European Society of Anaesthesiology.

Introduction: The EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation (w5% to 6% of exon 20 insertions), which, at the structural and enzyme kinetic level, more closely resembles EGFR tyrosine kinase inhibitor (TKI)sensitizing mutants, such as EGFR exon 19 indels and L858R. A limited number of preclinical models and clinical reports have studied the response of this mutant to EGFR TKIs. Methods: We used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first-(gefitinib, erlotinib), second-(afatinib), third-generation (osimertinib), and in-development EGFR exon 20-specific (poziotinib, mobocertinib [TAK-788]) TKIs. We also compiled outcomes of EGFR-A763_Y764insFQEAmutated lung cancers treated with EGFR TKIs. Results: Cells driven by EGFR-A763_Y764insFQEA were consistently sensitive to EGFR TKIs (as opposed to those driven by typical EGFR exon 20 insertions [A767_V769du-pASV, D770_N771insSVD and H773_V774insH]), which were only inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. Most case instances (62.5% [95% confidence interval: 39%-86%], n ¼ 16) with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib) with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI-treated cases was 22 months (95% confidence interval: 16-25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations. Conclusions: To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sen-*Corresponding author. Disclosure: Dr. Costa reports receiving personal fees (consulting fees and honoraria) and nonfinancial support (institutional research support) from Takeda/Millennium Pharmaceuticals, AstraZeneca, and Pfizer; and nonfinancial support (institutional research support) from Merck Sharp and Dohme Corporation, Merrimack Pharmaceuticals, Bristol-Myers Squibb, Clovis Oncology, Spectrum Pharmaceuticals, and Tesaro, all outside of the submitted work. Dr. Rangachari reports receiving nonfinancial support (institutional research support) from Bristol-Myers Squibb, Novocure, and AbbVie/Stemcentrx, all outside of the submitted work. Dr. VanderLaan reports receiving personal fees (consulting fees and honoraria) from Gala Therapeutics, Flatiron Health, Caris Life Sciences, and Foundation Medicine, all outside of the submitted work. Dr. Kobayashi reports receiving research support from Boehringer Ingelheim, MiNA Therapeutics, and Taiho Therapeutics; and personal fees (honoraria) from Boehringer Ingelheim, Bristol-Myers Squibb, and Takeda Pharmaceuticals outside of the submitted work. The remaining authors declare no conflict of interest.

Summary What is known and objective Polymyxins, especially polymyxin B, has become the last line of therapy against Gram‐negative pathogens’ carbapenemase producers. However, given increasing use of polymyxin B in clinical settings its therapeutic value has been evaluated worldwide due to its toxic effects. The aim of this study was to assess the efficacy and safety of antimicrobial therapy with polymyxin B in patients with multidrug‐resistant bacteria in Brazil. Methods This was a prospective cohort study in a 403‐bed academic tertiary care centre, located in the countryside of Brazil. Patients receiving polymyxin B intravenous treatment for at least 72 hours were eligible for the study. Antimicrobial susceptibility, adverse reactions and clinical outcomes were submitted for descriptive analysis. Main outcomes measure the following: Patients' conditions following treatment (Treatment Success, Mortality, Treatment Failure, Inadequate Empiric Treatment or Indeterminate Response) and toxicities induced by polymyxin B (nephrotoxicity and skin hyperpigmentation). Results and discussion Among 247 patients, treatment success was achieved in 25.1%, while mortality was observed in 32.8%. Empirical therapy was prescribed for 26.3% of the patients. Nephrotoxicity was reported in 40.5%. The carbapenemase producer, Klebsiella pneumonia, was the bacterium most associated with mortality (22.2%). Conclusions Even though polymyxin B is currently the main therapy against carbapenemase producers, its use demands robust criteria to lead to positive clinical outcomes.

Introduction: EGFR exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR tyrosine kinase inhibitors (EGFR TKIs). Novel EGFR TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S). Methods: We used models of EGFR mutations to probe representative first, second, third generation, and indevelopment EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance. Results: Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N7 71insSVD, H773_V774insH, and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit the phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to greater than 200-fold resistance in proliferation assays probing mobocertinib and osimertinib. A review of clinical studies of mobocertinib disclosed responses that could be lasting. Conclusions: This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; and EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.