Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR–Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer

Journal of Clinical Oncology, Год журнала: 2024, Номер 42(34), С. 4029 - 4039

Опубликована: Авг. 22, 2024

PURPOSE Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for -mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab TKI-resistant, nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837 ). METHODS Adults pathologically confirmed stage IV NSCLC, documented DEL19 L858R mutation, progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles 200 mg placebo once every 3 weeks plus four carboplatin cisplatin then maintenance pemetrexed. Dual primary end points progression-free survival (PFS) overall (OS). Final PFS testing was completed at second interim analysis (IA2; data cutoff, December 3, 2021); OS tested final (FA; January 17, 2023). Efficacy boundaries one-sided P = .0117 OS. RESULTS Four hundred ninety-two (n 245) 247). At IA2, median 5.6 months versus 5.5 (hazard ratio [HR], 0.80 [95% CI, 0.65 0.97]; .0122). FA, 15.9 14.7 months, respectively (HR, 0.84 0.69 1.02]; .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% recipients 38.6% recipients. CONCLUSION Addition did not significantly prolong KEYNOTE-789.

Язык: Английский

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Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(6), С. e009165 - e009165

Опубликована: Июнь 1, 2024

The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding functional dynamics resistance mechanisms TKIs is essential for advancing treatment NSCLC.

Язык: Английский

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Exosomal Proteomics: Unveiling Novel Insights into Lung Cancer

Aging and Disease, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Although significant progress has been made in early lung cancer screening over the past decade, it remains one of most prevalent and deadliest forms worldwide. Exosomal proteomics emerged as a transformative field research, with potential to redefine diagnostics, prognostic assessments, therapeutic strategies through lens precision medicine. This review discusses recent advances exosome-related proteomic glycoproteomic technologies, highlighting their revolutionise treatment by addressing issues heterogeneity, integrating multiomics data, utilising advanced analytical methods. While these technologies show promise, there are obstacles overcome before they can be widely implemented, such need for standardization, gaps clinical application, importance dynamic monitoring. Future directions should aim challenges fully utilize exosomal cancer. promises new era personalized medicine that leverages molecular complexity exosomes groundbreaking advancements detection, prognosis, treatment.

Язык: Английский

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Recent advances to address challenges in extracellular vesicle-based applications for lung cancer

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(9), С. 3855 - 3875

Опубликована: Июнь 20, 2024

Lung cancer, highly prevalent and the leading cause of cancer-related death globally, persists as a significant challenge due to lack definitive tumor markers for early diagnosis personalized therapeutic interventions. Recently, extracellular vesicles (EVs), functioning natural carriers intercellular communication, have received increasing attention their ability traverse biological barriers deliver diverse cargoes, including cytosolic proteins, cell surface microRNA, lncRNA, circRNA, DNA, lipids. EVs are increasingly recognized valuable resource non-invasive liquid biopsy, well drug delivery platforms, anticancer vaccines precision medicine in lung cancer. Herein, given diagnostic potential tumor-associated we discuss this topic from translational standpoint. We delve into specific roles that play cancer carcinogenesis offer particular perspective on how advanced engineering technologies can overcome current challenges expedite and/or enhance translation laboratory research clinical settings.

Язык: Английский

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Remodeling of tumor microenvironments by EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

iScience, Год журнала: 2025, Номер 28(2), С. 111736 - 111736

Опубликована: Янв. 2, 2025

Patients with EGFR mutations exhibit immunosuppressive microenvironments, limiting responsiveness to immunotherapy. We used digital spatial profiling analyze non-small cell lung carcinomas in 25 patients before and after tyrosine kinase inhibitor (TKI) treatment, including 14 treated first-line osimertinib, focusing on CD45-positive immune regions pan-cytokeratin-positive tumor regions. Osimertinib treatment resulted altered angiogenic pathways proportions, reduced plasma cells (22.2%-11.7%; p = 0.025) increased macrophage infiltration (p 0.145). The most predominant subtypes was the interferon-γ (IFN-γ)-dominant C2 subtype lymphocyte-depleted C4 subtype. Two who showed opposite pattern, transiting from C2, had durable responses subsequent atezolizumab/bevacizumab/carboplatin/paclitaxel treatment. Our results shed light immunomodulatory effects of osimertinib suggest that co-targeting angiogenesis anti-programmed death (ligand) 1 might be effective EGFR-TKI-resistant cancer.

Язык: Английский

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Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges

Biomedicines, Год журнала: 2025, Номер 13(2), С. 470 - 470

Опубликована: Фев. 14, 2025

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is complex system composed cells, immune and non-immune non-cellular components. Evidence indicates that dynamic changes TME during TKI are associated with development resistance. Research has focused on identifying how each component interacts tumors TKIs to understand therapeutic targets could address In this review, we describe components, such as fibroblasts, blood vessels, checkpoint proteins, cytokines, interact EGFR-mutant they can promote TKIs. Furthermore, discuss potential strategies targeting novel approach.

Язык: Английский

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EGFR-Mutant Lung Adenocarcinoma Cell-Derived Exosomal miR-651-5p Induces CD8+ T Cell Apoptosis via Downregulating BCL2 Expression

Biomedicines, Год журнала: 2025, Номер 13(2), С. 482 - 482

Опубликована: Фев. 15, 2025

Background: The efficacy of programmed cell death 1 (PD-1) or ligand (PD-L1) inhibitors in epidermal growth factor receptor (EGFR)-mutant non-small lung cancer (NSCLC) patients is not satisfactory. Studies have indicated that the ratio CD8+ tumor infiltration lymphocytes (TILs) was associated with immunotherapy efficacy; however, it significantly lower EGFR-mutant than wild type patients. underlying mechanisms need to be studied. Methods: Database analysis, clinical specimens, small RNA sequencing, and single-cell sequencing were used analyze miRNA expression immune infiltration. Cell co-culture flow cytometry conducted detect apoptosis. mouse model performed influence miR-651-5p antagomirs on microenvironment. Results: found highly expressed adenocarcinoma cell-derived exosomes, which could promote T apoptosis, while inhibitor decreased PC9-secreted exosomes induced Mechanistically, EGFR signaling pathway promoted by activating transcription Fos proto-oncogene (FOS) lines. B-cell lymphoma 2 (BCL2) target miR-651-5p, apoptosis inhibiting BCL2 expression. In addition, antagomir increased enhanced PD-1 treating humanized model. Conclusions: promotes through exosomal miR-651-5p. antagonists increase enhance anti-tumor effect inhibitor, suggesting a new combination therapy improve NSCLC

Язык: Английский

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Functional tumor-derived exosomes in NSCLC progression and clinical implications

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 19, 2025

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases and remains one the leading causes cancer-related mortality worldwide. The high rate is primarily driven by delayed diagnosis, rapid metastasis, frequent recurrence. Tumor-derived exosomes (TEXs) have emerged as critical mediators in NSCLC progression, offering valuable insights into tumor microenvironment. Exosomes are small membrane vesicles that facilitate intercellular communication transport bioactive molecules, including proteins, RNAs, DNAs, thereby reflecting genetic complexity tumors. These play a key role promoting epithelial-mesenchymal transition (EMT), neovascularization, drug resistance, immune evasion, which pivotal development NSCLC. This review explores diverse roles TEXs focusing on their involvement pre-metastatic niche formation, tissue modulation. Specifically, we discuss exosome-associated RNAs proteins NSCLC, contribute to growth metastasis. Furthermore, explore potential biomarkers emphasizing application prognosis, prediction resistance targeted therapies immunotherapies.

Язык: Английский

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Identification and validation of a lenvatinib resistance-related prognostic signature in HCC, in which PFKFB4 contributes to tumor progression and lenvatinib resistance

BMC Gastroenterology, Год журнала: 2025, Номер 25(1)

Опубликована: Апрель 23, 2025

Язык: Английский

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Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Сен. 2, 2024

Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in progression. The review begins detailed exposition on origins TAMs their functional heterogeneity, providing foundational understanding TAM characteristics. Next, it delves into specific molecular mechanisms through which induce EMT, including cytokines, chemokines stromal cross-talking. Following this, explores TAM-induced features select types notable characteristics, highlighting recent insights impact Finally, concludes discussion potential therapeutic targets strategies aimed at mitigating infiltration disrupting signaling network, thereby underscoring emerging treatments combat TAM-mediated cancer. This comprehensive analysis reaffirms necessity for continued exploration TAMs’ regulatory roles within biology refine approaches improve patient outcomes.

Язык: Английский

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