Mechanism of Enhanced Efficacy of Ivonescimab in Neoadjuvant Therapy for Non-Small Cell Lung Cancer

Официальное название

Mechanisms of Enhanced Efficacy of Ivonescimab in Neoadjuvant Therapy for Non-Small Cell Lung Cancer

Обзор

This is an exploratory clinical study focusing on the neoadjuvant treatment of non-small cell lung cancer (NSCLC). The study primarily aims to compare the efficacy and safety of Ivonescimab, a novel PD-1/VEGF bispecific antibody, with those of conventional PD-1 inhibitors. Beyond evaluating its direct therapeutic benefits, this research also seeks to elucidate the potential mechanisms underlying the enhanced efficacy of Ivonescimab. Additionally, the study will conduct secondary exploratory analyses, including the identification and validation of predictive and prognostic biomarkers, as well as multi-omics profiling to investigate the molecular mechanisms of action. Collectively, these efforts aim to provide comprehensive experimental data to support the rational clinical application of Ivonescimab and the development of precision medicine strategies for NSCLC.

Подробное описание

Lung cancer is one of the leading causes of cancer-related deaths in China and worldwide, imposing a significant societal burden. Although comprehensive treatment strategies centered around surgery have improved patient prognosis, and perioperative immunotherapy has profoundly reshaped the therapeutic landscape, this field still faces substantial knowledge gaps and key challenges.

This study focuses on Ivonescimab, a first-in-class PD-1/VEGF bispecific antibody. Ivonescimab simultaneously blocks PD-1 to reactivate antitumor immune response by releasing T-cell inhibition and inhibits VEGF to suppress tumor angiogenesis while modulating the immunosuppressive tumor microenvironment. The primary objectives of this research are to evaluate the efficacy and safety of Ivonescimab compared with conventional immunotherapy and to investigate its potential mechanisms of action, thereby providing scientific evidence to support its clinical application.The secondary objectives are to identify and validate potential predictive and prognostic biomarkers associated with the clinical efficacy and safety of Ivonescimab, and to perform multi-omics analyses (including genomics, transcriptomics, proteomics, and metabolomics) to explore the underlying molecular mechanisms of Ivonescimab in regulating antitumor immune response, remodeling tumor angiogenesis, and modulating the tumor microenvironment, so as to lay a theoretical foundation for the precise application of Ivonescimab and the development of combined therapeutic strategies.

Вмешательства

• Препарат Ivonescimab
  Patients in the experimental group will receive ivonescimab as neoadjuvant therapy.
• Препарат PD-1 Inhibitors
  Patients in the positive control group will receive PD-1 inhibitors monotherapy as neoadjuvant treatment.

Первичные конечные точки

• Pathological Complete Response (pCR [Срок оценки: At surgery (typically 3-6 months post-treatment initiation)]

Вторичные конечные точки (6)

• Major Pathological Response (MPR) [Срок оценки: At surgery (typically 3-6 months post-treatment initiation)]
• Objective Response Rate (ORR) [Срок оценки: After two cycles or four cycles of neoadjuvant therapy (each cycle is 21 days).]
• Event-free Survival (EFS) [Срок оценки: Through study completion, an average of 2 years.]
• Overall Survival (OS) [Срок оценки: Through study completion, an average of 2 years.]
• MRD (minimal residual disease) dynamics after neoadjuvant immunotherapy [Срок оценки: Periprocedural and every three to six months post-treatment (up to three years).]
• Immune-Related Adverse Event (irAE) Incidence [Срок оценки: Periprocedural and up to 6 months post-treatment.]

Критерии участия

Критерии включения

Patients with non-small cell lung cancer (Stage IB-IIIB) who require radical surgery following neoadjuvant therapy.

Критерии исключения

• Histology of other malignant tumors, including concurrent malignant tumors of other organ systems;
• Unresectable advanced disease (Stage IV) or locally advanced unresectable (Stage IIIC);
• Pregnancy or lactation;
• Insufficient sample quality;
• Severe organ dysfunction (e.g. cardiac or renal insufficiency);
• Other judgments by the Investigator that the patient should not participate in the study.

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

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

Китай · 1 центр

• Peking University People's Hospital — Пекин

Публикации

• Wang L, Luo Y, Ren S, Zhang Z, Xiong A, Su C, Zhou J, Yu X, Hu Y, Zhang X, Dong X, Meng S, Wu F, Hou X, Dai Y, Song W, Li B, Wang ZM, Xia Y, Zhou C. A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. J Thorac Oncol. 2024 Mar;19(3):465-47 PMID 37879536
• Frentzas S, Austria Mislang AR, Lemech C, Nagrial A, Underhill C, Wang W, Wang ZM, Li B, Xia Y, Coward JIG. Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer. 2024 Apr 19;12(4):e008037. doi: 10.1136/jitc-2023-008037. PMID 38642937
• Zhao S, Zhao H, Yang W, Zhang L. The next generation of immunotherapies for lung cancers. Nat Rev Clin Oncol. 2025 Aug;22(8):592-616. doi: 10.1038/s41571-025-01035-9. Epub 2025 Jun 17. PMID 40528044
• Chen Z, Yang F, Jiang Z, Sun L, Wu L, Han Z, Fan Y, Zhao Y, Li X, Xu H, Meng X, Liu Y, Zhang Z, Luo H, Ma X, Ma X, Shi Q, Zhang Z, Yang R, Wang P, Pan P, Ai X, Li J, Pu X, Wang Z, Fang J, He M, He Y, Guo S, Li J, Wang H, Zhang J, Chu Q, Liu X, Ying S, Wu H, Sun H, Ji Y, Zhou M, Cao C, Tang K, Li Z, Li D, Zhang Z, Li J, Zhou J, Yang H, Du Y, Yang H, Shi J, Chen H, Li W, Lu D, Hu M, Maxwell Wang Z, PMID 41125109
• Xiong A, Wang L, Chen J, Wu L, Liu B, Yao J, Zhong H, Li J, Cheng Y, Sun Y, Ge H, Yao J, Shi Q, Zhou M, Chen B, Han Z, Wang J, Bu Q, Zhao Y, Chen J, Nie L, Li G, Li X, Yu X, Ji Y, Sun D, Ai X, Chu Q, Lin Y, Hao J, Huang D, Zhou C, Shan J, Yang H, Liu X, Wang J, Shang Y, Mei X, Yang J, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhou C. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung PMID 40057343

Идентификаторы

NCT: NCT07359040 · BRWEP2024W034080205

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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