Prognosis and Concurrent Genomic Alterations in Patients With Advanced NSCLC Harboring MET Amplification or MET Exon 14 Skipping Mutation Treated With MET Inhibitor: A Retrospective Study

Abstract

BackgroundMET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated.MethodsWe retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29).ResultsAmong evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%).ConclusionMET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification.

Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations

“… 3 , 22 Several studies have revealed the beneficial effects of MET inhibitors in patients with MET-driven NSCLC. 23 , 24 , 25 , 26 Nevertheless, the efficacy of MET tyrosine kinase inhibitors (TKIs) in patients with PSC remains poorly described with limited clinical literature available.…”

Crizotinib efficacy and safety in patients with advanced NSCLC harboring MET alterations: A real-life data of Turkish Oncology Group

“…In another retrospective study, MET mutation group also had a better PFS than MET amplified patient group (11.0 months vs 7.0 months). [11]…”

“…In another retrospective study, MET mutation group also had a better PFS than MET amplified patient group (11.0 months vs 7.0 months). [11] Among patients with NSCLC harboring MET exon 14 alteration, the patients treated with MET inhibitor had better survival comparing to the patients not treated with targeted therapy, in a retrospective study. [12] In this study, 22 patients had crizotinib in any line.…”

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

“…It is capable of regulating cell proliferation, migration and invasion by activating the downstream MEK–ERK pathway and PI3K pathway 4 . The oncogenic driving variants of MET gene mainly include METex14 skipping and MET amplification 5 . METex14 encodes a structural domain containing the ubiquitin ligase binding site of Y1003 6 .…”

“… 4 The oncogenic driving variants of MET gene mainly include METex14 skipping and MET amplification. 5 METex14 encodes a structural domain containing the ubiquitin ligase binding site of Y1003. 6 METex14 skipping is present in about 1%–3% of NSCLC patients and may cause deletion of the binding sites of Y1003 and c‐CBL, abnormal degradation of MET proteins and sustained activation of MET gene.…”