Crizotinib with or without an EGFR-TKI in treating EGFR-mutant NSCLC patients with acquired MET amplification after failure of EGFR-TKI therapy: a multicenter retrospective study

Abstract

Background MET amplification is associated with acquired resistance to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in treating non-small-cell lung cancer (NSCLC); however, the therapeutic strategy in these patients is undefined. Herein we report the clinical outcomes of patients with c-MET amplification resistance to EGFR-TKIs treated with crizotinib. Methods We retrospectively analyzed advanced NSCLC patients from five sites who were diagnosed with EGFR-mutant NSCLC and received EGFR-TKI treatment. After disease progression, these patients were confirmed to have a MET-to-centromere ratio (MET:CEN) ≥ 1.8 based on fluorescence in situ hybridization (FISH) examination and without a T790M mutation. We assessed the efficacy and safety of crizotinib to overcome EGFR-TKI resistance in EGFR-activating mutations NSCLC with acquired MET amplification. Results Amplification of the acquired MET gene was identified in 18 patients with EGFR-mutant NSCLC. Fourteen patients received crizotinib treatment after acquired resistance to EGFR-TKIs. Among the 14 patients, 6 (42.9%) received crizotinib plus EGFR-TKI and 8 (57.1%) received crizotinib monotherapy. The overall objective response rate (ORR) and disease control rate (DCR) were 50.0% (7/14) and 85.7% (12/14), respectively. The median PFS (mPFS) of patients receiving crizotinib monotherapy and crizotinib plus EGFR-TKI was 6.0 and 12.6 months, respectively (P = 0.315). Notably, treatment efficacy was more pronounced in patients with crizotinib than patients with chemotherapy (24.0 months vs. 12.0 months, P = 0.046). The mOS for 8 of 14 patients receiving crizotinib monotherapy and 6 of 14 patients receiving crizotinib plus EGFR-TKI was 17.2 and 24.0 months, respectively (P = 0.862). Among the 14 patients, 1 who received crizotinib monotherapy (grade 3 nausea) and 2 who received crizotinib plus EGFR-TKI (grade 3 elevated liver aminotransferase levels) received reduced doses of crizotinib (200 mg twice daily) to better tolerate the dose. Conclusions We observed the clinical evidence of efficacy generated by combination of crizotinib and previous EGFR-TKIs after the resistance to first-generation EGFR-TKIs. These results might increase evidence of more effective therapeutic strategies for NSCLC treatment. Combination therapy did not increase the frequency of adverse reactions.

<p>FGFR1 Induces Acquired Resistance Against Gefitinib By Activating AKT/mTOR Pathway In NSCLC</p>

“…Thus, researchers have extensively tried to clarify the mechanisms behind secondary resistance towards EGFR-TKIs. The T790M mutation in EGFR and amplification of the MET oncogene have been proved to be the leading reasons behind EGFR-TKI acquired resistance 9–12. In addition, hepatocyte growth factor (HGF) overexpression, EGFR amplification, epithelial-mesenchymal transition (EMT), and conversion to small-cell lung cancer have also been shown to be crucial mechanisms supporting the development of EGFR-TKI acquired resistance 13–15.…”

Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

“…Thus, it was speculated that wild-type EGFR could not be used as a single biomarker to predict the combined effect of cisplatin and gefitinib. Hierarchical analyses of most previous clinical trials are based on EGFR genotype, which may explain the contradictory conclusions from the literature (9,14,15,49). Moreover, the biological difference of tumors may cause this inconsistency.…”

“…The common therapeutic strategies usually include: Platinum-based chemotherapy, high-dose EGFR-TKIs, platinum-based chemotherapy combined with EGFR-TKIs, new targeted drugs monotherapy (7), such as AZD929 (EGFR-TKI inhibitor) (8), afatinib (dual EGFR and human EGFR 2 inhibitor) (9), vandetanib (dual EGFR and vascular EGFR inhibitor) (10) and crizotinib (for patients with anaplastic lymphoma kinase mutations) (11). Furthermore, common therapeutic strategies involve new agents combined with EGFR-TKI, such as apatinib (12), AXL receptor tyrosine kinase degradation (13) and Crizotinib (14). However, most of these agents are still in clinical trials, and the combination therapy of EGFR-TKIs and platinum-based chemotherapy is the preferred choice for most patients.…”

Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment

“…U pacientů s aktivačními mutacemi genu pro receptor epidermálního růstového faktoru (epidermal growth factor receptor -EGFR) nebo přestavbou ALK či ROS1 bylo dosaženo výrazného zlepšení léčebných výsledků [3,4]. Mezi další terapeutické cíle patří B-RAF, c-met, RET a další [5][6][7]. Zásadní přínos znamenalo zařazení imunoterapie do léčby NSCLC, zejména inhibitory PD-1 a PD-L1 [8].…”