunodeficiency virus (HIV) infection.
25. Any major surgical procedure requiring general anesthesia ≤ 28 days before initiation of study treatment.
26. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that would be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs (Adverse Events) or result in insufficient or might impair compliance with study conduct.
27. Concurrent participation in another clinical study.
28. Pregnant or lactating women, or male and female patients who plan to have children during the study period. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tislelizumab plus chemotherapy; Tislelizumab plus Carboplatin/Nab-paclitaxel as induction treatment and followed by Tislelizumab plus pemetrexed as maintenance treatment.	Drug: Tislelizumab; Tislelizumab 200mg administered intravenously (IV) on Day 1 of each 21-day cycle; Other Names: BGB-A317; Drug: Carboplatin; Carboplatin AUC 5 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles; Drug: Pemetrexed; Pemetrexed 500mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle; Drug: Nab paclitaxel; Nab-paclitaxel 260mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles
EXPERIMENTAL: Tislelizumab plus chemotherapy plus Bevacizumab; Tislelizumab plus Nab-paclitaxel and Bevacizumab as induction treatment and followed by Tislelizumab plus Bevacizumab as maintenance treatment.	Drug: Tislelizumab; Tislelizumab 200mg administered intravenously (IV) on Day 1 of each 21-day cycle; Other Names: BGB-A317; Drug: Nab paclitaxel; Nab-paclitaxel 260mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles; Drug: Bevacizumab; Bevacizumab 7.5mg/kg administered intravenously (IV) on Day 1 of each 21-day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-Year Progression-Free Survival Rate (1-Year PFS Rate)	Progression-free survival (per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first. Subjects who do not have disease progression will be censored at their last valid tumor assessment. PFS rate at 1 year as estimated by Kaplan-Meier method.	up to 24 months after enrollment or study close

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival (PFS per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.	up to 24 months after enrollment or study close
Objective Respond Rate (ORR)	ORR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).	up to 24 months after enrollment or study close
Disease Control Rate (DCR)	DCR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR), or stable disease (SD).	up to 24 months after enrollment or study close
Overall Survival (OS)	OS is defined as the time from the starting date of study drug to the date of death due to any cause.	up to 24 months after enrollment or study close
Duration of Response (DoR)	DoR (per RECIST 1.1) is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first.	up to 24 months after enrollment or study close

Collaborators and Investigators

• Sponsor: Shanghai Chest Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 15, 2020
• Primary Completion (ANTICIPATED): April 1, 2022
• Study Completion (ANTICIPATED): March 1, 2025

Study Registration Dates

• First Submitted: May 25, 2020
• First Submitted That Met QC Criteria: May 25, 2020
• First Posted (ACTUAL): May 28, 2020

Study Record Updates

• Last Update Posted (ACTUAL): November 22, 2021
• Last Update Submitted That Met QC Criteria: November 19, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Bevacizumab; Chemotherapy; PD-1; Non small cell lung cancer; Tislelizumab; EGFR mutation
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Folic Acid Antagonists; Carboplatin; Paclitaxel; Bevacizumab; Pemetrexed
• Other Study ID Numbers: BGB-A317-2001-IIT

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.: Yes