%0 Clinical Trial
%T Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations.
%A Xiong W
%A Hietala SF
%A Nyberg J
%A Papasouliotis O
%A Johne A
%A Berghoff K
%A Goteti K
%A Dong J
%A Girard P
%A Venkatakrishnan K
%A Strotmann R
%J Cancer Chemother Pharmacol
%V 90
%N 1
%D 07 2022
%M 35771259
%F 3.288
%R 10.1007/s00280-022-04441-3
%X Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.<BR>Exposure-efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure-safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30-1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia's method (QTcF).<BR>Tepotinib exhibited flat exposure-efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure-safety relationships for all endpoints within the exposure range observed with 30-1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.<BR>These analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.<BR>NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.