Capmatinib or tepotinib — does the choice matter?

Both are FDA-approved, similar mechanism (type Ib MET inhibitors), similar efficacy in published trials. Practical differences include AE profile (peripheral edema is class-effect for both; tepotinib has a numerically more common edema signal) and dosing. Institutional preference and AE management drive the call.

Is METex14 skipping the same as MET amplification?

No. METex14 skipping is a splice-site mutation that prevents MET degradation. MET amplification is gene copy gain that produces overexpression. Both can be MET-pathway-active; the targeting story is similar but the threshold for response and the resistance landscape differ. Some tumors have both. Be careful about which is reported.

What about checkpoint inhibitors in METex14 NSCLC?

METex14-skipping NSCLC, like other driver-mutation subsets, generally responds poorly to single-agent PD-1/PD-L1 inhibitors. Targeted therapy with capmatinib or tepotinib is the standard.

Variant cheat sheet · NSCLC

MET exon 14 skipping mutations in NSCLC

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

MET exon 14 skipping mutations in NSCLC are AMP/ASCO/CAP Tier I-A. Capmatinib (GEOMETRY mono-1) and tepotinib (VISION) are both FDA-approved. RNA-based or comprehensive NGS testing is critical — DNA-only panels miss a significant fraction of splice-region alterations causing exon 14 skipping. MET amplification is a separate biology with separate treatment implications.

Biology

MET exon 14 encodes the juxtamembrane domain containing a critical CBL E3 ligase binding site. Mutations affecting splice donor or acceptor sites cause exon 14 skipping, which removes the CBL binding domain. The result: MET escapes ubiquitin-mediated degradation and accumulates, driving constitutive signaling. Distinct from MET amplification (extra gene copies) — both can occur, sometimes co-occur, but the targeting calculus differs.

Epidemiology

MET exon 14 skipping occurs in roughly 3-4% of NSCLC, enriched in older patients, women, never-smokers, sarcomatoid carcinoma histology.

Detection

RNA NGS or comprehensive DNA panels with full splice-region coverage. DNA-only without splice-region capture under-detects exon 14 skipping.
FoundationOne CDx, Tempus xT, Caris MI Profile all cover METex14 skipping when RNA-based or comprehensive DNA panels are run.
Distinguish METex14 skipping from MET amplification — different biology, different responses.

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Capmatinib	METex14-skipping unresectable/metastatic NSCLC (GEOMETRY mono-1)	1L+	I-A
Tepotinib	METex14-skipping unresectable/metastatic NSCLC (VISION)	1L+	I-A
Crizotinib (off-label, historical)	METex14 NSCLC (less effective than capmatinib/tepotinib)	Historical	II-C

Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.

Resistance pathways

MET secondary kinase-domain mutations (D1228, Y1230, F1200) emerging on type Ib MET inhibitors.
Receptor tyrosine kinase bypass (KRAS, EGFR).
Phenotype switching to small-cell-like differentiation (rare).

Frequently asked questions

Capmatinib or tepotinib — does the choice matter?: Both are FDA-approved, similar mechanism (type Ib MET inhibitors), similar efficacy in published trials. Practical differences include AE profile (peripheral edema is class-effect for both; tepotinib has a numerically more common edema signal) and dosing. Institutional preference and AE management drive the call.
Is METex14 skipping the same as MET amplification?: No. METex14 skipping is a splice-site mutation that prevents MET degradation. MET amplification is gene copy gain that produces overexpression. Both can be MET-pathway-active; the targeting story is similar but the threshold for response and the resistance landscape differ. Some tumors have both. Be careful about which is reported.
What about checkpoint inhibitors in METex14 NSCLC?: METex14-skipping NSCLC, like other driver-mutation subsets, generally responds poorly to single-agent PD-1/PD-L1 inhibitors. Targeted therapy with capmatinib or tepotinib is the standard.