Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.)

Die Aufsatzübungen in der Oberklasse der Volksschule

von Jos. Scheel

Effective Permeability and thermal conductivities of graded sintered open cell metallic foams via a multiscale procedure

Within an interdisciplinary research group metal foams are investigated, which are meant to be used as effusion cooled wall elements in a combustion chamber of an advanced high efficiency gas turbine. Two of the properties of the metal foams which determine the thermodynamic behaviour of the wall elements are permeability and thermal conductivity. These two properties depend highly on the porosity of the metal foam. Changing the porosity of a metal foam along a direction leads to a gradient in the porosity and thermal conductivity. This grading of metal foams enables adjusting material properties accordingly to the position within the wall element. Metal foams with a gradation in one direction are fabricated and local material properties are determined. The local topology is determined via X-ray tomography. The homogenised thermal conductivity is measured using a Transient Plane Source Technique, also known as HotDisk, and the permeability is measured with a pressure drop experiment. The measurements are done at different positions along the gradation. The experiments demonstrate that the topology of metal foams can be varied within the same foam sample and that properties of the foams like permeability and thermal conductance change accordingly