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Role of METex14

METex14 skipping should be identified at diagnosis as it plays an important role in NSCLC oncogenesis.1,2


METex14 matters

Pie chart showing the prevalence of oncogenic drivers in lung adenocarcinoma including: 26% KRAS, 21% Wild type, 16% EGFR, 7% BRAF, 4% ALK, 2% ROS1, 2-4% METex14, 1-5% MET AMP, and 17% Other.
met-matters

Prevalence of Oncogenic Drivers in Lung Adenocarcinoma2-4

Based on 2021 estimates, 
~6,000-8,000 patients with NSCLC harboring METex14 alterations may be diagnosed each year in the US

Based on 2021 estimates, ~6,000-8,000 patients with NSCLC harboring METex14 alterations may be diagnosed each year in the US⁵

 

*METex14 skipping is a MET gene alteration and its estimated frequency in patients with NSCLC varies between studies. METex14 is estimated to occur in 2% of squamous cell carcinomas and 8%-30% of sarcomatoid carcinomas.6

3%-4% of patients may harbor METex14 skipping alterations2

Patients with METex14+ skipping alterations have been associated with having advanced disease and a poor prognosis.1

These patients tend to be significantly older than patients with other oncogenic drivers (54-65 years of age in ALK, ROS1, EGFR, and KRAS) with an average age of ~74 years at diagnosis.

~65% of patients with METex14 skipping alterations may be PD-L1 positive ( ≥1% expression)8

It is important to test for this primary oncogenic driver to identify patients at diagnosis and help inform treatment decisions1,2

 


  • Clinicians obtain molecular testing results for actionable biomarkers in eligible patients with metastatic NSCLC before administering first-line ICI therapy ± chemotherapy, if clinically feasible 
  • Targeted therapies for patients with metastatic NSCLC and specific oncogenic drivers independent of PD-L1 levels 

 

MET pathway

Normal MET pathway signaling4,10,11

  • Depending on the cellular context, activated MET signaling may induce processes including cell proliferation, motility, and apoptosis
  • MET alterations like METex14 skipping or MET amplification lead to a dysregulation of MET signaling
  • Dysregulated MET signaling may lead tumor cell proliferation, migration, and survival
met-pathway
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Image showing normal MET pathway signaling met-pathway

Mechanism of action

TEPMETKO® (tepotinib) MOA4,10,12

TEPMETKO is an inhibitor that targets MET tyrosine kinase activity, including aberrant activity observed with METex14 skipping alterations.

  • TEPMETKO inhibits hepatocyte growth factor (HGF)-dependent and ‑independent MET phosphorylation and MET-dependent downstream signaling pathways
  • TEPMETKO also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations
  • In vitro, TEPMETKO inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells

In animal models with oncogenic activation of MET, including METex14 skipping alterations, TEPMETKO inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.

met-moa
Image showing TEPMETKO® (tepotinib) mechanism of action met-moa
met-moa

 

ALK=anaplastic lymphoma kinase; AMP=amplification; EGFR=epidermal growth factor receptor; ICI=immune checkpoint inhibitor; KRAS=Kirsten rat sarcoma viral oncogene homolog; NSCLC=non-small cell lung cancer; ROS1=c-ros oncogene 1.
 

Normal MET pathway signaling 4,10

TEPMETKO® (tepotinib) MOA4,10,12

Image showing TEPMETKO® (tepotinib) mechanism of action

IMPORTANT SAFETY INFORMATION AND INDICATION

TEPMETKO can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ILD/pneumonitis occurred in 2.2% of patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death.

TEPMETKO can cause hepatotoxicity, which can be fatal. Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or total bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.2% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). The median time-to-onset of Grade 3 or higher increased ALT/AST was 30 days (range 1 to 178).

TEPMETKO can cause embryo-fetal toxicity. Based on findings in animal studies and its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose.

Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors and strong CYP3A inducers. Avoid concomitant use of TEPMETKO with certain 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.

Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload.

Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%).

The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.

Selected laboratory abnormalities (≥20%) from baseline in patients receiving TEPMETKO in descending order were: decreased albumin (76%), increased creatinine (55%), increased alkaline phosphatase (ALP) (50%), decreased lymphocytes (48%), increased ALT (44%), increased AST (35%), decreased sodium (31%), decreased hemoglobin (27%), increased potassium (25%), increased gamma-glutamyltransferase (GGT) (24%), increased amylase (23%), and decreased leukocytes (23%).

The most common Grade 3-4 laboratory abnormalities (≥2%) in descending order were: decreased lymphocytes (11%), decreased albumin (9%), decreased sodium (8%), increased GGT (5%), increased amylase (4.6%), increased ALT (4.1%), increased AST (2.5%), and decreased hemoglobin (2%).

A clinically relevant laboratory abnormality in <20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades 3 to 4.

INDICATION

TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see the full Prescribing Information and Medication Guide for additional Important Safety Information for TEPMETKO.

References: 1. Awad MM, Leonardi GC, Kravets S, et al. Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis. Lung Cancer. 2019;133:96-102. doi:10.1016/j.lungcan.2019.05.011. 2. Salgia R. MET in lung cancer: biomarker selection based on scientific rationale. Mol Cancer Ther. 2017;16(4):555-565. doi:10.1158/1535-7163.MCT-16-0472. 3. Rosell R, Karachaliou N. Large-scale screening for somatic mutations in lung cancer. Lancet. 2016;387(10026):1354-1355. doi:10.1016/S0140-6736(15)01125-3. 4. Drilon A, Cappuzzo F, Ou SHI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol. 2017;12(1):15-26. doi:10.1016/j.jtho.2016.10.014. 5. American Cancer Society. About lung cancer. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed April 14, 2021. 6. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J Thorac Oncol. 2016;11(9):1493-1502. doi:10.1016/j.jtho.2016.06.004. 7. Tong JH, Yeung SF, Chan AWH, et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22(12):3048 - 3056. doi:10.1158/1078-0432.CCR-15-2061. 8. Sabari JK, Leonardi GC, Shu CA, et al. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol. 2018;29(10):2085-2091. doi:10.1093/annonc/mdy334. 9. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Referenced with permission by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2021. © National Comprehensive Cancer Network Inc., 2021. All rights reserved. Accessed March 23, 2021. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content or its use or application and disclaims any responsibility for its use or application in any way. 10. Wu Y, Soo RA, Locatelli G, et al. Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer? Cancer Treat Rev. 2017;61:70-81. 11. Paik PK, Felip E, Veillon R, et al. Tepotinib in non–small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383:931-943. doi:10.1056/NEJMoa2004407. 12. TEPMETKO® (tepotinib) [prescribing information]. EMD Serono, Inc., Rockland, MA; 2021.