Surufatinib Combined With Toripalimab and Chemotherapy in the Treatment of Non-Small Cell Lung Cancer

A Open-label, Single Center, Phase II Study of Surufatinib Combined With Toripalimab and Chemotherapy in Patients With Advanced Non-squamous Non-small-cell Lung Cancer

A phase II study to assess the efficacy and safety of Surufatinib Combined With Toripalimab and Chemotherapy in patients with advanced non-squamous non-small cell lung cancer.

Inclusion Criteria:

1. Fully informed about the study and voluntary signing of the informed consent form;

2. Age ≥18 years, male or female;

3. Patients with histologically or cytologically confirmed unresectable or intolerant to definitive chemoradiotherapy stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC);

4. ECOG PS score of 0-1;

5. Expected survival ≥12 weeks;

6. Patients must have at least one measurable lesion (according to RECIST 1.1);

7. Prior to enrollment, patients are required to undergo testing of detectable specimens to confirm a pan-driver gene (including but not limited to EGFR mutation, ALK fusion, ROS1 and RET fusion; BRAF mutation, ERBB2 [also known as HER2] amplification/mutation, MET amplification, MET exon 14 skipping mutation, as well as NTRK fusion and related mutations) wild-type status. Additionally, these patients must not have received any prior systemic therapy regarding advanced non-small cell lung cancer (NSCLC). Patients with KRAS mutations are eligible for inclusion (assigned to Cohort 1).

8. Prior to enrollment, the patient must be confirmed to carry one of the following driver gene mutations, including but not limited to: EGFR mutation, ALK fusion, ROS1 and RET fusion; BRAF mutation, ERBB2 (HER2) amplification/mutation, MET amplification, MET exon 14 skipping mutation, and NTRK fusion. Patients with KRAS mutations are not permitted (assigned to Cohort 2). EGFR mutation cases are not expected to exceed 50% of all enrolled patients in Cohort 2.

9. Patients with driver gene mutations in Cohort 2 are required to have received adequate tyrosine kinase inhibitor (TKI) therapy, as follows:

   • EGFR mutant patients: 1) Patients who have received first-or second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as first-line therapy and do not exhibit T790M mutation resistance; 2) Patients with T790M mutations are required to receive third-generation EGFR-TKIs; 3) Patients who have progressed after third-generation EGFR-TKIs therapy.
   • ALK fusion-positive patients: Progression or intolerance on first-line therapy for ALK fusion-positive NSCLC;
   • For ROS1 fusion-positive patients: Progression or intolerance on first-line therapy for ROS1 fusion-positive NSCLC;
   • Patients with other driver gene mutations currently lacking standard first-line treatment are not forced to receive prior systematic treatment;
   • Patients with a history of bevacizumab use and/or multi-target small molecule anti-tumor angiogenesis tyrosine kinase inhibitors are permitted in cohort 2;

10. Patients with normal organ function prior to enrollment, meeting the following criteria:

1) Hematology testing:

a)Hemoglobin (HB) ≥90 g/L; b)Absolute neutrophil count (ANC) ≥1.5×109/L; c)Platelet count (PLT) ≥80×109/L. 2) Biochemical test results meeting the following criteria:

1. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times of the ULN; in cases of hepatic metastasis, ALT and AST ≤5 times of the ULN.

3. Serum creatinine (Cr) ≤1.5 times of ULN or Creatinine clearance rate (CCr) ≥60 mL/min.

   3) Left ventricular ejection fraction (LVEF) ≥ 50%; 4) Urinalysis showing urine protein <3+ or 24-hour urine protein quantification <3.0g.

   11. Male or female patients of reproductive potential voluntarily agree to use effective contraception during the study and for 6 months after the last administration, such as dual barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female patients shall be considered to have reproductive potential unless they have undergone natural or surgical sterilization (e.g., hysterectomy, bilateral adnexectomy, or radiation therapy, etc.).

   Exclusion Criteria:

   1. Patients having received immunotherapy for tumors (such as PD-1, PD-L1) prior to enrollment, excluding those who received definitive systemic treatment for recurrent or metastatic disease within 6 months after completion of curative therapy.
   2. History of severe hypersensitivity reactions to other monoclonal antibody administration.
   3. Patients with small cell lung cancer, including mixture of small cell and non-small cell lung cancer.
   4. Central-type, cavitary pulmonary squamous cell carcinoma, or non-small cell lung cancer with hemoptysis (>50 mL/day).
   5. Presence of symptomatic or clinically significant thyroid dysfunction during screening (hypothyroidism that can be controlled by thyroid hormone replacement therapy is eligible).
   6. Diagnosed with immunodeficiency, or currently receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy (dose >10 mg/day prednisone or other equivalent potency), and still on treatment within 2 weeks prior to first dose.
   7. Active autoimmune disease requiring systemic therapy (such as disease-modifying medications, corticosteroids, or immunosuppressants) within 2 years prior to enrollment, including but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; subjects requiring medical intervention with bronchodilators for asthma are excluded. Replacement therapies (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments;
   8. Receipt of prophylactic vaccines or live attenuated vaccines within 4 weeks prior to enrollment;
   9. Receipt of any approved or investigational systemic anti-tumor therapy (including chemotherapy, definitive radiotherapy, biological/immunotherapy, targeted therapy, etc.) within 5 elimination half-lives (if 5 half-lives exceed 21 days, then within 21 days) prior to enrollment;
   10. Participation in other clinical trials of drugs not yet approved or marketed in China, and receipt of investigational drug treatment within 5 elimination half-lives (if 5 half-lives exceed 21 days, then within 21 days) prior to enrollment.
   11. Receipt of major surgery or presence of unhealed wounds, ulcers, or fractures within 4 weeks prior to enrollment.
   12. Uncontrollable malignant ascites (uncontrollable by diuretics or paracentesis, as judged by the investigator).
   13. International Normalized Ratio (INR) >1.5 or Activated Partial Thromboplastin Time (APTT) >1.5×ULN.
   14. Patients with hypertension that is uncontrolled by medication, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg (except for those whose blood pressure can be controlled by dual antihypertensive medications prior to enrollment).
   15. Patients unable to take surufatinib orally;
   16. Current gastrointestinal diseases such as active gastric or duodenal ulcer, ulcerative colitis, or active lesions of unresected tumors, or other investigator-judged conditions that may cause gastrointestinal bleeding or perforation;
   17. Patients with evidence or history of significant hemorrhagic tendency within 3 months prior to enrollment (>30 mL within 3 months, occurrence of hematemesis, melena, or hematochezia), hemoptysis (>5 mL of fresh blood within 4 weeks), or thromboembolic events within 12 months (including stroke and/or transient ischemic attack).
   18. Patients with grade ≥1 myocardial ischemia, myocardial infarction, or severe arrhythmias (including QTc ≥450 ms in males, QTc ≥470 ms in females), and grade ≥1 heart failure (New York Heart Association classification).
   19. Past or concurrent untreated malignancies other than the current disease within 5 years.
   20. Active or uncontrolled severe infection (≥Grade 2 infection according to CTCAE v5.0 [Common Terminology Criteria for Adverse Events, version 5.0]).
   21. Known human immunodeficiency virus (HIV) infection; known clinically significant liver disease history, including viral hepatitis [known hepatitis B virus (HBV) carriers must be excluded if active HBV infection exists, that is, HBV DNA positive (>1×104copies/mL or >2000 IU/mL); known hepatitis C virus (HCV) infection and HCV RNA positive (>1×103 copies/mL), or other hepatitis or cirrhosis] (excluding patients who have normalized related test results after prior antiviral therapy).
   22. Presence of unstable or symptomatic brain metastases.
   23. Unresolved toxicity higher than Grade 1 per CTCAE v5.0 caused by any prior anticancer therapy, excluding alopecia and ≤Grade 2 neurotoxicity caused by oxaliplatin.
   24. Pregnancy (positive pre-treatment pregnancy test) or currently lactating female subjects.
   25. Receipt of brachytherapy (implantation of radioactive seeds) within 60 days prior to enrollment.
   26. Any other disease, clinically significant metabolic abnormalities, abnormal physical examination, or laboratory abnormalities, which, in the judgment of the investigator, may indicate an unfit condition for investigational drug use (e.g., active epilepsy requiring treatment), may affect the interpretation of study results, or place the patient at high risk.