A Phase II Study of QL1706 With Anti-angiogenesis Therapy and Chemotherapy in Extensive-stage Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a highly aggressive malignancy, accounting for 13-15% of all lung cancers. Approximately two-thirds of patients present with distant metastases at diagnosis, defined as extensive-stage SCLC (ES-SCLC). Prognosis remains poor, with median overall survival (mOS) of 12-15 months despite standard first-line chemotherapy using etoposide plus cisplatin/carboplatin (EP/EC), which offers limited benefit (mOS ~10 months; median progression-free survival [mPFS] ~5 months).

Immune checkpoint inhibitors (ICIs) have improved outcomes modestly. IMpower133, KEYNOTE-604, RATIONALE-312, and EXTENTORCH trials confirmed the benefit of adding PD-1/PD-L1 inhibitors to chemotherapy, but the survival plateau remains. Dual immune checkpoint blockade strategies, including PD-1/PD-L1 with CTLA-4 inhibitors, have not significantly improved outcomes and pose higher toxicity, as seen in CASPIAN and CheckMate451 studies.

Antiangiogenic therapy offers another promising direction. Studies such as SALUTE, ACTION-2, and BEAT-SC have explored bevacizumab or anlotinib combined with chemo-immunotherapy, showing potential survival gains. Notably, the ETER701 study using a four-drug combination achieved mOS of 19.3 months, although with increased adverse events.

QL1706 (Aito combination antibody) is a novel bifunctional antibody targeting PD-1 and CTLA-4 in a 2:1 fixed ratio, designed to optimize synergy while reducing CTLA-4 toxicity. Approved in 2024, it has demonstrated efficacy and tolerability in multiple solid tumors. In NSCLC, QL1706 combined with chemotherapy and antiangiogenic therapy showed mPFS up to 8.5 months and mOS of 26.5 months.

To date, no clinical data exist for QL1706 combined with antiangiogenic therapy and chemotherapy in ES-SCLC. A phase II, open-label, single-arm clinical trial is proposed to evaluate its efficacy and safety as first-line treatment. This study aims to explore a new therapeutic strategy to overcome the current survival limitations in ES-SCLC.

Inclusion criteria

Participants must meet all of the following criteria to be eligible for the study:

• Signed written informed consent and willingness to comply with study procedures.
• Age ≥18 years.
• Estimated life expectancy ≥3 months.
• ECOG performance status of 0 or 1.
• Histologically or cytologically confirmed, treatment-naïve extensive-stage small cell lung cancer (ES-SCLC).
• Willing to provide archived or fresh tumor tissue samples. If unavailable, enrollment may proceed per investigator assessment.
• At least one measurable lesion per RECIST v1.1.
• Fully understands and voluntarily participates in the study.
• Adequate organ function as defined below:

• Absolute neutrophil count ≥1.5 × 10⁹/L
• Platelets ≥100 × 10⁹/L
• Hemoglobin ≥90 g/L (without transfusion in prior 14 days)
• Serum creatinine ≤1× ULN or creatinine clearance >50 mL/min (Cockcroft-Gault)
• AST and ALT ≤2.5× ULN (≤5× ULN with liver metastases)
• Total bilirubin ≤1.5× ULN (except Gilbert's syndrome <51.3 µmol/L)
• TSH, FT3, FT4 within ±10% of normal limits

Exclusion criteria

• Prior chemotherapy, immunotherapy, targeted therapy, or radiotherapy.
• Histologic or cytologic evidence of non-small cell or mixed small cell/non-small cell carcinoma.
• Symptomatic brain metastases or leptomeningeal disease.
• Active or suspected autoimmune disease, except for stable vitiligo, type 1 diabetes, hypothyroidism requiring only hormone replacement, or conditions not expected to recur.
• Evidence or history of active pulmonary tuberculosis (TB), including treated TB within the past year.
• Concomitant condition requiring systemic corticosteroids or other immunosuppressive therapy.
• Pregnant or breastfeeding females.
• Symptomatic interstitial lung disease or suspected drug-related pneumonitis.
• Positive for HIV antibodies, active HBV (HBsAg+ with HBV DNA >10³ copies/mL), or active HCV infection (HCV-Ab+ with detectable RNA).
• History of significant neurological or psychiatric disorders (e.g., dementia, depression, epilepsy, bipolar disorder).
• Participation in another investigational drug study within 4 weeks prior to randomization.
• Use of anti-tumor traditional Chinese medicine within 2 weeks prior to first study dose.
• History of other malignancies within 2 years, except for cured non-melanoma skin cancers or certain in situ carcinomas.
• Clinically significant cardiovascular or cerebrovascular disease (e.g., NYHA class ≥2 heart failure, recent myocardial infarction or stroke within 6 months).
• History of thromboembolic events (e.g., DVT, PE, arterial thrombosis) within 6 months, except catheter-related thrombosis.
• Live vaccination within 28 days before randomization or planned during the study.
• Major surgery or significant trauma within 4 weeks prior to treatment initiation.
• Conditions affecting drug absorption (e.g., severe vomiting, GI obstruction, active GI bleeding or perforation).
• Active, uncontrolled bacterial, viral, or fungal infections despite appropriate treatment.
• Known hypersensitivity to any study drug or excipients.
• Any other condition deemed unsuitable by the investigator due to safety or compliance concerns.