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

Abstract

Purpose 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. Methods 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). Results 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. Conclusions 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. Registration Numbers NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

Long‐term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study

“…The higher frequency of AE reports of blood creatinine increase in Japanese patients (65.8%) compared with the global population (21.7%) may be a result of different medical practices to report laboratory abnormalities as AEs in Japan 25 . However, there was no evidence that creatinine increase was associated with renal impairment in the safety analysis of the overall VISION population 26,27 . This is also supported by the creatinine level changes in Japanese patients, demonstrating the reversibility of creatinine increases with tepotinib treatment.…”

“…A series of case studies has distinguished asymptomatic creatinine increase with tepotinib or capmatinib from acute kidney injury using non‐creatinine‐based methods to estimate glomerular filtration rate 28–30 . A potential explanation for observed creatinine increases could be that serum creatinine is increased by inhibition of renal transporters 27–29,31,32 . Studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins, organic cation transporter 2 and multidrug and toxin extrusion transporters 1 and 2 and, as a result, creatinine, being the substrate of these inhibitors, increases 33…”

“…A recent post‐marketing surveillance analysis of tepotinib in 147 patients reported peripheral edema in 37.4% of patients, reflecting the occurrence of edema with tepotinib in real‐world practice 14,15 . An exposure–response analysis of tepotinib identified an association between advanced age and increased risk of edema, independent of tepotinib exposure, while reporting a flat relationship within the observed exposure range (500 mg daily) between tepotinib exposure and edema 27 . Treatment interruptions (65.8%) and dose reductions (52.6%) enabled patients with AEs to remain on treatment, including five patients for more than 2 years.…”

“…[28][29][30] A potential explanation for observed creatinine increases could be that serum creatinine is increased by inhibition of renal transporters. [27][28][29]31,32 Studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins, organic cation transporter 2 and multidrug and toxin extrusion transporters 1 and 2 and, as a result, creatinine, being the substrate of these inhibitors, increases. 33 Peripheral edema considered a class effect of MET inhibitors, 26 was the second most common treatment-related AE (of any grade) with an occurrence of 60.5% in Japanese patients in VISION.…”

“…exposure-response analysis of tepotinib identified an association between advanced age and increased risk of edema, independent of tepotinib exposure, while reporting a flat relationship within the observed exposure range (500 mg daily) between tepotinib exposure and edema. 27…”