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

Официальное название

A Phase II Clinical Trial of Iparomlimab and Tuvonralimab in Combination With Bevacizumab and Platinum-based Chemotherapy in Previously Untreated Patients With Extensive-stage Small Cell Lung Cancer.

Обзор

This single-arm, open-label, Phase II study assesses first-line QL1706 + bevacizumab (anti-VEGF) + platinum/etoposide chemotherapy to treat naïve ES-SCLC patients.The main questions it aims to answer are: Evaluate efficacy and safety of this quadruplet regimen in ES-SCLC Explore correlations between tumor biomarkers and treatment efficacy Participants will: 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

Подробное описание

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.

Вмешательства

• Препарат QL1706 , bevacizumab, etoposide , cisplatin or carboplatin
  Participants will receive QL1706 (5 mg/kg, IV, day 1), bevacizumab (7.5 mg/kg, IV, day 1), etoposide (100 mg/m², IV, days 1-3), plus either cisplatin (75 mg/m² split over days 1-2, IV) or carboplatin (AUC=5, IV, day 1) every 21 days for 4-6 cycles. Dose adjustments may be made based on clinical judgment. Patients who do not experience disease progression or intolerable toxicity will proceed to maintenance therapy with QL1706 (5 mg/kg, IV, day 1) and bevacizumab (7.5 mg/kg, IV, day 1) every 21 da

Первичные конечные точки

• Progression-Free Survival (PFS) [Срок оценки: From enrollment to the end of monitoring at 2 years.]

Вторичные конечные точки (5)

• Overall Survival (OS) [Срок оценки: From enrollment to the end of monitoring at 2 years.]
• Objective Response Rate (ORR) [Срок оценки: From enrollment to the end of monitoring at 2 years.]
• Duration of Response (DoR) [Срок оценки: From enrollment to the end of monitoring at 2 years.]
• Disease Control Rate (DCR) [Срок оценки: From enrollment to the end of monitoring at 2 years.]
• The incidence of adverse events [Срок оценки: From enrollment to the end of monitoring at 2 years]

Критерии участия

Критерии включения

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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chine — Пекин

Публикации

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• Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, Pietanza MC, Wu YL, Zielinski C, Thomas M, Felip E, Gold K, Horn L, Aerts J, Nakagawa K, Lorigan P, Pieters A, Kong Sanchez T, Fairchild J, Spigel D. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016 Nov 1;34(31):3740-37 PMID 27458307
• Zhao Y, Ma Y, Zang A, Cheng Y, Zhang Y, Wang X, Chen Z, Qu S, He J, Chen C, Jin C, Zhu D, Li Q, Liu X, Su W, Ba Y, Hao Y, Chen J, Zhang G, Qu S, Li Y, Feng W, Yang M, Liu B, Ouyang W, Liang J, Yu Z, Kang X, Xue S, Yang G, Yan W, Yang Y, Liu Z, Peng Y, Fanslow B, Huang X, Zhang L, Zhao H. First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with adv PMID 37158938
• Hong MMY, Maleki Vareki S. Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy. Cancers (Basel). 2022 Mar 20;14(6):1580. doi: 10.3390/cancers14061580. PMID 35326731
• Cheng Y, Chen J, Zhang W, Xie C, Hu Q, Zhou N, Huang C, Wei S, Sun H, Li X, Yu Y, Lai J, Yang H, Fang H, Chen H, Zhang P, Gu K, Wang Q, Shi J, Yi T, Xu X, Ye X, Wang D, Xie C, Liu C, Zheng Y, Lin D, Zhuang W, Lu P, Yu G, Li J, Gu Y, Li B, Wu R, Jiang O, Wang Z, Wu G, Lin H, Zhong D, Xu Y, Shu Y, Wu D, Chen X, Wang J, Wang M, Yang R. Benmelstobart, anlotinib and chemotherapy in extensive-stage smal PMID 38992123
• Lamberti G, Rihawi K, Mazzoni F, Riccardi F, Follador A, Tiseo M, Frassoldati A, Colantonio I, Bonetti A, Genova C, Giardina D, Bertolini F, Cinieri S, Pasello G, Brighenti M, Andrini E, Tognetto M, Boni L, Ardizzoni A; GOIRC group. Carboplatin, etoposide, atezolizumab, and bevacizumab in the first-line treatment of patients with extensive stage small-cell lung cancer: the GOIRC-01-2019 CeLEBrATE PMID 40341031
• Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, Huang JE, Karlin DA, Faoro L, Scappaticci FA, Socinski MA. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1;29(16):2215-22. doi: 10.1200/JCO.2010.29.3423. Epub 2011 Apr 18. PMID 21502556
• Xie M, Vuko M, Rodriguez-Canales J, Zimmermann J, Schick M, O'Brien C, Paz-Ares L, Goldman JW, Garassino MC, Gay CM, Heymach JV, Jiang H, Barrett JC, Stewart RA, Lai Z, Byers LA, Rudin CM, Shrestha Y. Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study. Mol Cancer. 2024 May 30;23(1):115. doi: 10.1186 PMID 38811992

Идентификаторы

NCT: NCT07083375 · NCC5301

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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