A Phase II Study of Benmelstobart + Anlotinib + Chemotherapy as First-Line Treatment for LCNEC and EP-NEC

A Single-Center, Single-Arm, Phase II Study of Benmelstobart Combined With Anlotinib and Chemotherapy as First-Line Treatment for Large-Cell Neuroendocrine Carcinoma of the Lung and Extrapulmonary Neuroendocrine Carcinoma

To explore the Objective Response Rate (ORR) of Benmelstobart combined with Anlotinib and chemotherapy as first-line treatment for large-cell neuroendocrine carcinoma of the lung (LCNEC) and extrapulmonary neuroendocrine carcinoma (EP-NEC)

This study is a single-center, single-arm, phase II study designed to observe and evaluate Benmelstobart combined with Anlotinib and chemotherapy as first-line treatment for large-cell neuroendocrine carcinoma (LCNEC) of the lung and extrapulmonary neuroendocrine carcinoma (EP-NEC).

Enrolled patients are those with histologically or pathologically confirmed metastatic LCNEC or EP-NEC (AJCC 9th edition) who have not received systemic treatment. Eligible subjects will receive 4 cycles of Benmelstobart combined with Anlotinib and chemotherapy, followed by maintenance treatment with Benmelstobart combined with Anlotinib, with continuous medication until disease progression or intolerable toxicity. The purpose of this study is to evaluate the efficacy and safety of Benmelstobart Injection combined with Anlotinib Hydrochloride and chemotherapy as first-line treatment for advanced LCNEC and EP-NEC.

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic LCNEC or EP-NEC (per AJCC 9th Edition);

2. No prior systemic treatment for locally advanced or metastatic LCNEC or EP-NEC; For patients who have received adjuvant chemo/radiotherapy, neoadjuvant chemo/radiotherapy for non-metastatic disease with curative intent, or definitive chemoradiotherapy for locally advanced disease, the interval from the end of chemotherapy, radiotherapy, or chemoradiotherapy to the diagnosis of metastatic NEC must be at least 6 months (calculated from the end date of the last chemotherapy cycle or the end date of the last radiotherapy);

3. At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1; Lesions that have received prior radiotherapy can be considered measurable only if there is clear progression after radiotherapy and they are not the only lesion;

4. Aged 18-75 years;

5. ECOG Performance Status 0-1;

6. Life expectancy ≥3 months;

7. Sufficient hematological and organ function, meeting the following criteria:

   1. Hematology (no blood transfusion or blood products within 14 days, no correction with G-CSF or other hematopoietic stimulants): Absolute Neutrophil Count (ANC) ≥1.5×10⁹/L; Platelet Count (PLT) ≥100×10⁹/L; White Blood Cell (WBC) Count ≥3×10⁹/L;

   2. Biochemical tests:

      Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤2.5×Upper Limit of Normal (ULN), or ≤5×ULN in patients with liver metastasis; Total Bilirubin (TBIL) ≤1.5×ULN, or ≤3×ULN in patients with Gilbert's syndrome; Creatinine (Cr) ≤1.5×ULN or Creatinine Clearance (CCr) ≥50mL/min;

   3. Coagulation function:

      Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR), or Prothrombin Time (PT) ≤1.5×ULN;

   4. Doppler ultrasound assessment:

   Left Ventricular Ejection Fraction (LVEF) ≥50%;

8. Women and men of childbearing potential must agree to use contraceptive measures (e.g., intrauterine device [IUD], contraceptive pills, or condoms) during the study treatment period and within 6 months after the last dose of study medication; Women must have a negative serum pregnancy test within 7 days before study randomization and must not be breastfeeding;

9. Subjects voluntarily participate in this study, sign the informed consent form, have good compliance, and cooperate with follow-up.

Exclusion Criteria:

1. Patients with brain metastasis and/or carcinomatous meningitis (excluding asymptomatic patients or patients with stable condition who have no imaging evidence of new/enlarged central nervous system metastasis for at least 2 weeks after brain metastasis treatment and have discontinued steroids or anticonvulsants for at least 14 days before the study; If active or new untreated asymptomatic central nervous system metastasis is detected during the screening phase, subjects must receive radiotherapy, or have no imaging evidence of new/enlarged brain metastasis for at least 2 weeks without treatment);

2. Prior use of anti-angiogenic drugs such as Anlotinib, Apatinib, Bevacizumab, or immunotherapeutic drugs targeting PD-1, PD-L1, etc.;

3. History of other malignant tumors within 5 years (except cured carcinoma in situ of the cervix or basal cell carcinoma of the skin);

4. Factors affecting oral drug administration (dysphagia, post-gastrointestinal resection, chronic diarrhea, intestinal obstruction, etc.);

5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;

6. Spinal cord compression not cured or relieved by surgery and/or radiotherapy, or no clinical evidence of stable condition for ≥1 week after treatment of previously diagnosed spinal cord compression before randomization;

7. Imaging (Computed Tomography [CT]/Magnetic Resonance Imaging [MRI]) showing tumor invasion of large blood vessels or unclear boundary with large blood vessels;

8. Patients with imaging evidence of tumor invasion around major blood vessels, or judged by the investigator to have a high risk of tumor invading major blood vessels leading to fatal massive hemorrhage during the subsequent study period;

9. History of severe bleeding tendency or coagulation dysfunction, including but not limited to: clinically significant hemoptysis (hemoptysis >1 tablespoon per day) within 3 months before enrollment; or bleeding symptoms or bleeding tendency of significant clinical significance within 4 weeks before randomization, such as gastrointestinal bleeding, hemorrhagic gastric ulcer (including gastrointestinal perforation and/or fistula, except for patients with gastrointestinal perforation or fistula who have undergone surgical resection and are eligible for enrollment), unhealed wounds, ulcers, or fractures;

10. Unresolved treatment-related toxicity (>Grade 1) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (except alopecia);

11. Major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days before randomization;

12. Arterial/venous thromboembolic events (such as cerebrovascular accident [including transient ischemic attack], deep vein thrombosis, and pulmonary embolism) within 6 months before randomization;

13. Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years before the first dose;

14. Vaccination with prophylactic or attenuated vaccines within 28 days before the first dose;

15. Severe allergic reaction to other monoclonal antibodies;

16. History of psychotropic drug abuse that cannot be abstained from, or mental disorders;

17. Any severe and/or uncontrolled disease:

    1. Poorly controlled blood pressure (systolic blood pressure ≥150mmHg or diastolic blood pressure ≥100mmHg);
    2. Grade II or above myocardial ischemia or myocardial infarction, arrhythmia (including corrected QT interval [QTc] ≥450ms in men and QTc ≥470ms in women); congestive heart failure with New York Heart Association (NYHA) Functional Class II-IV;
    3. Active or uncontrolled severe infection (≥Grade 2);
    4. Liver cirrhosis, active hepatitis (hepatitis B: positive hepatitis B surface antigen and hepatitis B virus deoxyribonucleic acid >ULN; hepatitis C: positive hepatitis C antibody and hepatitis C virus titer >ULN);
    5. Human Immunodeficiency Virus (HIV) positive;
    6. Poorly controlled diabetes (fasting blood glucose >10mmol/L);
    7. Urinary protein ≥++, and confirmed 24-hour urinary protein >1.0g;

18. Participation in other clinical trials within 28 days before the study;

19. Other conditions that increase the risk related to study participation or study drugs and are deemed by the investigator to make the patient unsuitable for enrollment.