MET exon 14-skipping mutations
Somatic mutations that affect MET exon 14, which contains the Y1003
residue required for ubiquitin-mediated degradation, lead to increased
MET stability and prolonged signaling from hepatocyte growth factor
stimulation [70]. On May 6, 2020, an accelerated approval to
capmatinibwas granted by FDA for adult patients with metastatic NSCLC
withMET exon 14-skipping mutations. This approval was based on the
GEOMETRY mono-1trial, a multicenter, nonrandomized, open-label,
multicohort study in which 97 patients with metastatic NSCLC with
confirmed MET exon 14-skipping mutationswere treated with
capmatinib[71]. The ORR was much higher, 68% among the 28
treatment-naive patients, with a response duration of 12.6 months (95%
CI, 5.5–25.3) compared to ORR of 41% among the 69 previously treated
patients, with a response duration of 9.7 months (95% CI, 5.5–13.0)
[71].
The single-arm, international phase II VISION trial presented at ASCO
2020 has also shown tepotinib to have activity in patients withMET exon
14-skipping mutations. After nine months follow-up, the primary efficacy
population of 99 patients had a 46.5% ORR, with duration of response of
11.1 months [72].