Raymond M. Esper

PURPOSE The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAF V600E/K -mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAF V600E -mutant metastatic non–small-cell lung cancer (NSCLC). METHODS In this ongoing, open-label, single-arm, phase II study (ClinicalTrials.gov identifier: NCT03915951 ), patients with BRAF V600E -mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety. RESULTS At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with BRAF V600E -mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard ( https://clinical-trials.dimensions.ai/pharos/ ). CONCLUSION For patients with treatment-naïve and previously treated BRAF V600E -mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.

During peripheral nervous system development, Schwann cells are precisely matched to the axons that they support. This is mediated by axonal neuregulins that are essential for Schwann cell survival and differentiation. Here, we show that sensory and motor axons rapidly release heparin-binding forms of neuregulin in response to Schwann cell-derived neurotrophic factors in a dose-dependent manner. Neuregulin release occurs within minutes, is saturable, and occurs from axons that were isolated using a newly designed chamber slide apparatus. Although NGF and glial cell line-derived neurotrophic factor (GDNF) were the most potent neurotrophic factors to release neuregulin from sensory neurons, GDNF and BDNF were most potent for motor neurons and were the predominant neuregulin-releasing neurotrophic factors produced by cultured Schwann cells. Comparable levels of neuregulin could be released at a similar rate from neurons after protein kinase C activation with the phorbol ester, phorbol 12-myristate 13-acetate, which has also been shown to promote the cleavage and release of neuregulin from its transmembrane precursor. The rapid release of neuregulin from axons in response to Schwann cell-derived neurotrophic factors may be part of a spatially restricted system of communication at the axoglial interface important for proper peripheral nerve development, function, and repair.

PURPOSE: To evaluate the degree to which published medical rehabilitation research offers evidence of reliability, validity and other clinimetric qualities of the data reported. METHOD: Descriptive study of published intervention research papers published in six US medical rehabilitation journals in 1997 and 1998. Selected characteristics of the papers and the outcome measures used were abstracted by one or two raters. RESULTS: The 171 papers identified included 651 outcome measures. Some type of data reliability information was provided for 20.1% of these measures; for validity, this was 6.9%. However, this information was based on data collected for the sample studied for only 7.7% (reliability) and 0.6% (validity). CONCLUSIONS: Most rehabilitation research falls short of standards, including the Standards promulgated by an American Congress of Rehabilitation Medicine Advisory Group. Authors, peer reviewers and editors need to change their practices to improve this situation.