Real-world Afatinib Outcomes in Advanced Non-small Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND/AIM: Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib can overcome the treatment resistance-associated EGFR T790M mutation, and the sequence of afatinib followed by osimertinib is an effective therapeutic strategy for NSCLC patients. This study comprehensively evaluated the outcomes of sequential therapy following frontline afatinib and identified predictive factors for T790M mutation acquisition. PATIENTS AND METHODS: Data from patients with advanced NSCLC treated with frontline afatinib at a Taiwanese hospital group from June 2014 to March 2018 were retrospectively reviewed. The EGFR T790M mutation was detected by tissue sequencing or liquid biopsy. The patients' clinicopathological features were collected, and univariate and multivariate analyses were performed to identify potential predictive and prognostic factors. RESULTS: A total of 635 patients treated with afatinib were enrolled in this study. Until August 2021, 553 patients experienced progression, and 225 patients underwent T790M mutation testing. The T790M positive rate was 54.2%. Both exon 19 deletion and progression-free survival were associated with T790M positivity. Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression. CONCLUSION: This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.

Discovery and development of a novel N-(3-bromophenyl)-{[(phenylcarbamoyl)amino]methyl}-N-hydroxythiophene-2-carboximidamide indoleamine 2,3-dioxygenase inhibitor using knowledge-based drug design.

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.

Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors.

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.

Clinical characteristics, antimicrobial resistance and capsular types of community-acquired, healthcare-associated, and nosocomial Klebsiella pneumoniae bacteremia.

Background: Klebsiella pneumoniae bacteremia is a major cause of morbidity and mortality worldwide. We aimed to compare the clinical characteristics, distribution of capsular types, and antimicrobial resistance of K. pneumoniae bacteremia among community-acquired (CA), healthcare-associated (HCA), and nosocomial infections. Methods: This retrospective study of patients with K. pneumoniae bacteremia was conducted at Taipei Veterans General Hospital from January to December 2015. Clinical characteristics of K. pneumoniae bacteremia were collected. The K. pneumoniae isolates were subjected to antimicrobial susceptibility testing and capsular genotyping. Results: In total, 337 patients with K. pneumoniae bacteremia were identified: 70 (20.8%), 102 (30.3%), and 165 (48.9%) presented with CA, HCA, and nosocomial infection, respectively. The 28-day mortality of HCA bacteremia was lower than that of nosocomial bacteremia (17.6% versus 30.9%, p = 0.016); however, that of the HCA and CA bacteremia was similar (17.6% versus 14.3%, p = 0.557). CA isolates had the highest prevalence of virulent capsular types (51.4%), followed by HCA (36.3%) and nosocomial isolates (19.4%). The proportion of multidrug-resistant (MDR) isolates was highest in nosocomial infections (41.8%), followed by HCA (23.5%) and CA infections (5.7%). Conclusion: CA, HCA and nosocomial K. pneumoniae are distinct entities, as evidenced by the differences in clinical characteristics, antimicrobial resistance, and capsular types found in this study.