tepotinib — Drug Monograph

Brand names: Tepmetko

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Tepotinib is a highly selective, potent, oral MET tyrosine kinase inhibitor that binds with high affinity to the ATP-binding site of the MET kinase domain, including the active and inactive conformations. By blocking MET autophosphorylation, tepotinib abrogates both ligand-dependent (HGF-driven) and ligand-independent (e.g., MET exon 14 skipping mutation-driven, MET amplification-driven) constitutive MET signaling, suppressing downstream proliferative and survival cascades including RAS/MAPK, PI3K/AKT/mTOR, and STAT3. The METex14 skipping mutation eliminates the Y1003 ubiquitination site,…

FDA Indications

• Metastatic NSCLC in adults whose tumors harbor a MET exon 14 skipping mutation (METex14), as detected by an FDA-approved test — accelerated approval February 2021 (VISION trial)

Common Side Effects

• Peripheral edema (>60% — most common adverse effect)
• Nausea
• Elevated creatinine (decreased eGFR — transporter-mediated)
• Fatigue
• Diarrhea
• Elevated ALT/AST
• Hypoalbuminemia
• Decreased appetite
• Dyspnea
• Musculoskeletal pain

Clinical Pearl

Tepotinib and capmatinib represent the two approved MET inhibitors for METex14-skipping NSCLC; their clinical profiles are similar but tepotinib's once-daily dosing with food may offer a practical compliance advantage over capmatinib's twice-daily regimen. As with capmatinib, the serum creatinine elevation is largely driven by inhibition of renal tubular transporters (OCT2/MATE) rather than true nephrotoxicity — the use of cystatin C-based eGFR estimation can help distinguish transporter…

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC