This is a Two-cohort, Exploratory Clinical Study Assessing the Activity of Benmelstobart Combined With Chemotherapy With or Without Anlotinib in Resectable Limited-Stage Small Cell Lung Cancer

Perioperative Treatment With Benmelstobart Combined With Chemotherapy With or Without Anlotinib in Resectable Limited-Stage Small Cell Lung Cancer: A Randomized, Two-Cohort, Multicenter, Phase II Clinical Study

A total of 66 patients were enrolled in this exploratory study and randomly assigned to cohort 1 and cohort 2, with 33 patients in each group. Cohort 1: Neoadjuvant therapy (benmelstobart combined with chemotherapy and anlotinib, 3 cycles, every 21 days is a cycle). Surgery was performed 4-6 weeks after the final administration of benmelstobart as assessed by the investigator. Adjuvant therapy was evaluated by the investigator 4-6 weeks after surgery. Patients who achieved R0 resection received adjuvant therapy (benmelstobart combined with anlotinib, 12 cycles, every 21 days is a cycle). Cohort 2: Neoadjuvant therapy (benmelstobart combined with chemotherapy, 3 cycles, every 21 days is a cycle). Surgery was performed 4-6 weeks after the final administration of benmelstobart as assessed by the investigator. Adjuvant therapy was evaluated by the investigator 4-6 weeks after surgery. Patients who achieved R0 resection received adjuvant therapy (benmelstobart, every 21 days is a cycle) .

Inclusion Criteria:

• Patients voluntarily participate in this study, sign the informed consent form, demonstrate good compliance, and cooperate with follow-up.
• Aged 18 to 75 years (inclusive) at the time of signing informed consent, regardless of gender.
• Histologically confirmed small cell lung cancer (SCLC).
• Confirmed as stage I-IIIB SCLC (T1-3N0-2M0) per AJCC 9th Edition.
• Patients who have received 1 cycle of chemotherapy are eligible; no other prior treatments are permitted.
• ECOG Performance Status (PS) 0 or 1.
• Assessed by the investigator as having no surgical contraindications.
• At least one measurable lesion per RECIST 1.1 criteria.
• Expected survival ≥8 weeks.
• Women of childbearing potential (aged 15-49) must have a negative serum pregnancy test within 7 days before treatment initiation and agree to use reliable contraception during the study until 8 weeks after discontinuation. Normal function of major organs meeting the following criteria:
• Hematologic tests (no blood transfusion, blood products, G-CSF, or hematopoietic stimulants within 14 days): Hemoglobin (Hb) ≥90 g/L; Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelets (PLT) ≥80×10⁹/L.
• Biochemical tests meeting: Total bilirubin (TBIL) ≤1.5×ULN; ALT/AST ≤2.5×ULN; Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (CCr) ≥60 mL/min.
• Urine protein <2+; for patients not on anticoagulation: INR ≤1.5, APTT ≤1.5×ULN. Patients on full-dose or parenteral anticoagulants may enroll if dosing has been stable for ≥2 weeks and coagulation tests are within therapeutic ranges.

Exclusion Criteria:

• Histologically confirmed mixed-type SCLC.

• Extensive-stage SCLC.

• ECOG PS >1.

• Active or untreated CNS metastases confirmed by CT/MRI during screening/prior imaging.

• Uncontrolled tumor-related pain.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage (≥1×/month).

• Uncontrolled/symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL, or corrected serum calcium >ULN).

• Systemic immunostimulants (e.g., IFN-α, IL-2, TNF) within 4 weeks prior to enrollment (cancer vaccines allowed if prior).

• Systemic corticosteroids (>10 mg prednisone/day or equivalent) or immunosuppressants within 14 days, except: Replacement therapy (≤10 mg prednisone/day); Topical/ocular/intra-articular/nasal/inhaled steroids with minimal systemic absorption; Short-term (≤7 days) prophylactic use (e.g., contrast allergy) or for non-autoimmune conditions.

• Imaging-confirmed tumor invasion of major vessels or high risk of fatal hemorrhage per investigator; or cavitary/necrotic lung tumors.

• Other malignancies within 5 years except: cervical CIS, cured basal cell carcinoma, Ta/Tis bladder tumors.

• Prior use of anlotinib or other antiangiogenic agents.

• Prior anti-PD-1/PD-L1/CTLA-4 antibodies or other T-cell co-stimulation/checkpoint pathway therapies (e.g., ICOS, CD40/CD137/GITR/OX40 agonists).

• Hypersensitivity to anlotinib or benmelstobart components.

• Factors impairing oral drug intake (e.g., dysphagia, chronic diarrhea, intestinal obstruction).

• Uncontrolled comorbidities including:

  1. Poorly controlled hypertension (SBP ≥150 mmHg, DBP ≥100 mmHg);
  2. Grade ≥1 myocardial ischemia/infarction, arrhythmias (QTc ≥480 ms), or ≥NYHA Class II heart failure;
  3. Abnormal coagulation (INR >1.5, PT >ULN+4s, APTT >1.5×ULN), bleeding tendency, or thrombolytic/anticoagulant therapy (prophylactic low-dose heparin [6,000-12,000 U/day] or aspirin [≤100 mg/day] allowed if INR ≤1.5);
  4. Active/severe uncontrolled infections;
  5. Cirrhosis, decompensated liver disease, active/chronic hepatitis requiring antivirals;
  6. Renal failure requiring dialysis;
  7. Immunodeficiency (HIV+, congenital/acquired immunodeficiency) or organ transplant history;
  8. Poorly controlled diabetes (FBG >10 mmol/L);
  9. Urine protein ≥++ or 24-h urine protein >1.0 g;
  10. Epilepsy requiring treatment;
  11. Non-healing wounds/fractures.

• Significant hemoptysis (>50 mL/day within 2 weeks) or clinically significant bleeding (e.g., GI bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ≥++).

• Interstitial lung disease (ILD), drug-induced ILD, steroid-requiring radiation pneumonitis, or active ILD.

• Arterial/venous thromboembolism within 6 months (e.g., stroke [including TIA], DVT, PE).

• Grade ≥2 peripheral neuropathy (excluding trauma-related).

• Major surgery/severe trauma with residual effects within 14 days.

• Concurrent clinical trials or <4 weeks from prior trial treatment.

• Live/attenuated vaccination within 30 days before benmelstobart or planned during study.

• History of severe hypersensitivity to monoclonal antibodies.

• Pregnant/lactating women.

• Uncontrolled psychiatric/neurological disorders affecting compliance.

• Other factors per investigator judgment that may lead to study termination (e.g., severe illness, lab abnormalities, or social/family constraints compromising safety/data collection).