There are several limitations in this study First the
There are several limitations in this study. First, the number of cases in which we compared EBUS-TBNA and resected specimens was inadequate due to the fact that most patients who underwent EBUS-TBNA had advanced diseases and thus only a few of them received surgery. Second, the processes of the EBUS-TBNA procedure including the number of samples collected and punctures were not uniformly determined because of the retrospective nature of this study. Also, several cases were not successfully evaluable for PD-L1 by FISH due to sampling and technical problems. Additional large studies are necessary to confirm our findings. Third, we applied clone E1L3N for the PD-L1 staining in this study. This is a laboratory developed test that is not a companion/complementary diagnostic assay such as 22C3, 28-8, and SP142 for the use of specific PD-1/PD-L1 inhibitors. E1L3N has not been validated in clinical trials dealing with ICIs and it does not have the industrial staining platform. However, the correlation among the aforementioned PD-L1 13(S)-HODE has been intensively studied [, , ,52] and E1L3N showed strong correlations with other antibodies [10,52]. Lastly, prospective clinical trials are warranted to confirm the applicability of EBUS-TBNA-derived specimens for the evaluation of PD-L1 IHC and CNAs and to evaluate the predictability of efficacy of PD-L1 CNAs in the treatment with ICIs in patients with NSCLC.
Funding This work was partly supported by grants from the Japanese Ministry of Health, Labor and Welfare (19–19, 10103838), the Japan Society for the Promotion of Science (22590356, 23790396), the Ministry of Education, Culture, Sports, Science and Technology (S-001), the National Cancer Center Research and Development Fund (25-A-1), and Research on Global Health Issues from the Japanese Ministry of Health, Labor and Welfare, Japan Agency for Medical Research and Development (AMED).
Role of funding source
Conflicts of interest
Introduction Lung cancer is the leading cause of cancer-related deaths worldwide [1,2]. Over the past decade, significant improvements have been made in understanding cancer pathogenesis and many new drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) without actionable oncogenic drivers. Immune checkpoint inhibitors have revolutionized lung cancer therapy in the first line setting [, , ] (alone or in combination with cytotoxic agents) regardless of histology and, in the second line, of PD-L1 expression, being these drugs a new standard of care for selected patients [, , , ]. Angiogenesis is a central pathway for the development, growth and metastatization of NSCLC and a valid target for cancer drugs [10,11]. Vascular endothelial growth factor (VEGF) is the most potent proangiogenic agent that solid tumors can secrete in favour of their uncontrolled growth. Therapeutic approaches in the angiogenesis field include monoclonal antibodies and small molecules VEGF receptor tyrosine kinase inhibitors . In this field, nintedanib is a modern, orally available, multi-target small-molecule with anti-angiogenic activity targeting the vascular endothelial growth factor receptors (VEGFR) 1–3, the platelet-derived growth factor receptor (PDGFR) α/β and the ﬁbroblast growth factor receptors (FGFR) 1–3 . Nintetanib plus docetaxel q3wks resulted more effective than docetaxel alone, as second line treatment option for non-oncogene addicted NSCLC patients after first-line platinum based chemotherapy. The randomized phase III, placebo-controlled, LUME-Lung1 trial  has showed, regardless of histology, a higher median PFS for the combination treatment versus placebo (3.4 vs 2.7 months, respectively; hazard ratio = 0.79; 95% confidence interval: 0.68–0.92; p = 0.0019). Median OS resulted greater for patients treated with nintedanib plus docetaxel in the subgroup with adenocarcinoma histology (12.6 vs 10.3 months, respectively; HR = 0.83; 95% CI: 0.70–0.99; p = 0.0359), while no differences have been described in the entire population (all the histologies). Incidence of treatment related Adverse Events (AEs) resulted numerically higher in the nintedanib containing arm. However, toxicity profile of the combination treatment was manageable, establishing the role of nintedanib plus docetaxel as a valid second-line treatment option for NSCLC patients .