Distinct Progression and Efficacy of First-Line Osimertinib Treatment According to Mutation Subtypes in Metastatic NSCLC Harboring EGFR Mutations

Introduction: Osimertinib (OSI), a third-generation EGFR tyrosine kinase inhibitor, is the standard treatment for patients with naive EGFR-mutant NSCLC. Nevertheless, information on how the mutation subtype affects disease progression after the failure of OSI treatment is scarce. Methods: We retrospectively reviewed patients with EGFR-mutant NSCLC who received OSI as a first-line treatment between April 2015 and December 2021. Results: This study included 229 patients. The objective response rate was 71%, with intracranial and extracranial response rates of 71% and 90%, respectively. The median progression-free survival was 23.3 mo (95% confidence interval [CI]: 19.6–26.7), and the median overall survival was 33.7 mo (95% CI: 31.3–58.6). Multivariate analysis revealed that the EGFR exon 21 L858R point mutation (L858R) (hazard ratio [HR] = 1.56, 95% CI: 1.04–2.34, p = 0.0328) and liver metastasis (HR = 2.63, 95% CI: 1.53–4.49, p = 0.0004) were significant predictors of progression-free survival in OSI treatment. The concomitant disease progression involving the central nervous system metastasis was significantly more common in patients with L858R (p = 0.048), whereas concomitant disease progression involving primary lesions was significantly more common in patients with exon 19 deletion mutation (p = 0.01). In addition, the probability of disease progression over time was higher for L858R compared with that for exon 19 deletion mutation, in patients with central nervous system metastasis (log-rank test, p = 0.027). Conclusions: The mutation subtype had an impact not only on the clinical outcome of the first-line OSI treatment but also on progression patterns after OSI treatment in patients with NSCLC harboring EGFR mutations

Covering the intercostal artery branching of the Adamkiewicz artery during endovascular aortic repair increases the risk of spinal cord ischemiaCentral MessagePerspective

Objectives: This study aimed to determine the relationship between covering the intercostal artery branching of the Adamkiewicz artery (ICA-AKA) and spinal cord ischemia (SCI) during thoracic endovascular aortic repair (TEVAR). Methods: Patients who underwent TEVAR from 2008 to 2022 were enrolled. Stent grafts covered the ICA-AKA in 108 patients (covered AKA group) and stent grafts didn’t cover the ICA-AKA in 114 patients (uncovered AKA group). The characteristics of 58 patients from each group were matched based on propensity scores. Results: No significant differences in SCI rates were detected between the covered AKA (10%; 11/108) and uncovered AKA (3.5%; 4/114) groups (P = .061). Shaggy aorta (odds ratio [OR], 5.16; 95% confidence interval [CI], 1.74-15.3, P = .003), iliac artery access (OR, 6.81; 95% CI, 2.22-20.9, P = .001), and procedural time (OR, 1.01; 95% CI, 1.00-1.02, P = .003) were risk factors for SCI in the entire cohort. Although covering the ICA-AKA (OR, 2.60; 95% CI, 0.86-7.88, P = .058) was not a significant risk factor, shaggy aorta (OR, 8.15; 95% CI, 2.07-32.1, P = .003), iliac artery access (OR, 9.09; 95% CI, 2.22-37.2, P = .002), and procedural time (OR, 1.01; 95% CI, 1.01-1.02, P = .008) were risk factors for SCI in the covered AKA group. No significant risk factors were detected in the uncovered AKA group. Conclusions: Covering the ICA-AKA was not an independent risk for SCI in TEVAR. However, covering the ICA-AKA was indirectly associated with the risk of SCI in patients with shaggy aorta, iliac access, and procedural time

Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation

Background: Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated. Methods: Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI. Results: The average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types. Conclusions: PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered. Keywords: Dabigatran, Proton pump inhibitor, Drugâdrug interactio

Clinical Characteristics and Pharmacokinetics Change of Long-Term Responders to Antiprogrammed Cell Death Protein 1 Inhibitor Among Patients With Advanced NSCLC

Introduction: Immune checkpoint inhibitors (ICIs) induce long-term, durable responses in patients with advanced NSCLC. Nevertheless, these responses are limited to a few patients, and most responders have disease progression. The purpose of this study was to determine the differences in clinical factors and blood drug concentrations between long-term responders (LTRs) and non-LTRs. Methods: We retrospectively analyzed consecutive patients with advanced NSCLC who received antiprogrammed cell death protein 1 (PD-1) inhibitor monotherapy (nivolumab) from December 22, 2015, to May 31, 2017. Patients who obtained a clinical benefit for more than 6 months were referred to as “responders”; among these, individuals who had a durable response for more than 2 years were defined as “LTRs.” Those with a clinical benefit for less than 2 years were defined as “non-LTRs.” Results: A total of 212 patients received anti–PD-1 inhibitor monotherapy. The responders accounted for 35% (75 of 212) of the patients. Of these, 29 (39%) were LTRs and 46 (61%) were non-LTRs. The overall response rate and median tumor shrinkage in the LTR group were significantly higher than those in the non-LTR group (76% versus 35%, p < 0.0001, and 66% versus 16%, p < 0.001, respectively). The groups had no significant difference in PD-L1 expression and serum drug concentration at 3- and 6-month post-treatment initiation. Conclusions: Significant tumor shrinkage was associated with a long-term response to an anti–PD-1 inhibitor. Nevertheless, the PD-L1 expression level and pharmacokinetic profile of the inhibitor could not be used to predict the durable response among the responders