LUNG CANCER: MET amplification (≥6 copies) and exon 14 skipping are predictors of response to MET inhibition in NSCLC
MET amplification (≥6 copies) and exon 14 skipping are predictors of response to MET inhibition in NSCLC
Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial
• This study provides first evidence of clinically meaningful antitumor activity of capmatinib in MET-dysregulated NSCLC.
• Accurate biomarker selection of the patients is needed to identify the patients expected to respond better to capmatinib.
• MET amplification GCN ≥6 and/or METex14 skipping are strong predictive biomarkers for response to capmatinib.
• Overexpression alone cannot be considered as a reliable biomarker to predict the efficacy of capmatinib.
• Capmatinib is well tolerated with the majority of the AEs grade 1 and 2.
Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC.
Patients and METHODS
Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats.
Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 ( n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%).
MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC ( NCT01324479).