Efficacy and Safety Evaluation of PLB1004 in Patients With Non-squamous NSCLC Harboring EGFR Exon 20 Insertion.

Randomized, controlled, open label, multicenter phase III study to evaluate the efficacy and safety of PLB1004 Versus platinum-based chemotherapy with or without Sintilimab in the first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) Exon 20 insertion(ex 20) mutations.

Inclusion criteria

• Ability to understand and willingness to sign a written informed consent document.
• Aged at least 18 years old.
• Histologically or cytologically confirmed locally advanced or metastatic NSCLC (stage IIIB~IV).
• Tumor tissue is positive for EGFR Ex20ins as documentally confirmed by next-generation sequencing (NGS) testing or written confirmation of PCR testing by a local laboratory accredited by the Clinical Laboratory Improvement Act Amendments (CLIA), International Organization for Standardization/Independent Ethics Committee (ISO/IEC), American College of Pathologists (CAP), or a central laboratory designated by the sponsor by a tertiary A hospital or with Clinical Laboratory Improvement Act Amendments (CLIA), International Organization for Standardization/Independent Ethics Committee (ISO/IEC), American College of Pathologists (CAP) accreditation (or other equivalent accreditation).
• At least one measurable lesion as defined by RECISTV1.1（Brain lesions were not included in measurable target lesions）
• ECOG performance status 0 to 1.
• Life expectancy is not less than 12 weeks.
• No previous systemic treatment for locally advanced or metastatic non-squamous cell cancer NSCLC. Note: Subjects are allowed to receive neoadjuvant/adjuvant therapy as long as the relevant therapy has ended at least 6 months before the disease is diagnosed as locally progressive or metastatic tumors

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Exclusion criteria

• Have one of the following previous anti-tumor treatments: prior to the first dose of PLB1004

a) Any anti-EGFR TKI for the EGFR ex20ins mutation.. b) Received Chinese patent drugs with anti-tumor indications within 1 week before administration of the first study drugReceived Chinese patent drugs with anti-tumor indications within 1 week before administration of the first study drug c) required administration of the multidrug and toxin efflux protein (MATE) transporter substrate metformin within 1 week before and during the first study drug administration d）Strong inhibitors or strong inducers of the cytochrome P450 3A4 enzyme (CYP3A4) were required within 1 week before and during the study e) required immunosuppressive medication within 2 weeks before or during the first dose of study drug f) Major surgery within 4 weeks prior to starting PLB1004 or who have not recovered from side effects of such procedure except for the biopsy of Thoracoscopy and the clinical test of Mediastinoscopy could ≤ 7 days prior to starting PLB1004 g) Radiotherapy to lung fields and whole-brain fields ≤4 weeks prior to starting PLB1004. For all other anatomic sites, radiotherapy ≤2 weeks prior to starting PLB1004 or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions is not included.

• Patients with spinal cord compression ,brain membrane metastasis and symptomatic central nervous system (CNS), who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study manage CNS symptoms.
• Before randomization, patients did not recover from any toxicity and/or complications of previous chemotherapy, surgery, radiotherapy and other anti-cancer treatments, that is, did not fall to grade 1 or lower (National Cancer Research Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0), except for hair loss and irrecoverable permanent radiation damage
• Did not recover from any toxicity and/or complications of previous anti-cancer treatments such as chemotherapy, surgery, and radiotherapy, that is, did not fall to grade 1 or lower (National Cancer Research Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0), except for alopecia and irrecoverable permanent radiation damage
• A tendency to coagulopathy or bleeding, including an arterial or venous thromboembolic event (including a history of myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or any other major thromboembolism) within 6 months before randomization; Any life-threatening bleeding event (including the need for blood transfusion, surgical or local treatment, or continued medical therapy) or major vascular invasion was considered by the investigator to be bleeding prone
• Severe cardiac disease, such as any serious arrhythmia (including ventricular arrhythmia, drug-refractory supraventricular and other arrhythmias), grade III or higher cardiac dysfunction (New York Heart Association [NYHA], see Appendix 4 for details), and left ventricular ejection fraction (LVEF) <50% on echocardiography;
• Mean corrected QT intervals (QTcF) of three electrocardiograms during screening, calculated according to Fridericia's formula at rest, were >470 ms;
• Presence of uncontrolled hypertension (treated systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg)
• Dysphagia, or active digestive disease or major gastrointestinal surgery that may affect the administration or absorption of the study drug (e.g., ulcerative lesions, uncontrolled nausea, vomiting, diarrhea, and malabsorption syndromes);
• Allergy or intolerance to the drug class and excipient components of the study drug
• pregnant or nursing women.
• Received live vaccine within 4 weeks before randomization;

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