The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy

Abstract

Background: : MET amplification is one of the EGFR-independent mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance. Combinatorial therapy of EGFR-TKI and crizotinib has been explored as a strategy to overcome resistance by simultaneously targeting both EGFR and MET pathways; however, no consensus still exists on the optimal combination regimen with the most benefit. Methods: : Retrospective analysis was performed on the clinical and sequencing data obtained from eleven patients with lung adenocarcinoma who acquired MET amplification at progression from prior EGFR-TKI therapy and received a combination of EGFR-TKI and crizotinib. Results: : Acquired MET amplification was detected in four and seven patients who progressed from first-line gefitinib and second-line osimertinib, respectively. Six and five patients received a combination of either firstgeneration (gefitinib, erlotinib, or icotinib) or third-generation (osimertinib) EGFR-TKI and crizotinib, respectively. Nine patients achieved partial response, resulting in an overall response rate of 81.8 %. The median progression-free survival of the cohort was 5.8 months. Moreover, analysis of acquired resistance mechanisms from nine patients identified EGFR T790 M from three patients who progressed from first-generation EGFR-TKI and crizotinib, while EGFR T790 M/trans-C797S and L718Q, EGFR G724S, and CCDC6-RET fusion were detected from one patient each who progressed from osimertinib and crizotinib regimen. Loss of MET amplification was also observed in a majority of the patients at progression from the combination therapy. Conclusions: : Our study provides clinical evidence of the efficacy of combinatorial regimen with either first-or third-generation EGFR-TKI and crizotinib after the emergence of MET amplification-mediated EGFR-TKI resistance in patients with EGFR-mutant NSCLC.

Overexpression of RhoV Promotes the Progression and EGFR-TKI Resistance of Lung Adenocarcinoma

“…Still now, the resistance of the gefitinib mechanism is confusing. Gefitinib-resistant (GR) patients manifest many pathways abnormal activation, including MET/HER2 amplification, activation of the RAS-mitogen-activated protein kinase (MAPK)-ERK, or RAS-phosphatidylinositol 3-kinase (PI3K)-AKT pathways ( 27 – 29 ). In this study, we found that PC9-GR cells showed a high expression of RhoV, which means RhoV might associate with GR circumstance.…”

A Large Real-World Study on the Effectiveness of the Combined Inhibition of EGFR and MET in EGFR-Mutant Non-Small-Cell Lung Cancer After Development of EGFR-TKI Resistance

“…Until now, there is still no consensus on the optimal subsequent-line treatment regimen for patients who acquired MET amplification-mediated EGFR-TKI resistance. The efficacy of crizotinib either alone or in combination with any EGFR-TKI has been explored among patients who were detected with MET amplification after progression from EGFR-TKI treatment (16,19,20,22,36,37). Due to the limited sample size, the data in these studies were inadequate to strongly support the standard clinical use of combination therapies targeting both EGFR and MET after MET amplification-mediated EGFR-TKI resistance.…”

“…The reciprocal crosstalk between EGFR and MET in lung adenocarcinoma suggests that simultaneous inhibition through the combined use of EGFR-TKI and MET-TKI would benefit and potentially improve the survival outcomes of patients with concurrent EGFR and MET aberrations (17,18). Over the years, a growing number of studies have demonstrated the clinical benefit of different combinations of various generations of EGFR-TKIs and various MET-TKIs including crizotinib (16,(19)(20)(21)(22)(23), capmatinib (21,24), and savolitinib (25)(26)(27). Recently, tepotinib plus gefitinib showed promising antitumor activity in NSCLC with concomitant EGFR mutation and MET amplification or high MET overexpression compared with chemotherapy (28).…”

Early‐onset interstitial pneumonitis in a patient with advanced non‐small cell lung cancer treated with crizotinib and osimertinib

“…Elevated MET copy number amplification in this patient may be a resistance mechanism to EGFR‐TKI. Combination therapy has been reported to have a better overall response rate (ORR), progression‐free survival (PFS) and overall survival (OS) in patients than monotherapy, 1,2 although there have been some successful reports of crizotinib monotherapy in EGFR ‐mutant NSCLC that acquired MET amplification.…”