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].