Language：English   Publishing type：Research paper (scientific journal)  

Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit the anti-tumor effects of anti-PD-1 monoclonal antibody (αPD-1 mAb). To investigate whether nintedanib-a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor-suppresses immunosuppressive cells and enhances the anti-tumor effects of αPD-1 mAb in preclinical models, flowcytometry, immunohistochemistry, and RNA sequencing of tumor-tissue, tumor-draining lymph nodes, spleens were conducted. RNA sequencing of murine tumor tissues revealed that nintedanib decreased the gene signatures related to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). Flow cytometry showed that nintedanib significantly decreased the MDSC and CAF percentage in tumor-bearing hosts and increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating into tumors. Immunohistochemical analysis demonstrated that nintedanib treatment significantly increased the number of CD8+ T cells in the internal area of the tumor. Adding nintedanib to anti-PD-1 mAb therapy significantly inhibited in vivo tumor progression. These results indicate that nintedanib suppresses MDSCs and CAFs by inhibiting VEGFR-, PDGFR-, and FGFR-mediated signaling, thereby increasing effector T-cell infiltration into tumors and enhancing the anti-tumor effects of αPD-1 mAb therapy.

DOI： 10.1007/s00262-026-04350-x

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The safety of administering immune checkpoint inhibitors (ICIs) after talc pleurodesis, particularly the impact of talc on the development of immune-related interstitial lung disease (ILD), remains unclear. METHODS: We retrospectively analysed patients with primary lung cancer or malignant pleural mesothelioma who received ICIs within 90 days of talc pleurodesis at facilities participating in the Niigata Lung Cancer Treatment Study Group between November 2016 and June 2023. RESULTS: A total of 52 cases were included, with 17 patients (32.7 %) developing ILD following ICI administration. The median time to ILD onset after ICI administration was 62 days. The median overall survival was 6 months in patients who developed ILD and 16.4 months in those who did not (P = 0.081). Among the five patients with pre-existing interstitial changes, four (80.0 %) developed ILD after ICI administration, identifying a high-risk subgroup. CONCLUSION: A high incidence of ILD was observed in patients who received ICI therapy after talc pleurodesis. Additionally, overall survival tended to be shorter in patients who developed ILD.

DOI： 10.1016/j.lungcan.2025.108590

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

IMPORTANCE: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. OBJECTIVE: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. EXPOSURES: Systemic therapy. MAIN OUTCOMES AND MEASURES: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). CONCLUSIONS AND RELEVANCE: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

DOI： 10.1001/jamaoncol.2023.6277

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

DOI： 10.3390/cancers15010204

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. METHODS: We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021. RESULTS: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7-4.2) and 10 (95% CI: 7.4-14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1-4.0) vs. 4.2 (95% CI: 2.3-4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2-14.8) vs. 10.4 (95% CI: 3.8-NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events. CONCLUSIONS: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

DOI： 10.21037/tlcr-22-225

PubMed

researchmap