OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Tepotinib – Tepmetko®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Tepotinib	1100598-32-0	C29-H28-N6-O2

ANNOTATED BIBLIOGRAPHY

References updated: 08 September 2023

Abbreviations: MET, mesenchymal epithelial transition receptor kinase gene; NSCLC, non-small cell lung cancer.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents, does not discuss tepotinib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. 2020. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/214096Orig1s000MultidisciplineR.pdf

  (FDA website with initial multidiscipline clinical review of the safety and efficacy of tepotinib; states that the overall objective response rate was 43% in both treatment naïve and treatment refractory patients, and that adverse events arose in most patients and while 44% of patients had an ALT elevations, only 4% were above 5 times ULN, ALT elevations led to dose interruption in 7%, dose adjustment in 2%, but early discontinuation in none, one treated patient died of acute liver failure with ALT above 20 times ULN, but the event was considered unrelated to therapy; the reviewers concluded that “safety issues considered significant enough to warrant inclusion in the Warnings and Precautions section of the [product label] were interstitial lung disease/pneumonitis and hepatotoxicity”).
• Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, Heng JC, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34:721-30. [PubMed: 26729443]

  (Among 6376 cancers undergoing genome sequencing, MET exon 14 mutations were found in 28 of 933 [3%] NSCLC, KRAS mutations in 34%, EGFR in 19%, ALK 4% and BRAF in 4%; those with the MET exon 14 skipping mutations tended to be older than those with KRAS or EGFR mutations).
• Markham A. Tepotinib: first approval. Drugs. 2020;80:829-833. [PubMed: 32361823]

  (Summary of the mechanism of action, history of development, pharmacodynamics, clinical efficacy and safety of tepotinib shortly after its first approval in Japan, does not discuss or mention ALT elevations or hepatotoxicity).
• Wu YL, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J, Kim DW, et al.; INSIGHT Investigators. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020;8:1132-1143. [PubMed: 32479794]

  (Among 55 adults with advanced or metastatic NSCLC with MET overexpression or amplification mutations treated with tepotinib and gefitinib vs standard platinum-based chemotherapy, the objective response rates were 45% vs 33% and adverse events were frequent [98% vs 100%] and included ALT elevations in 29% vs 9%, but there were no serious hepatic adverse events or treatment related deaths).
• Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC, Mazieres J, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383:931-943. [PMC free article: PMC8422679] [PubMed: 32469185]

  (Among 152 adults with advanced NSCLC with confirmed MET exon 14 skip mutations treated with tepotinib, the objective response rate was 46% and median duration of response of 11 months, while adverse events occurred in 98% of patients including treatment related serious adverse events in 15%, dose reductions in 33%, and permanent discontinuations in 11%, with ALT elevations in 7% which were above 5 times ULN in 2%).
• Ryoo BY, Cheng AL, Ren Z, Kim TY, Pan H, Rau KM, Choi HJ, et al. Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression. Br J Cancer. 2021;125:200-208. [PMC free article: PMC8292411] [PubMed: 33972742]

  (Among 90 Asian patients with advanced hepatocellular carcinoma with MET overexpression treated with tepotinib [300, 500 or 1000 mg once daily] or sorafenib [400 mg twice daily], time to progression was slightly longer with tepotinib [2.9 vs 1.4 months], while adverse events rates were lower [82% vs 98% overall] with ALT elevations in 9% vs 16% [none greater than 5 times ULN]).
• Mathieu LN, Larkins E, Akinboro O, Roy P, Amatya AK, Fiero MH, Mishra-Kalyani PS, et al. FDA approval summary: capmatinib and tepotinib for the treatment of metastatic NSCLC harboring MET Exon 14 Skipping Mutations or Alterations. Clin Cancer Res. 2022;28:249-254. [PubMed: 34344795]

  (Summary of the data supporting the FDA accelerated approvals of capmatinib and tepotinib for metastatic NSCLC with MET exon 14 skipping mutations or alterations, mentions that the safety profiles were similar for the two agents, both of which had evidence of hepatotoxicity considered serious enough to include in Warnings and Precautions sections of the product labels).
• Tseng LW, Chang JW, Wu CE. Safety of tepotinib challenge after capmatinib-induced pneumonitis in a patient with non-small cell lung cancer harboring MET exon 14 skipping mutation: a case report. Int J Mol Sci. 2022;23:11809. [PMC free article: PMC9570266] [PubMed: 36233109]

  (69 year old Taiwanese man with metastatic NSCLC harboring MET exon14 skipping mutation developed an interstitial pneumonitis within a month of starting capmatinib that resolved with stopping and methyl prednisolone therapy, yet later tolerated tepotinib therapy without recurrence for one month when it was stopped because of disease progression).
• Veillon R, Sakai H, Le X, Felip E, Cortot AB, Smit EF, Park K, et al. Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management. Clin Lung Cancer. 2022;23:320-332. [PMC free article: PMC10068910] [PubMed: 35466070]

  (In a secondary analysis of common adverse events from an open label trial of tepotinib in 255 adults with MET exon 14 skipping NSCLC [Paik 2020], 31 patients developed treatment related ALT or AST elevations [12%], six [4%] being 5- to 20-fold elevated, and two [1.5%] greater than 20-fold elevated with median onset at 6 weeks and resolution after 5 weeks; patients were largely asymptomatic, none had jaundice, none required drug discontinuation, nine had temporary interruption, and two dose reduction).
• Mazieres J, Paik PK, Garassino MC, Le X, Sakai H, Veillon R, Smit EF, et al. Tepotinib treatment in patients with MET exon 14-skipping non-small cell lung cancer: long-term follow-up of the VISION phase 2 nonrandomized clinical trial. JAMA Oncol. 2023;9:1260-1266. [PMC free article: PMC10240398] [PubMed: 37270698]

  (Among 313 patients with advanced or metastatic NSCLC with MET exon 14 skipping mutations treated with tepotinib in two cohorts, the objective response rates was 51% and adverse events occurred in 99% leading to dose reductions in 36% and discontinuations in 25%, and including ALT elevations in 14% which were above 5 times ULN in 2.2%).
• Liam CK, Ahmad AR, Hsia TC, Zhou J, Kim DW, Soo RA, Cheng Y, et al. Randomized trial of tepotinib plus gefitinib versus chemotherapy in EGFR-mutant NSCLC with EGFR inhibitor resistance due to MET amplification: INSIGHT final analysis. Clin Cancer Res. 2023;29:1879-1886. [PMC free article: PMC10183805] [PubMed: 36971777]

  (Among 55 patients with advanced or metastatic NSCLC with MET overexpression treated with tepotinib and gefitinib vs standard platinum-based chemotherapy [Wu 2020], final analysis after 57.5 months of follow up showed similar progression free survival [4.9 vs 4.4 months] and adverse event rates; among those receiving tepotinib and gefitinib, ALT elevations arose in 32% and were above 5 times ULN in 3%).