The influence of positional isomerism on G-quadruplex binding and anti-proliferative activity of tetra-substituted naphthalene diimide compounds.

The synthesis together with biophysical and biological evaluation of a series of tetra-substituted naphthalene diimide (ND) compounds, are presented. These compounds are positional isomers of a recently-described series of quadruplex-binding ND derivatives, in which the two N-methyl-piperidine-alkyl side-chains have now been interchanged with the positions of side-chains bearing a range of end-groups. Molecular dynamics simulations of a pair of positional isomers are in accord with the quadruplex stabilization and biological data for these compounds. Analysis of structure-activity data indicates that for compounds where the side-chains are not of equivalent length then the positional isomers described here tend to have improved cell proliferation potency and in some instances, superior quadruplex stabilization ability.

Real-world treatment patterns and clinical outcomes after introduction of immune checkpoint inhibitors: Results from a retrospective chart review of patients with advanced/metastatic non-small cell lung cancer in the EU5.

BACKGROUND: Real-world evidence is increasingly used to guide treatment and regulatory decisions for non-small cell lung cancer (NSCLC). Real-world treatment patterns and clinical outcomes among patients with advanced/metastatic NSCLC in France, Germany, Italy, Spain, and the UK (EU5) were assessed. METHODS: This retrospective physician-completed patient chart review assessed treatment patterns (regimen, duration of treatment [DOT], time to discontinuation), and clinical outcomes (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]) of patients with stage IIIB/C or IV NSCLC who received pembrolizumab-based first-line induction chemotherapy. RESULTS: Overall, 322 patients were included; at first-line maintenance (1LM), 92% had stage IV NSCLC, 68% had nonsquamous histology, and 89% had no central nervous system (CNS)/brain metastasis. The two most common 1LM regimens were pembrolizumab monotherapy (76% overall) and pembrolizumab + pemetrexed (21% overall). Docetaxel monotherapy was the most common second-line regimen in all countries except Germany (54% overall). For 1LM therapy, the overall median DOT and DOR were 5 and 10 months, respectively; PFS was 7 months and OS was 8 months. Germany had a longer duration of each outcome except for DOR which was longer in Spain. Clinical outcomes were generally poorer for patients with squamous histology and CNS/brain metastases. CONCLUSIONS: This study demonstrated differences in treatment patterns and clinical outcomes in NSCLC across the EU5 and patient subgroups. Improved survival was generally associated with response to first-line therapy, nonsquamous histology, and CNS/brain metastases absence. These real-world data provide valuable insights which may aid treatment decision-making and clinical trial design.

Understanding Molecular Testing Uptake Across Tumor Types in Eight Countries: Results From a Multinational Cross-Sectional Survey.

PURPOSE: The growth in understanding of molecular biology and genomics has augmented the development of targeted cancer treatments; however, challenges exist in access to molecular testing, an essential precursor to treatment decision-making. We used data from a cross-sectional survey to evaluate the differences in uptake of molecular testing. METHODS: Using the aggregated results of a questionnaire developed and distributed to clinicians by IQVIA, including treatment details and investigations undertaken for patients, we compared proportions of patients receiving molecular testing and targeted treatment by cancer type for the United Kingdom, France, Italy, Germany, Spain, South Korea, Japan, and China. We used multivariable logistic regression methods to understand the effect of country on the odds of receiving a molecular test. RESULTS: There was a total of 61,491 cases. Across countries and cancer types, uptake rates for molecular testing ranged between 2% and 98%, with the greatest differences seen in gastric cancers (range, 23% to 70%), and significant variations were observed for both European and Asian countries. China consistently demonstrated a significantly reduced uptake for all molecular tests assessed; however; uptake of drug treatment in gastric cancers after testing positive for the human epidermal growth factor receptor 2 gene was higher than in some European countries (China, 85%; European range, 8% to 66%). The uptake of epidermal growth factor receptor gene testing was greater in some Asian countries relative to the United Kingdom, where incidence of lung cancer is higher (Japan: odds ratio, 3.1 [95% CI, 2.6 to 3.8]; South Korea: odds ratio, 2.7 [95% CI, 2 to 3.4]). CONCLUSION: We have highlighted inequity in access to molecular testing and subsequent treatments across countries, which warrants improvements.