Phase II trial of tepotinib vs sorafenib in Asian patients (pts) with advanced hepatocellular carcinoma (HCC)

Ryoo, Baek‐Yeol; Ren, Zhenggang; Kim, T.-Y.; Pan, Henry; Rau, Kun‐Ming; Choi, Hea-Soon; Park, J.-W.; Kim, J.H.; Yen, Chia Jui; Kim, B.-H.; Zhou, Dejun; Straub, Josef; Zhao, Cai-Y.; Qin, Shukui

doi:10.1093/annonc/mdy282.005

Cited by 9 publications

(12 citation statements)

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“…Grades 3–4 tepotinib-related TEAEs included edema, fatigue and asymptomatic increases in serum levels of AST, ALT and lipase. The treatment-related grade 3–4 events that occurred in this trial are similar in nature and incidence to those observed in completed and ongoing trials of tepotinib ( 19 , 26–29 ). Amylase and lipase increases are considered as class effects because they have been observed in trials of other selective MET inhibitors, such as capmatinib and savolitinib ( 30–32 ), as well as in other trials of tepotinib ( 19 , 26–29 ).…”

Section: Discussionsupporting

confidence: 67%

“…Therefore, the RP2D of 500 mg given orally once daily was confirmed as appropriate for Japanese patients. Additional Phase Ib/II studies in Europe, USA, China, Taiwan, Singapore and South Korea also have confirmed the RP2D and shown that tepotinib is generally well tolerated in specific patient populations, such as those with hepatocellular carcinoma and NSCLC ( 26–29 ).…”

Section: Discussionmentioning

confidence: 86%

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Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

Shitara

Yamazaki

Tsushima

et al. 2020

Japanese Journal of Clinical Oncology

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Objectives Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506). Methods Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment. Results Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1–2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily. Conclusions These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 86%

Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

Shitara

Yamazaki

Tsushima

et al. 2020

Japanese Journal of Clinical Oncology

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“…These data suggest that tepotinib warrants further investigation in cancer patients with MET dysregulation. Phase Ib/II trials of tepotinib 500 mg once daily in patients with MET-overexpressing hepatocellular carcinoma (NCT01988493 and NCT02115373) and non-small cell lung carcinoma (NSCLC) with MET alterations (NCT01982955 and NCT02864992) have confirmed both the tolerability of tepotinib and demonstrated clinical activity (22)(23)(24)(25). A pooled safety analysis of 260 patients who received tepotinib 500 mg in five phase Ib/II studies also showed the 500 mg dose to be generally well tolerated (26).…”

Section: Discussionmentioning

confidence: 95%

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

Falchook

Kurzrock

Amin

et al. 2020

Clinical Cancer Research

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Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D). Patients and Methods: Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects. Results: One hundred and forty-nine patients received tepotinib (R1: n ¼ 42; R2: n ¼ 45; R3: n ¼ 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve !95% MET inhibition in !90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression. Conclusions: Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

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“…In this study, a single 500 mg dose of tepotinib was well tolerated by healthy volunteers; although 75% experienced TEAEs, most were mild and resolved rapidly. Tepotinib has also been found to be well tolerated in phase I/Ib and phase II clinical trials in patients with solid tumors, which have further characterized its side-effect profile [9,17,18,21,35,36]. Ongoing phase II trials in NSCLC and hepatocellular carcinoma will add further insight into the side-effect profile and efficacy of tepotinib [16-18, 20-22, 35].…”

Section: Discussionmentioning

confidence: 99%

“…Tepotinib alone or in combination has been shown to be active in various preclinical tumor models [8,[10][11][12][13][14][15][16]. It is currently being studied in clinical trials involving patients with hepatocellular carcinoma (NCT01988493, NCT02115373) [17,18] a n d N S C L C ( N C T 0 1 9 8 2 9 5 5 , N C T 0 2 8 6 4 9 9 2 , NCT03940703) [16,[19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

et al. 2020

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Tepotinib (MSC2156119J) is an oral, potent, highly selective MET inhibitor. This open-label, phase I study in healthy volunteers (EudraCT 2013-003226-86) investigated its mass balance (part A) and absolute bioavailability (part B). In part A, six participants received tepotinib orally (498 mg spiked with 2.67 MBq [ 14 C]-tepotinib). Blood, plasma, urine, and feces were collected up to day 25 or until excretion of radioactivity was <1% of the administered dose. In part B, six participants received 500 mg tepotinib orally as a film-coated tablet, followed by an intravenous [ 14 C]-tepotinib tracer dose (53-54 kBq) 4 h later. Blood samples were collected until day 14. In part A, a median of 92.5% (range, 87.1-96.9%) of the [ 14 C]-tepotinib dose was recovered in excreta. Radioactivity was mainly excreted via feces (median, 78.7%; range, 69.4-82.5%). Urinary excretion was a minor route of elimination (median, 14.4% [8.8-17.7%]). Parent compound was the main constituent in excreta (45% [feces] and 7% [urine] of the radioactive dose). M506 was the only major metabolite. In part B, absolute bioavailability was 72% (range, 62-81%) after oral administration of 500 mg tablets (the dose and formulation used in phase II trials). In conclusion, tepotinib and its metabolites are mainly excreted via feces; parent drug is the major eliminated constituent. Oral bioavailability of tepotinib is high, supporting the use of the current tablet formulation in clinical trials. Tepotinib was well tolerated in this study with healthy volunteers.

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Phase II trial of tepotinib vs sorafenib in Asian patients (pts) with advanced hepatocellular carcinoma (HCC)

Cited by 9 publications

References 0 publications

Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

Phase I trial of the MET inhibitor tepotinib in Japanese patients with solid tumors

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

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