A Comprehensive Monograph on Tepotinib (TEPMETKO®): A Selective MET Tyrosine Kinase Inhibitor for METex14 Skipping Non-Small Cell Lung Cancer

I. Executive Summary

Tepotinib, marketed under the brand name TEPMETKO®, is an orally administered, highly selective, and potent small molecule inhibitor of the Mesenchymal-Epithelial Transition (MET) receptor tyrosine kinase.[1] It represents a significant advancement in precision oncology, specifically developed for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor

MET gene alterations leading to exon 14 (METex14) skipping.[3] This genetic alteration, found in approximately 3-4% of NSCLC cases, is a key oncogenic driver associated with an aggressive disease course and poor prognosis, particularly in the typically older patient population it affects.[5]

The clinical development of tepotinib was anchored by the pivotal Phase II VISION trial (NCT02864992), a large, single-arm, biomarker-driven study that prospectively enrolled patients based on the presence of METex14 skipping alterations.[7] The trial demonstrated robust, consistent, and remarkably durable clinical efficacy. In treatment-naïve patients, tepotinib achieved an overall response rate (ORR) of 57% with a median duration of response (DOR) of 46.4 months. In previously treated patients, the ORR was 45% with a median DOR of 12.6 months.[7] This profound and lasting activity has fundamentally altered the treatment paradigm for this molecular subtype of NSCLC, shifting the goal from short-term palliation to long-term disease management.

The safety profile of tepotinib is well-characterized and considered manageable with appropriate clinical oversight. The most common adverse reactions include peripheral edema, nausea, fatigue, and diarrhea.[11] While generally low-grade, these events require proactive management to maintain patient quality of life and treatment continuity. Serious adverse events of clinical importance include interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, and pancreatic toxicity, for which specific monitoring and dose modification protocols have been established to mitigate risk.[5]

Tepotinib's pharmacokinetic profile is favorable for clinical use, featuring a long terminal half-life of approximately 32 hours that supports convenient once-daily dosing, and a high oral bioavailability when taken with food.[12] Its pharmacokinetics are notably stable across a wide range of patient characteristics, including age and mild-to-moderate renal or hepatic impairment, simplifying its administration in a typically co-morbid population.[12]

The global regulatory trajectory of tepotinib underscores its clinical importance. It was first approved in Japan in March 2020, followed by an accelerated approval from the U.S. Food and Drug Administration (FDA) in February 2021.[1] Based on mature data from the VISION trial confirming its substantial clinical benefit, the FDA converted this to a traditional (full) approval in February 2024, solidifying tepotinib's position as a standard-of-care therapy for patients with metastatic

METex14 skipping NSCLC.[7] Approval by the European Medicines Agency (EMA) followed in February 2022, further establishing its role in the global oncology armamentarium.[1]

II. Drug Identity and Physicochemical Properties

A precise understanding of a drug's identity and its fundamental physical and chemical properties is essential, as these characteristics underpin its formulation, delivery, pharmacokinetic behavior, and ultimately, its clinical application.

Nomenclature and Identifiers

Tepotinib is the established International Nonproprietary Name (INN) and United States Adopted Name (USAN) for the active pharmaceutical ingredient.[1] It is marketed globally under the brand name TEPMETKO®.[11] Throughout its development, it was also known by several research and developmental codes, most notably EMD-1214063 and MSC2156119.[2] For unambiguous identification across scientific literature, clinical trials, and regulatory databases, a comprehensive set of identifiers has been assigned. These include the DrugBank Accession Number DB15133, the Chemical Abstracts Service (CAS) Registry Number 1100598-32-0, and the PubChem Compound ID (CID) 25171648.[1] A consolidated list of these and other key identifiers is provided in Table 1.

Chemical Structure and Formula

Tepotinib is a synthetic, small molecule compound classified as a kinase inhibitor.[1] Its definitive chemical structure corresponds to the International Union of Pure and Applied Chemistry (IUPAC) name: 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile.[1]

The molecular formula of tepotinib is C29​H28​N6​O2​.[2] For computational chemistry and informatics purposes, its structure is represented by the Simplified Molecular Input Line Entry System (SMILES) string:

CN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1 and the International Chemical Identifier (InChI) Key: AHYMHWXQRWRBKT-UHFFFAOYSA-N.[11]

Physical and Chemical Properties

Tepotinib exists as a solid powder at room temperature.[2] It has a molecular weight (molar mass) of 492.583 g·mol⁻¹.[2] Key predicted physicochemical properties include a boiling point of

626.5±65.0 °C and a density of 1.25 g/cm³.[19] The molecule has a predicted acid dissociation constant (pKa) of

8.93±0.10, indicating it possesses a basic character primarily associated with the methylpiperidinyl nitrogen atom.[14]

A critical property influencing its biopharmaceutical behavior is its solubility. Tepotinib is characterized as a low-solubility drug, with very poor aqueous solubility (<2.56 mg/mL).[19] In contrast, it is more soluble in organic solvents such as dimethyl sulfoxide (DMSO), with a solubility of

≥4.93 mg/mL.[19] This low aqueous solubility is a pivotal factor that dictates the drug's formulation and administration requirements. To overcome the absorption challenges posed by poor solubility, the drug substance is micronized, and the clinical protocol mandates administration with food.[12] The presence of food, particularly a high-fat meal, enhances the solubilization and subsequent absorption of the lipophilic tepotinib molecule, leading to a 1.6-fold increase in total exposure (AUC) and a 2-fold increase in peak concentration (Cmax).[12] This direct link between a fundamental physicochemical property and a crucial clinical directive highlights the importance of patient education; failure to adhere to the "take with food" instruction can result in significantly reduced drug exposure and potentially compromise therapeutic efficacy.

Table 1: Physicochemical Properties and Identifiers of Tepotinib
Property	Value / Identifier
International Nonproprietary Name (INN)	Tepotinib 1
Commercial Brand Name	TEPMETKO® 11
DrugBank ID	DB15133 1
CAS Registry Number	1100598-32-0 1
PubChem CID	25171648 11
Developmental Codes	EMD-1214063, MSC2156119 2
Molecular Formula	C29​H28​N6​O2​ 2
Molecular Weight	492.583 g·mol⁻¹ 2
IUPAC Name	3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile 2
Physical State	Solid powder 2
Water Solubility	<2.56 mg/mL 19
pKa (Predicted)	8.93±0.10 19
InChIKey	AHYMHWXQRWRBKT-UHFFFAOYSA-N 11

III. Pharmacology and Mechanism of Action

Tepotinib is a targeted anti-cancer agent whose therapeutic efficacy is derived from its precise and potent inhibition of the MET receptor tyrosine kinase, a key driver of tumorigenesis in select cancers.[1]

Primary Mechanism of Action: MET Kinase Inhibition

The primary pharmacological action of tepotinib is as a highly selective, reversible, and ATP-competitive inhibitor of the MET tyrosine kinase.[21] The MET receptor, also known as the hepatocyte growth factor receptor (HGFR), is encoded by the

MET proto-oncogene. In normal physiology, its activation by its ligand, hepatocyte growth factor (HGF), triggers signaling cascades involved in cellular growth, motility, and morphogenesis. However, in certain cancers, aberrant activation of MET—through gene amplification, rearrangement, overexpression, or specific mutations—drives uncontrolled cell proliferation, survival, invasion, and metastasis.[2]

Tepotinib exerts its effect by binding to the ATP-binding pocket of the MET kinase domain, thereby preventing the phosphorylation of the receptor.[1] This inhibition is highly potent, with a half-maximal inhibitory concentration (

IC50​) in the low nanomolar range (3-4 nM) in cell-free enzymatic assays.[18] A crucial feature of tepotinib is its ability to inhibit both the ligand (HGF)-dependent and the ligand-independent phosphorylation of MET.[3] This is particularly important for its clinical indication, as

MET exon 14 skipping alterations lead to a structurally abnormal MET protein that is constitutively active, independent of HGF binding. Tepotinib effectively targets and inhibits this oncogenic variant, forming the molecular basis of its efficacy in METex14 skipping NSCLC.[1]

Selectivity Profile

A defining characteristic of tepotinib's molecular design is its high degree of selectivity for the MET kinase. In comparative kinase profiling assays, tepotinib was found to be over 200-fold more selective for MET than for a broad panel of other kinases, including IRAK4, TrkA, Axl, IRAK1, and Mer.[18] This high selectivity is a critical attribute that distinguishes it from less-selective multi-kinase inhibitors. By minimizing "off-target" kinase inhibition, tepotinib's safety profile is more predictable and generally more manageable. This molecular precision allows for the administration of a dose sufficient to achieve profound and sustained inhibition of the MET target without incurring the dose-limiting toxicities often associated with broader-spectrum kinase inhibitors. This favorable therapeutic window is a key enabler of the long-term, continuous dosing required for durable disease control, as observed in the VISION trial. The molecular design for high selectivity is therefore not merely a technical feature but a direct contributor to the drug's clinical success and the durability of patient responses.

Disruption of Downstream Oncogenic Signaling

The therapeutic consequence of MET inhibition is the blockade of its downstream oncogenic signaling pathways.[1] Aberrant MET signaling is known to activate several critical intracellular cascades that promote cancer cell survival and proliferation. Tepotinib's action effectively shuts down these signals. Key pathways disrupted by tepotinib include:

1. The PI3K/AKT/mTOR Pathway: This pathway is a central regulator of cell survival, growth, and metabolism. By blocking MET-mediated activation of PI3K, tepotinib promotes apoptosis (programmed cell death) in MET-dependent tumor cells.[2]
2. The RAS/RAF/MEK/ERK (MAPK) Pathway: This cascade is a primary driver of cell proliferation. Tepotinib's inhibition of MET prevents the activation of this pathway, thereby halting uncontrolled cell division.[2]

Preclinical studies have confirmed that by disrupting these pathways, tepotinib effectively inhibits tumor cell proliferation, anchorage-independent growth (a hallmark of cancer cells), and the migration and invasion of MET-dependent tumor cells in vitro and in vivo.[1]

Impact on the Tumor Microenvironment and EMT

Tepotinib's mechanism may also extend beyond direct effects on the cancer cell to influence the surrounding tumor microenvironment. By inhibiting MET signaling, tepotinib can reduce the secretion of cytokines and growth factors that promote tumor progression.[2] Furthermore, it has been shown to modulate the process of epithelial-mesenchymal transition (EMT), a cellular program that allows cancer cells to become more migratory and invasive. In gastric cancer cell models, tepotinib down-regulated the expression of EMT-promoting genes (e.g.,

c-MYC) while up-regulating genes that suppress EMT and maintain an epithelial state (e.g., E-cadherin).[14] This suggests a potential anti-metastatic effect by stabilizing the cancer cells in a less aggressive phenotype.

Secondary Pharmacological Activities

In addition to its primary activity against MET, in vitro studies have shown that tepotinib can inhibit melatonin 2 (MTNR1B) and imidazoline 1 receptors at clinically achievable concentrations.[3] The clinical relevance of these secondary targets is not yet fully understood and remains an area for further investigation. It is possible that these off-target interactions could contribute to certain aspects of the drug's side effect profile or, hypothetically, to ancillary therapeutic effects not directly related to MET inhibition.

IV. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of tepotinib describes its journey through the body and is characterized by properties that support a convenient once-daily oral dosing regimen. Its behavior is well-defined by a high oral bioavailability when taken with food, extensive distribution, primary hepatic metabolism, and a long elimination half-life.[12]

Absorption

Tepotinib is administered orally as a 450 mg dose once daily.[12] Following oral administration under fed conditions, it is well absorbed, reaching a median time to maximum plasma concentration (Tmax) of approximately 8 hours at steady state.[12] Despite its low aqueous solubility, tepotinib achieves a high mean absolute oral bioavailability of 71.6% when taken with food.[12]

The effect of food on absorption is clinically significant. Co-administration with a high-fat, high-calorie meal increases the mean total exposure (AUC) by 1.6-fold and the peak plasma concentration (Cmax) by 2-fold compared to the fasted state.[12] This enhancement is critical for achieving consistent and therapeutic drug levels, forming the basis for the label's instruction to take tepotinib with food.[23] At the recommended dose of 450 mg, tepotinib exposure (both AUC and Cmax) increases dose-proportionally.[12] Upon repeated daily dosing, the drug accumulates, with steady-state Cmax and AUC values being approximately 2.5-fold and 3.3-fold higher than after a single dose, respectively.[12]

Distribution

Once absorbed, tepotinib is extensively distributed throughout the body tissues. This is reflected by its large geometric mean apparent volume of distribution (Vz/F) of 1,038 L.[12] In the bloodstream, tepotinib is highly bound to plasma proteins (~98%), primarily to serum albumin and alpha-1-acid glycoprotein.[12] This high degree of protein binding is independent of drug concentration within the clinically relevant range.[14] Preclinical evidence indicates that tepotinib can penetrate the blood-brain barrier, a finding that is corroborated by the clinical observation of robust intracranial activity in patients with brain metastases in the VISION trial.[25]

Metabolism

Tepotinib is cleared from the body primarily through hepatic metabolism and biliary excretion.[20] The drug is metabolized by multiple pathways, with no single pathway accounting for more than 25% of the dose.[20] The primary enzymes responsible for its biotransformation are cytochrome P450 (CYP) isoforms CYP3A4 and CYP2C8, with some additional contribution from uridine diphosphate-glucuronosyltransferase (UGT) enzymes.[2] The major circulating metabolite identified in human plasma is M506 (specifically, the R-enantiomer MSC2571109A), which accounts for approximately 40-41% of the total drug-related material in circulation.[14] Despite its significant presence, this metabolite is not considered to contribute meaningfully to the overall therapeutic efficacy of tepotinib.[20]

Excretion

The elimination of tepotinib is characterized by a long terminal half-life of approximately 32 hours.[12] This long half-life is a key pharmacokinetic feature that supports a convenient once-daily dosing schedule. The apparent oral clearance (CL/F) of tepotinib is 23.8 L/h.[12] The primary route of excretion is through the feces. Following a single oral radiolabeled dose, approximately 85% of the radioactivity was recovered in the feces, with a substantial portion (45% of the total dose) excreted as the unchanged parent drug.[12] In contrast, renal excretion plays a minor role, with only 13.6% of the dose recovered in the urine (7% as unchanged drug).[12] This excretion pattern confirms that biliary clearance of both unchanged tepotinib and its metabolites is the dominant elimination pathway.

A notable feature of tepotinib is the remarkable stability of its pharmacokinetic profile across diverse patient populations. Extensive population pharmacokinetic (PopPK) analyses, incorporating data from 12 clinical studies, have demonstrated that intrinsic patient factors such as age (spanning 18 to 89 years), race, sex, body weight, mild-to-moderate renal impairment (creatinine clearance 30-89 mL/min), and mild-to-moderate hepatic impairment (Child-Pugh A and B) do not have a clinically meaningful effect on tepotinib exposure.[12] This pharmacokinetic robustness is a significant clinical advantage. The target patient population for

METex14 skipping NSCLC is typically elderly, with a median age in the early 70s, and often presents with multiple co-morbidities.[8] A drug with a "forgiving" pharmacokinetic profile that does not require complex dose adjustments based on these common variables simplifies prescribing, reduces the potential for dosing errors, and ensures more predictable therapeutic exposures, thereby enhancing both safety and the likelihood of achieving an effective clinical outcome.

Table 2: Summary of Key Pharmacokinetic Parameters of Tepotinib
Parameter	Value (Geometric Mean, unless otherwise specified)
Recommended Oral Dose	450 mg once daily with food 12
Absolute Bioavailability (Fed)	71.6% 12
Median Time to Max Concentration (Tmax)	8 hours 12
Apparent Volume of Distribution (Vz/F)	1,038 L 12
Plasma Protein Binding	~98% 12
Elimination Half-life (t1/2)	~32 hours 12
Apparent Clearance (CL/F)	23.8 L/h 12
Primary Metabolic Enzymes	CYP3A4, CYP2C8 12
Primary Route of Excretion	Feces (~85% of dose) 12

V. Clinical Efficacy in Metastatic NSCLC

The clinical efficacy of tepotinib has been definitively established through the pivotal VISION trial, which demonstrated substantial and durable anti-tumor activity in patients with metastatic NSCLC harboring MET exon 14 skipping alterations. The results from this trial formed the basis for its global regulatory approvals and have positioned tepotinib as a standard of care for this molecularly defined patient population.

The Pivotal VISION Trial (NCT02864992): A Landmark Study

Study Design and Patient Population

The VISION trial is a Phase II, multicenter, multi-cohort, single-arm, open-label study designed to rigorously evaluate the efficacy and safety of tepotinib monotherapy.[7] A key strength of the trial's design was its prospective, biomarker-driven enrollment. Patients were eligible only if their tumors were confirmed to have

METex14 skipping alterations, which were identified using centralized testing of either tumor tissue biopsy (TBx) or plasma-derived circulating tumor DNA (ctDNA) from a liquid biopsy (LBx).[8] This approach ensured that the study population was precisely targeted.

Patients received tepotinib at a dose of 450 mg (active moiety) orally once daily until disease progression or unacceptable toxicity.[7] The final efficacy analysis, which supported the drug's traditional FDA approval, included 313 patients. This population was divided into two main cohorts: 164 treatment-naïve patients (receiving tepotinib as first-line therapy) and 149 previously treated patients (who had received at least one prior line of systemic therapy).[7] The demographic and clinical characteristics of the study population were consistent with those typically seen in patients with

METex14 skipping NSCLC, with a median age of 72 years, a majority having adenocarcinoma histology (81%), and a high rate of metastatic disease at baseline (94%).[8]

Primary and Secondary Endpoints

The primary endpoint of the VISION trial was the Overall Response Rate (ORR), defined as the percentage of patients with a confirmed partial or complete response. This was assessed by a Blinded Independent Review Committee (BIRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).[7] Important secondary endpoints included Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and a comprehensive assessment of the drug's safety profile.[9]

Efficacy Outcomes with Long-Term Follow-up

The long-term follow-up data from the VISION trial, with a median follow-up of 32.6 months, revealed not only a high rate of initial response but also an exceptional durability of benefit, particularly in the first-line setting.[10]

Overall Population (N=313)

Across the entire efficacy population, tepotinib demonstrated a BIRC-assessed ORR of 51.4% (95% Confidence Interval [CI]: 45.8–57.1). The responses were highly durable, with a median DOR of 18.0 months (95% CI: 12.4–46.4). The median PFS for the overall population was 11.2 months (95% CI: 9.5–13.8), and the median OS was 19.6 months (95% CI: 16.2–22.9).[9]

Treatment-Naïve Patients (First-Line, N=164)

The results in the first-line setting were particularly compelling. In this cohort of 164 patients, the ORR was 57% (95% CI: 49–65). The most striking finding was the median DOR, which reached an unprecedented 46.4 months (95% CI: 13.8–not estimable).[7] This outcome signifies that for responding patients, the disease can be controlled for a median duration of nearly four years with a single oral agent. The median PFS in this group was 12.6 months, and the median OS was 21.3 months.[10] These results firmly establish tepotinib as a highly effective first-line standard of care, transforming the prognosis for newly diagnosed patients with this disease. This level of durable benefit represents a fundamental shift from the historical outcomes seen with chemotherapy in this typically older population, where survival was often measured in months, not years.[28] This redefines the therapeutic goal from short-term palliation to long-term, chronic disease management, necessitating a new approach to patient care that includes long-term toxicity monitoring and support.

Previously Treated Patients (Second-Line+, N=149)

Tepotinib also demonstrated significant and durable activity in the 149 patients who had received prior systemic therapies, including platinum-based chemotherapy (84% of this cohort) and/or immune checkpoint inhibitors.[8] The ORR in this pre-treated population was 45% (95% CI: 37–53). The median DOR was 12.6 months (95% CI: 9.5–18.5), confirming that tepotinib provides a meaningful and lasting clinical benefit even in a refractory setting.[7]

Subgroup Analyses: Consistent Efficacy in Diverse Populations

A key strength of the VISION trial data is the consistent efficacy of tepotinib observed across various clinically relevant subgroups.

Age-Based Analysis

Given the advanced median age of the patient population, efficacy in the elderly was a critical question. Tepotinib demonstrated meaningful clinical activity irrespective of age. In an analysis of 152 patients, the ORR was 48.8% in patients aged <75 years and 39.7% in those aged ≥75 years.[26] The activity was maintained even in the most elderly patients (

≥80 years), providing reassurance for its use in this often-frail population.[30]

Patients with Brain Metastases

Approximately 13% of patients in the VISION trial had central nervous system (CNS) metastases at baseline.[8] Tepotinib showed robust activity in this challenging subgroup. The systemic ORR in patients with brain metastases was 47.8%, with a median PFS of 9.5 months, results that were comparable to the overall study population.[26] Furthermore, a retrospective analysis using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria confirmed direct intracranial activity. Of 15 evaluable patients, 13 (87%) achieved intracranial disease control. Among the 7 patients with measurable brain lesions, 5 (71%) had a partial intracranial response.[26] This evidence of blood-brain barrier penetration and CNS efficacy is of high clinical importance.

Biopsy Source (Liquid vs. Tissue)

The VISION trial's innovative design allowing enrollment based on either TBx or LBx provided a unique opportunity to compare outcomes based on the method of biomarker detection. While ORRs were similar between patients identified by TBx (54.3%) and LBx (51.7%), there was a trend towards better time-dependent outcomes in the TBx-positive cohort. The median PFS was 13.7 months for TBx-positive patients versus 8.9 months for LBx-positive patients, with a similar trend for median OS (22.9 vs. 17.6 months).[27] Further analysis suggested that patients positive by LBx tended to have a higher baseline tumor burden. This indicates that while LBx is a valid and convenient method for detecting

METex14 skipping, it may preferentially identify patients with more advanced disease and a consequently poorer prognosis, a factor that should be considered when interpreting outcomes.[27]

Health-Related Quality of Life (HRQoL)

Patient-reported outcomes are a crucial component of assessing a therapy's overall value. In the VISION trial, patients treated with tepotinib maintained a stable overall HRQoL throughout the study, as measured by standard instruments like the EORTC QLQ-C30 and EQ-5D-5L VAS.[31] This stability was observed even in subgroups with a high symptom burden, such as those with brain, liver, or bone metastases.[31] Notably, patients experienced a clinically meaningful improvement in cough, a common and debilitating symptom of NSCLC, further supporting the net clinical benefit of the treatment.[31]

Table 3: Efficacy Results from the VISION Trial in Key Patient Subgroups
Patient Subgroup	N	ORR % (95% CI)	Median DOR, months (95% CI)	Median PFS, months (95% CI)	Median OS, months (95% CI)
Overall Population	313	51.4 (45.8–57.1)	18.0 (12.4–46.4)	11.2 (9.5–13.8)	19.6 (16.2–22.9)
Treatment-Naïve (1L)	164	57.3 (49.4–65.0)	46.4 (13.8–NE¹)	12.6 (9.7–17.7)	21.3 (14.2–25.9)
Previously Treated (2L+)	149	45.0 (36.8–53.3)	12.6 (9.5–18.5)	10.9 (8.2–12.7)²	Not Reported
Baseline Brain Metastases	23	47.8 (26.8–69.4)	9.5 (5.5–NE)	9.5 (5.7–11.2)	Not Reported
Tissue Biopsy (TBx) Positive	208	54.3 (47.3-61.2)³	18.0 (12.4-22.1)³	13.7 (9.7-16.6)³	22.9 (18.8-29.7)³
Liquid Biopsy (LBx) Positive	178	51.7 (44.1-59.2)³	15.2 (9.5-20.8)³	8.9 (8.2-11.1)³	17.6 (14.2-21.3)³
Data from long-term follow-up analyses of the VISION trial.9 Some subgroup data may be from earlier data cuts.
¹NE = Not Estimable.
²PFS data for previously treated cohort from an earlier data cut.30
³ORR, DOR, PFS, and OS for TBx and LBx subgroups from a specific comparative analysis.27

VI. Safety Profile and Management of Adverse Events

The safety and tolerability of tepotinib have been extensively evaluated in a large patient population, primarily from the VISION trial. While adverse events are common, the overall safety profile is considered predictable and manageable with proactive monitoring and adherence to established dose modification guidelines, allowing most patients to continue treatment long-term.

Overview of Safety Population

The primary safety data for tepotinib comes from 313 patients with METex14 skipping NSCLC enrolled in the VISION trial.[13] This dataset is supported by a larger pooled analysis of 506 patients with various solid tumors treated with tepotinib across multiple studies.[13] In this pooled population, 44% of patients were exposed to treatment for 6 months or longer, and 22% for more than one year, providing robust long-term safety information.[13]

Most Common Adverse Reactions

The most frequently observed adverse reactions (AEs), occurring in ≥20% of patients, are consistent across studies and include edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.[3]

Edema is the hallmark adverse event associated with tepotinib and other MET inhibitors. It was reported in 81% of patients in the VISION trial (any grade).[13] While the majority of cases are low-grade (Grade 1 or 2), Grade 3 or 4 edema occurred in 16% of patients.[13] This high incidence of edema, though mostly mild, represents the most significant challenge to patient quality of life and is the leading cause for dose interruptions (28% of patients) and dose reductions (22% of patients).[13] Effective management of this side effect is therefore critical to maintaining treatment continuity and achieving the long-term benefits of the therapy. Supportive care measures, such as compression stockings, limb elevation, and, in some cases, diuretic use, are important components of management.[30]

Common Laboratory Abnormalities

In addition to clinical symptoms, treatment with tepotinib is associated with several common laboratory abnormalities. Those worsening from baseline in ≥20% of patients include decreased albumin (81%), decreased lymphocytes (57%), increased creatinine (55%), increased gamma-glutamyltransferase (GGT), increased amylase, increased lipase, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST).[3] The most common Grade 3-4 laboratory abnormalities (

≥2%) were decreased lymphocytes, decreased albumin, decreased sodium, and increased levels of GGT, amylase, lipase, ALT, and AST.[3]

Table 4: Incidence of Common (≥20%) Adverse Reactions and Laboratory Abnormalities in the VISION Trial (N=313)
Adverse Reaction / Laboratory Abnormality	Any Grade Incidence (%)	Grade 3–4 Incidence (%)
Clinical Adverse Reactions
Edema	81	16
Nausea	31	1.3
Fatigue	Not Reported in this table, but listed as ≥20% 12
Musculoskeletal Pain	30	3.2
Diarrhea	Not Reported in this table, but listed as ≥20% 12
Dyspnea	24	2.6
Decreased Appetite	21	1.9
Rash	21	1.3
Laboratory Abnormalities
Decreased Albumin	81	9
Decreased Lymphocytes	57	15
Increased Creatinine	55	0.6
Increased Alkaline Phosphatase	50	4.2
Increased ALT	44	4.7
Increased AST	35	2.6
Decreased Sodium	31	8
Decreased Hemoglobin	27	2.6
Increased Amylase	23	5
Increased Lipase	18	3.7
Data compiled from prescribing information for TEPMETKO®.3

Serious and Clinically Significant Adverse Reactions

While most AEs are low-grade, tepotinib carries a risk of serious and potentially fatal toxicities that require vigilant monitoring and specific management strategies. Serious adverse reactions occurred in 51% of patients, with the most frequent being pleural effusion (6%), pneumonia (6%), and edema (5%).[8] Fatal adverse reactions occurred in 1.9% of patients.[13]

Interstitial Lung Disease (ILD)/Pneumonitis

ILD/pneumonitis is a rare but life-threatening pulmonary toxicity associated with tepotinib. It occurred in 2-2.2% of patients treated with the drug, and at least one fatal event has been reported.[8] Patients must be monitored closely for new or worsening respiratory symptoms such as dyspnea, cough, or fever.

Hepatotoxicity

Liver toxicity is a known risk. Increased ALT and/or AST of any grade occurred in 18% of patients, with Grade 3 or 4 elevations observed in 4.7%.[3] A fatal case of hepatic failure (0.2%) has been reported.[8] The median time to onset for Grade 3 or higher transaminase elevations was 47 days, highlighting the need for frequent monitoring early in the course of treatment.[3]

Pancreatic Toxicity

Elevations in pancreatic enzymes (amylase and/or lipase) are also a concern. Any-grade elevations occurred in 13% of patients, with Grade 3 and 4 increases occurring in 5% and 1.2% of patients, respectively.[3]

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, tepotinib can cause harm to a developing fetus. Consequently, pregnancy testing is required before initiating treatment in females of reproductive potential, and effective contraception must be used by both female patients and male patients with female partners of reproductive potential during treatment and for one week after the final dose.[4]

Management of Adverse Events

A systematic approach to managing adverse events is crucial for patient safety and for enabling patients to remain on this effective therapy. This involves a combination of routine monitoring and clear, toxicity-specific dose modification guidelines.

Monitoring

• Pulmonary: Patients should be monitored at each visit for new or worsening pulmonary symptoms (dyspnea, cough, fever).[23]
• Hepatic: Liver function tests (ALT, AST, and total bilirubin) must be monitored prior to starting therapy, every two weeks during the first three months of treatment, and then monthly or as clinically indicated. More frequent testing is required for patients who develop elevations.[5]
• Pancreatic: Amylase and lipase levels should be monitored at baseline and regularly during treatment.[8]

Dose Modification

The recommended dose reduction for managing AEs is from 450 mg to 225 mg once daily. If the 225 mg dose is not tolerated, tepotinib should be permanently discontinued.[33] Specific management protocols are outlined in Table 5.

Table 5: Recommended Dose Modifications for Key Adverse Reactions
Adverse Reaction	Recommended Action
Interstitial Lung Disease (ILD)/Pneumonitis
Any Grade (Suspected or Confirmed)	Withhold immediately if suspected. Permanently discontinue if confirmed. 23
Hepatotoxicity
Grade 3 ALT/AST Elevation (without bilirubin elevation)	Withhold until recovery to baseline. If recovery ≤7 days, resume at same dose. If recovery >7 days, resume at reduced dose (225 mg). 3
Grade 4 ALT/AST Elevation	Permanently discontinue. 3
ALT/AST >3x ULN with Total Bilirubin >2x ULN	Permanently discontinue. 3
Grade 3 Total Bilirubin Elevation (without ALT/AST elevation)	Withhold until recovery to baseline. If recovery ≤7 days, resume at reduced dose (225 mg). If recovery >7 days, permanently discontinue. 3
Pancreatic Toxicity
Grade 3 Amylase/Lipase Elevation	Withhold until recovery to ≤Grade 2 or baseline. If recovery ≤14 days, resume at reduced dose (225 mg). If recovery >14 days, permanently discontinue. 34
Grade 4 Amylase/Lipase Elevation or Grade 3-4 Pancreatitis	Permanently discontinue. 34
Other Adverse Reactions
Grade 2 (Intolerable)	Consider withholding until resolution, then resume at reduced dose (225 mg). 33
Grade 3	Withhold until resolution, then resume at reduced dose (225 mg). 33

VII. Dosage, Administration, and Drug Interactions

The effective and safe use of tepotinib in clinical practice requires strict adherence to its approved dosage and administration guidelines, mandatory biomarker testing for patient selection, and a thorough understanding of its potential for drug-drug interactions.

Recommended Dosing and Administration

The recommended dosage of TEPMETKO is 450 mg, administered as two 225 mg tablets, taken orally once daily.[5] Treatment should continue until evidence of disease progression or the development of unacceptable toxicity.[5]

Key administration instructions include:

• Administration with Food: Tepotinib must be taken with food to ensure optimal and consistent absorption.[12]
• Swallowing Tablets: Patients should be instructed to swallow the tablets whole. They should not be chewed, crushed, or split.[33]
• Administration for Patients with Dysphagia: For patients who have difficulty swallowing solids, the tablets can be dispersed in 30 mL of non-carbonated water (no other liquids should be used). The patient should stir the mixture until the tablets disperse into small pieces (they will not dissolve completely) and consume it immediately or within one hour. The glass should be rinsed with an additional 30 mL of water, which should also be consumed to ensure the full dose is administered.[17] This dispersion can also be administered via a naso-gastric tube.[32]
• Management of Missed Doses or Vomiting: If a dose is missed, it can be taken as soon as remembered, unless the next scheduled dose is due within 8 hours. In that case, the missed dose should be skipped. If a patient vomits after taking a dose, they should not take an extra dose but should take the next dose at the regularly scheduled time.[23]

Pharmacogenomic Considerations and Patient Selection

Tepotinib is a paradigm of precision medicine, as its use is exclusively indicated for a genetically defined subgroup of NSCLC patients. Its efficacy is contingent upon the presence of an oncogenic driver—MET exon 14 skipping alterations.[1] Therefore,

pharmacogenomic testing is mandatory to identify eligible patients before initiating therapy.

An FDA-approved companion diagnostic test should be used to detect METex14 skipping alterations in either tumor tissue specimens or in plasma-derived ctDNA.[8] While liquid biopsy offers a less invasive option, if a

METex14 skipping alteration is not detected in a plasma sample, a tumor tissue biopsy should be performed for definitive testing if feasible, as tissue analysis is generally considered the gold standard.[8] This biomarker-driven approach is essential to ensure that this highly effective targeted therapy is directed only to those patients who can derive clinical benefit.

Clinically Significant Drug Interactions

Understanding the potential for drug-drug interactions (DDIs) is critical for managing safety in an oncology population often receiving multiple concurrent medications. Tepotinib's DDI profile has been characterized through both in vitro studies and dedicated clinical trials.

Effect of Other Drugs on Tepotinib (Victim Potential)

In vitro experiments suggested that tepotinib is a substrate of both the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter, raising theoretical concerns about interactions with modulators of these pathways.[12] However, subsequent clinical DDI studies in healthy volunteers demonstrated that these interactions are not clinically significant.

• CYP3A4/P-gp Inhibitors: Co-administration with itraconazole, a strong inhibitor of both CYP3A4 and P-gp, resulted in only a modest 22% increase in tepotinib AUC.[36]
• CYP3A4/P-gp Inducers: Co-administration with carbamazepine, a strong inducer of both pathways, led to a 35% decrease in tepotinib AUC.[36]

Neither of these changes in exposure was considered clinically relevant, as they fall within the observed inter-patient variability and are not expected to impact efficacy or safety based on exposure-response analyses.[36] Consequently,

no dose adjustment is required when tepotinib is co-administered with strong CYP3A4 or P-gp inhibitors or inducers.[36]

Effect of Tepotinib on Other Drugs (Perpetrator Potential)

The most clinically important interaction is tepotinib's role as an inhibitor of the P-gp efflux transporter.[1] By inhibiting P-gp, tepotinib can increase the plasma concentrations and potential toxicity of co-administered drugs that are P-gp substrates.

• A clinical study confirmed this effect, showing that tepotinib increased the AUC of dabigatran etexilate (a sensitive P-gp substrate) by approximately 51% and its Cmax by 38%.[32]
• Because of this, the prescribing information warns against the co-administration of tepotinib with P-gp substrates where even small changes in concentration could lead to serious or life-threatening toxicities (e.g., digoxin, dabigatran, certain chemotherapeutic agents).[3] If concomitant use is unavoidable, a dose reduction of the P-gp substrate should be considered as recommended in its own labeling.[12]

Tepotinib does not appear to be a clinically significant inhibitor or inducer of CYP3A4, as a DDI study with the sensitive CYP3A4 substrate midazolam showed no effect on its pharmacokinetics.[39]

Table 6: Summary of Clinically Significant Drug Interactions and Management Recommendations
Interacting Agent Class	Effect on Co-administered Drug / Tepotinib	Clinical Management Recommendation
Sensitive P-gp Substrates (e.g., dabigatran, digoxin, afatinib, apixaban, colchicine) 41	Tepotinib (a P-gp inhibitor) increases the concentration and potential toxicity of the P-gp substrate.	Avoid co-administration with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling. 3
Strong CYP3A4/P-gp Inhibitors (e.g., itraconazole, ketoconazole, ritonavir) 36	Increases tepotinib exposure (AUC) by ~22%. This effect is not considered clinically significant.	No dose adjustment of tepotinib is required. 36
Strong CYP3A4/P-gp Inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's Wort) 36	Decreases tepotinib exposure (AUC) by ~35%. This effect is not considered clinically significant.	No dose adjustment of tepotinib is required. 36
Sensitive CYP3A4 Substrates (e.g., midazolam) 42	Tepotinib does not have a clinically significant effect on the exposure of CYP3A4 substrates.	No dose adjustment of the CYP3A4 substrate is required. 40

VIII. Regulatory History and Global Status

The regulatory journey of tepotinib reflects its significant clinical impact and the success of a targeted, biomarker-driven development strategy. Its path to approval across major global markets was efficient, marked by several "firsts" and the attainment of special regulatory designations that recognized its potential to address a high unmet medical need.

Development and Manufacturer

Tepotinib was discovered and developed in-house by the science and technology company Merck KGaA, Darmstadt, Germany.[22] In the United States and Canada, the company's healthcare business operates under the name EMD Serono, which is responsible for the commercialization of TEPMETKO® in these regions.[35]

Global Approval Timeline

Tepotinib achieved a significant milestone by becoming the first oral MET inhibitor to receive regulatory approval anywhere in the world for the treatment of advanced NSCLC with MET gene alterations. This inaugural approval was granted in Japan in March 2020 by the Ministry of Health, Labour and Welfare (MHLW), facilitated by its designation under the SAKIGAKE (pioneer) fast-track review system.[1]

US Food and Drug Administration (FDA) Approval Pathway

In the United States, tepotinib's development was expedited through several key FDA programs. It was granted both Breakthrough Therapy Designation and Orphan Drug Designation, acknowledging its potential for substantial improvement over existing therapies for a serious condition and its application in a rare disease sub-population, respectively.[7]

The FDA initially granted Accelerated Approval on February 3, 2021. This approval was for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping alterations and was based on the primary endpoints of ORR and DOR from the initial cohort of the VISION trial.[1] The accelerated pathway allows for earlier patient access to promising drugs while the company gathers additional data to confirm clinical benefit.

On February 15, 2024, following the submission of a more extensive dataset from the VISION trial—which included an additional 161 patients and an added 28 months of follow-up to further characterize the durability of response—the FDA converted the accelerated approval to Traditional (Full) Approval.[7] This conversion represents the highest level of regulatory validation, confirming that the drug's clinical benefit has been robustly verified. This successful transition from accelerated to full approval based on mature data from a single-arm Phase II study serves as an important precedent. It validates the regulatory strategy of using well-designed, biomarker-selected trials with compelling and durable endpoints to secure full approval for targeted therapies in rare oncologic indications, potentially accelerating the availability of effective treatments for patients with limited options.

European Medicines Agency (EMA) Approval

In Europe, the EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion in December 2021.[11] This led to the formal marketing authorization for TEPMETKO by the European Commission (EC) on

February 16, 2022.[1] The approved indication in the European Union is for tepotinib as a monotherapy for the treatment of adult patients with advanced NSCLC harboring

METex14 skipping alterations, specifically for those who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.[1] This indication is slightly more restrictive than the broader first-line and subsequent-line approval in the United States.

Other Regulatory Bodies

Beyond these major markets, tepotinib has also received approvals and is available in numerous other countries. In Great Britain, it was granted a conditional Marketing Authorisation by the Medicines and Healthcare Products Regulatory Agency (MHRA) in September 2021, and it is recommended for use on the National Health Service (NHS).[48] Its availability continues to expand globally as regulatory reviews are completed in other jurisdictions.[22]

IX. Conclusion

Tepotinib (TEPMETKO®) has emerged as a cornerstone therapy in the management of metastatic non-small cell lung cancer characterized by MET exon 14 skipping alterations. As a highly selective and potent oral MET tyrosine kinase inhibitor, its development and approval epitomize the success of a precision oncology strategy, targeting a specific molecular driver with a tailored therapeutic agent.

The comprehensive clinical data from the pivotal Phase II VISION trial have unequivocally established its profound and durable efficacy. The high overall response rates and, most notably, the exceptionally long duration of response—extending to a median of nearly four years in the first-line setting—have fundamentally altered the natural history of this aggressive disease. This transforms the treatment approach from one of short-term palliation to a viable long-term disease management strategy, offering patients a significant extension of life with maintained quality of life. The consistent activity observed across diverse and challenging patient subgroups, including the elderly and those with brain metastases, further solidifies its broad clinical utility within its indicated population.

The drug's well-characterized and manageable safety profile, coupled with a favorable pharmacokinetic profile that supports convenient once-daily dosing and requires minimal adjustment for patient-specific factors, enhances its practical application in a real-world clinical setting. While adverse events such as peripheral edema require proactive management, established monitoring and dose modification guidelines allow for safe long-term administration in the majority of patients.

The successful regulatory journey of tepotinib, culminating in its conversion to full FDA approval, not only validates its substantial clinical benefit but also serves as a model for efficient, biomarker-driven drug development in rare cancer subtypes. In conclusion, tepotinib represents a transformative therapeutic advance, providing a new and effective standard of care that has redefined the prognosis for patients with METex14 skipping NSCLC.

Works cited

1. Tepotinib | C29H28N6O2 | CID 25171648 - PubChem, accessed August 25, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Tepotinib
2. CAS 1100598-32-0 Tepotinib - BOC Sciences, accessed August 25, 2025, https://www.bocsci.com/product/tepotinib-cas-1100598-32-0-456948.html
3. TEPMETKO® (tepotinib) tablets, for oral use - accessdata.fda.gov, accessed August 25, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214096s003lbl.pdf
4. EMD Serono's TEPMETKO (tepotinib), accessed August 25, 2025, https://www.tepmetko.com/us-en/patients-and-caregivers.html
5. Tepotinib - LiverTox - NCBI Bookshelf, accessed August 25, 2025, https://www.ncbi.nlm.nih.gov/books/NBK595113/
6. NSCLC: tepotinib, first therapy approved against the METex14 ..., accessed August 25, 2025, https://www.diatechpharmacogenetics.com/en/blog/2022/03/03/nsclc-tepotinib-first-therapy-approved-against-the-metex14-skipping-alterations/
7. FDA approves tepotinib for metastatic non-small cell lung cancer | FDA, accessed August 25, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tepotinib-metastatic-non-small-cell-lung-cancer
8. Largest METex14+ trial - TEPMETKO.com, accessed August 25, 2025, https://www.tepmetko.com/us-en/home/clinical-data/vision-trial.html
9. Robust and Durable Clinical Activity of Tepotinib in Patients with ..., accessed August 25, 2025, https://www.esmo.org/oncology-news/robust-and-durable-clinical-activity-of-tepotinib-in-patients-with-metex14-skipping-nsclc
10. Long-term outcomes of tepotinib in patients with MET exon 14 skipping NSCLC from the VISION study. | Journal of Clinical Oncology - ASCO Publications, accessed August 25, 2025, https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9060
11. Tepotinib - Wikipedia, accessed August 25, 2025, https://en.wikipedia.org/wiki/Tepotinib
12. FDA Approves TEPMETKO for Metastatic NSCLC | ACCP - American College of Clinical Pharmacology, accessed August 25, 2025, https://accp1.org/members/ACCP1/5Publications_and_News/FDABurst2021/TEPMETKO-Metastatic-NSCLC.aspx
13. TEPMETKO® (tepotinib) Prescribing Information - EMD Serono, accessed August 25, 2025, https://www.emdserono.com/us-en/pi/tepmetko-pi.pdf
14. Tepotinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 25, 2025, https://go.drugbank.com/drugs/DB15133
15. Population pharmacokinetic analysis of tepotinib, an oral MET kinase inhibitor, including data from the VISION study - PubMed, accessed August 25, 2025, https://pubmed.ncbi.nlm.nih.gov/35385993/
16. Tepmetko | European Medicines Agency (EMA), accessed August 25, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/tepmetko
17. Tepotinib (oral route) - Side effects & dosage - Mayo Clinic, accessed August 25, 2025, https://www.mayoclinic.org/drugs-supplements/tepotinib-oral-route/description/drg-20509584
18. Tepotinib | 99.58%(HPLC) | In Stock | c-Met inhibitor - Selleck Chemicals, accessed August 25, 2025, https://www.selleckchem.com/products/emd-1214063.html
19. Tepotinib | 1100598-32-0 - ChemicalBook, accessed August 25, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB72550731.htm
20. Population pharmacokinetic analysis of tepotinib, an oral MET ..., accessed August 25, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9054876/
21. Tepotinib (EMD-1214063) | c-Met Inhibitor | MedChemExpress, accessed August 25, 2025, https://www.medchemexpress.com/EMD-1214063.html
22. 2022-02-18 TEPMETKO® for Patients with Advanced NSCLC with ..., accessed August 25, 2025, https://www.emdserono.com/us-en/company/news/press-releases/tepmetko-ec-approval-advanced-nsclc-18-02-2022.html
23. Dosing and Treatment Management Guide - TEPMETKO (tepotinib), accessed August 25, 2025, https://www.tepmetko.com/content/dam/web/healthcare/clinicaltrial/oncology/tepmetko/documents/TEPMETKO-Dosing-and-Treatment-Management-Guide.pdf
24. Tepotinib and Alcohol/Food Interactions - Drugs.com, accessed August 25, 2025, https://www.drugs.com/food-interactions/tepotinib.html
25. The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations - AACR Journals, accessed August 25, 2025, https://aacrjournals.org/mct/article/22/7/833/727412/The-Preclinical-Pharmacology-of-Tepotinib-A-Highly
26. Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping ..., accessed August 25, 2025, https://aacrjournals.org/clincancerres/article/28/6/1117/682037/Tepotinib-Efficacy-and-Safety-in-Patients-with-MET
27. Liquid and Tissue Biopsies for Identifying MET Exon 14 Skipping NSCLC: Analyses from the Phase II VISION Study of Tepotinib - AACR Journals, accessed August 25, 2025, https://aacrjournals.org/clincancerres/article/31/13/2675/763091/Liquid-and-Tissue-Biopsies-for-Identifying-MET
28. FDA Grants Full Approval to Tepotinib for Non-Small Cell Lung Cancer - Targeted Oncology, accessed August 25, 2025, https://www.targetedonc.com/view/fda-grants-full-approval-tepotinib-for-non-small-cell-lung-cancer
29. Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice - PubMed, accessed August 25, 2025, https://pubmed.ncbi.nlm.nih.gov/34789481/
30. Has the Enemy “MET” Its Match? Subgroup Analysis Results from VISION Study - AACR Journals, accessed August 25, 2025, https://aacrjournals.org/clincancerres/article-pdf/28/6/1055/3055060/1055.pdf
31. Health-related quality of life (HRQoL) with tepotinib in patients with ..., accessed August 25, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.8575
32. TEPMETKO, INN - tepotinib - European Medicines Agency, accessed August 25, 2025, https://www.ema.europa.eu/en/documents/product-information/tepmetko-epar-product-information_en.pdf
33. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 25, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214096s000lbl.pdf
34. Tepotinib: uses, dosing, warnings, adverse events, interactions, accessed August 25, 2025, https://www.oncologynewscentral.com/drugs/monograph/180797-321020/tepotinib-oral
35. Tepmetko (tepotinib) FDA Approval History - Drugs.com, accessed August 25, 2025, https://www.drugs.com/history/tepmetko.html
36. Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P ..., accessed August 25, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12273743/
37. Tepotinib Inhibits Several Drug Efflux Transporters and ..., accessed August 25, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8584989/
38. Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo - MDPI, accessed August 25, 2025, https://www.mdpi.com/1422-0067/22/21/11936
39. (PDF) Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates - ResearchGate, accessed August 25, 2025, https://www.researchgate.net/publication/372161911_Assessment_of_the_potential_of_the_MET_inhibitor_tepotinib_to_affect_the_pharmacokinetics_of_CYP3A4_and_P-gp_substrates/download
40. Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates - PubMed, accessed August 25, 2025, https://pubmed.ncbi.nlm.nih.gov/37415001/
41. Tepmetko (tepotinib) dosing, indications, interactions, adverse ..., accessed August 25, 2025, https://reference.medscape.com/drug/tepmetko-tepotinib-4000127
42. Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates - PMC, accessed August 25, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10447267/
43. European Medicines Agency Validates Application for Tepotinib for the Treatment of Advanced NSCLC with METex14 Skipping Alterations - PR Newswire, accessed August 25, 2025, https://www.prnewswire.com/in/news-releases/european-medicines-agency-validates-application-for-tepotinib-for-the-treatment-of-advanced-nsclc-with-metex14-skipping-alterations-868437423.html
44. FDA Approves TEPMETKO ® as the First and Only Once-daily Oral MET Inhibitor for Patients with Metastatic NSCLC with METex14 Skipping Alterations - Merck KGaA, Darmstadt, Germany, accessed August 25, 2025, https://www.emdgroup.com/en/news/tepotinib-fda-approval-metex14-03-02-2021.html
45. www.tepmetko.com, accessed August 25, 2025, https://www.tepmetko.com/us-en/home.html#:~:text=EMD%20Serono's%20TEPMETKO%20(tepotinib)
46. FDA Approves Tepmetko (tepotinib) for People with Metastatic Non-Small Cell Lung Cancer with MET-Exon 14 Mutation, accessed August 25, 2025, https://go2.org/blog/fda-approves-tepmetko-tepotinib-for-people-with-metastatic-non-small-cell-lung-cancer-with-met-exon-14-mutation/
47. Tepotinib Approved by European Commission for Advanced MET exon 14+ NSCLC, accessed August 25, 2025, https://www.cancernetwork.com/view/tepotinib-approved-by-european-commission-for-advanced-met-exon-14-nsclc
48. NICE recommends Merck's TEPMETKO® (tepotinib) as the first oral MET inhibitor treatment as an option for adult patients with advanced NSCLC with METex14 skipping alterations, accessed August 25, 2025, https://www.merckgroup.com/uk-en/NICE%20recommends%20TEPMETKO%C2%AE%20(tepotinib)%20for%20NSCLC%20with%20METex14%20skipping%20alterations.pdf