Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

MET receptor variant R970C favors calpain-dependent generation of a fragment promoting epithelial cell scattering.

The receptor tyrosine kinase MET and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas deregulation of MET signaling is associated with tumorigenesis leading to various cancers, including lung carcinoma. Mutations in the MET kinase domain lead to constitutive kinase activity and are associated with tumorigenesis. In lung cancer, however, some mutations are found in the juxtamembrane domain, and their functional consequences are unknown. Because the juxtamembrane domain of MET is targeted by several proteolytic cleavages, involved in its degradation during cell death or under steady-state conditions, we evaluated the influence of these mutations on the MET proteolytic cleavages. In stably transfected epithelial cells expressing MET, the juxtamembrane mutations R970C, P991S, and T992I were found not to modify the known caspase or presenilin-dependent regulated intramembrane proteolysis. Yet when overexpressed, the R970C variant caused generation of an as yet undescribed 45-kDa fragment (p45 MET). This fragment was found in the confluent lung cancer cell line NCI-H1437 carrying the R970C mutation and at a lesser extent in cell lines expressing WT MET, suggesting that R970C mutation favors this cleavage. Generation of p45 MET required the activity of the calpain proteases, confirming the involvement of proteolysis. Ectopic expression of reconstituted p45 MET in epithelial cell lines favored cell scattering and invasion indicating active role of this fragment in HGF/SF induced responses. Hence, although the juxtamembrane mutations of MET do not affect its known proteolytic cleavages, the R970C MET variant favors calpain dependent proteolytic cleavage in lung cancer cells.

Factors predicting prolonged empirical antifungal treatment in critically ill patients.

OBJECTIVE: To determine the incidence, risk factors, and impact on outcome of prolonged empirical antifungal treatment in ICU patients. METHODS: Retrospective observational study performed during a one-year period. Patients who stayed in the ICU >48 h, and received empirical antifungal treatment were included. Patients with confirmed invasive fungal disease were excluded. Prolonged antifungal treatment was defined as percentage of days in the ICU with antifungals > median percentage in the whole cohort of patients. RESULTS: Among the 560 patients hospitalized for >48 h, 153 (27%) patients received empirical antifungal treatment and were included in this study. Fluconazole was the most frequently used antifungal (46% of study patients). Median length of ICU stay was 19 days (IQR 8, 34), median duration of antifungal treatment was 8 days (IQR 3, 16), and median percentage of days in the ICU with antifungals was 48% (IQR 25, 80). Seventy-seven patients (50%) received prolonged empirical antifungal treatment. Chemotherapy (OR [95% CI] 2.6 [1.07-6.69], p = 0.034), and suspected infection at ICU admission (3.1 [1.05-9.48], p = 0.041) were independently associated with prolonged empirical antifungal treatment. Duration of mechanical ventilation and ICU stay were significantly shorter in patients with prolonged empirical antifungal treatment compared with those with no prolonged empirical antifungal treatment. However, ICU mortality was similar in the two groups (46 versus 52%, p = 0.62). CONCLUSION: Empirical antifungal treatment was prescribed in a large proportion of study patients. Chemotherapy, and suspicion of infection at ICU admission are independently associated with prolonged empirical antifungal treatment.