Efficacy and safety evaluation of PLB1004 in patients with locally advanced/metastatic non-squamous NSCLCharboring 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:

1. Ability to understand and willingness to sign a written informed consent document.

2. Aged at least 18 years old.

3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC (stage IIIB~IV).

4. 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).

5. At least one measurable lesion as defined by RECISTV1.1（Brain lesions were not included in measurable target lesions）

6. ECOG performance status 0 to 1.

7. Life expectancy is not less than 12 weeks.

8. 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:

1. 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.

2. 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.

3. 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

4. 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

5. 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

6. 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;

7. Mean corrected QT intervals (QTcF) of three electrocardiograms during screening, calculated according to Fridericia's formula at rest, were >470 ms;

8. Presence of uncontrolled hypertension (treated systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg)

9. 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);

10. Allergy or intolerance to the drug class and excipient components of the study drug

11. pregnant or nursing women.

12. Received live vaccine within 4 weeks before randomization;

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