Source: FDA, National Drug Code (US) Revision Year: 2021
Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.
In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including METex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.
Tepotinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.
At the recommended dosage, no large mean increases in QTc (i.e. >20 ms) were detected in patients with various solid tumors. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.
The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC0-12h and Cmax) increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg. At the recommended dosage, the geometric mean (coefficient of variation [CV] ) steady state Cmax was 1,291 ng/mL (48.1) and the AUC0-24h was 27,438 ng∙h/mL (51.7%). The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h after multiple daily doses of tepotinib.
The median Tmax of tepotinib is 8 hours (range from 6 to 12 hours). The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects.
The mean AUC0-INF of tepotinib increased by 1.6-fold and Cmax increased by 2-fold, following administration of a high-fat, high-calorie meal (approximately 800 to 1,000 calories, 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). The median Tmax shifted from 12 hours to 8 hours.
The geometric mean (CV%) apparent volume of distribution (VZ/F) of tepotinib is 1,038 L (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration at clinically relevant exposures.
The apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours following oral administration of TEPMETKO in patients with cancer.
Tepotinib is primarily metabolized by CYP3A4 and CYP2C8. One major circulating plasma metabolite (M506) has been identified.
Following a single oral administration of a radiolabeled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in feces (45% unchanged) and 13.6% in urine (7% unchanged). The major circulating metabolite M506 accounted for about 40.4% of the total radioactivity in plasma.
No clinically significant effects on tepotinib pharmacokinetics were observed based on age (18 to 89 years), race/ethnicity (White, Black, Asian, Japanese, and Hispanic), sex, body weight (35.5 to 136 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min), or mild to moderate hepatic impairment (Child-Pugh A and B). The effect of severe renal impairment (CLcr <30 mL/min) and severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of tepotinib has not been studied.
P-gp Substrates: Coadministration of TEPMETKO with dabigatran etexilate (P-gp substrate) increased dabigatran Cmax by 40% and AUC0-INF by 50%.
Acid-Reducing Agents: No clinically significant differences in tepotinib pharmacokinetics were observed when coadministered with multiple daily doses (40 mg daily for 5 days) of omeprazole (proton pump inhibitor) under fed conditions.
CYP3A Substrates: Coadministration of TEPMETKO had no clinically significant effect on the pharmacokinetics of midazolam (sensitive CYP3A substrate).
MATE2 and OCT2 Substrates: No clinically relevant differences in glucose levels were observed when metformin (MATE2 and OCT2 substrate) was coadministered with tepotinib.
CYP2C9 Substrates: Physiologically based pharmacokinetic modeling suggested CYP2C9 inhibition is not clinically significant.
Cytochrome P450 Enzymes: Tepotinib is a substrate of CYP3A4 and CYP2C8. Tepotinib and M506 do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 or CYP2E1, and do not induce CYP1A2 or 2B6 at clinically relevant concentrations.
UDP-Glucuronosyltransferase (UGT): Tepotinib and M506 do not inhibit UGT 1A1, 1A9, 2B17, 1A3/4/6 and 2B7/15 at clinically relevant concentrations.
Transporter Systems: Tepotinib is a P-gp substrate. Tepotinib may inhibit intestinal BCRP at clinically relevant concentrations. Tepotinib does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1, B3, or organic anion transporter (OAT)1 and 3.
Carcinogenicity studies have not been performed with tepotinib. Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic in a rat micronucleus test.
Fertility studies of tepotinib have not been performed. There were no morphological changes in male or female reproductive organs in repeat-dose toxicity studies in dogs.
The efficacy of TEPMETKO was evaluated in a single-arm, open-label, multicenter, non-randomized, multicohort study (VISION, NCT02864992). Eligible patients were required to have advanced or metastatic NSCLC harboring METex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study.
Identification of METex14 skipping alterations was prospectively determined using central laboratories employing either a PCR-based or next-generation sequencing-based clinical trial assay using tissue (58%) and/or plasma (65%) samples.
Patients received TEPMETKO 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC.
The efficacy population included 69 treatment naïve patients and 83 previously treated patients. The median age was 73 years (range 41 to 94 years); 48% female; 71% White, 25% Asian; 27% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 73% had ECOG PS 1; 43% never smoked; 86% had adenocarcinoma; 98% had metastatic disease; and 10% had CNS metastases. Amongst previously treated patients, 89% received prior platinum-based chemotherapy.
Efficacy results are presented in Table 4.
Table 4. Efficacy Results in the VISION study:
| Efficacy parameter | Treatment-Naïve N=69 | Previously Treated N=83 |
|---|---|---|
| Overall response rate, % (95% CI)*,† | 43 (32, 56) | 43 (33, 55) |
| Median duration of response, months‡ (95% CI) | 10.8 (6.9, NE) | 11.1 (9.5, 18.5) |
| Patients with DOR ≥6 months, % | 67 | 75 |
| Patients with DOR ≥9 months, % | 30 | 50 |
CI=confidence interval, NE=Not estimable
* Blinded Independent Review Committee (BIRC) review
† Confirmed Responses
‡ Product-limit (Kaplan-Meier) estimates, 95% CI for the median using the Brookmeyer and Crowley method.
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