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

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 T790M 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.