High Incidence of C797S Mutation in Patients With Long Treatment History of EGFR Tyrosine Kinase Inhibitors Including Osimertinib

Introduction: Although treatment with osimertinib confers survival benefits in patients with lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib remains poorly understood. We conducted a prospective observational study to identify the mechanism on the basis of repeated tissue biopsies. Methods: Patients with EGFR-mutated advanced lung cancer with a T790M mutation detected on a tissue biopsy underwent a rebiopsy after developing acquired resistance to osimertinib. Nucleic acids extracted from the biopsy samples were subjected to targeted resequencing (Oncomine Comprehensive Assay), and circulating cell-free DNA (ccfDNA) was analyzed by CAncer Personalized Profiling by deep Sequencing (AVENIO ctDNA Surveillance Kit). Results: Between November 2016 and March 2020, a total of 87 patients were screened. Among them, 44 developed acquired resistance. Of these, 19 samples from rebiopsies and 12 from preosimertinib biopsies were able to be analyzed by an Oncomine Comprehensive Assay. A ccfDNA analysis was performed in 16 patients. Regarding the mechanisms of acquired resistance, structural change in EGFR, namely, C797S, G796S, or L792V, was the most frequent alteration, being observed in 57.9% of the cases. MET gain was observed in 31.6% of the cases, and gains in cell cycle genes were observed in 26.3% of the cases. In addition, we identified GAS6 gain and an ATM mutation in a patient with small-cell transformation and a BRAF V600E mutation in a patient with oligoprogressive disease. Conclusions: A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo