Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2022-06-30

AUTHORS

Wenyuan Xiong, Sofia Friberg Hietala, Joakim Nyberg, Orestis Papasouliotis, Andreas Johne, Karin Berghoff, Kosalaram Goteti, Jennifer Dong, Pascal Girard, Karthik Venkatakrishnan, Rainer Strotmann

ABSTRACT

PurposeTepotinib 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.MethodsExposure–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).ResultsTepotinib 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.ConclusionsThese 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.Registration NumbersNCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992. More... »

PAGES

53-69

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00280-022-04441-3

DOI

http://dx.doi.org/10.1007/s00280-022-04441-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1149107575

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/35771259


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