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
Li Liu, Jingjing Qu, Jianfu Heng, Chunhua Zhou, Yi Xiong, Haiyan Yang, Wenjuan Jiang, Liang Zeng, Songlin Zhu, Yongchang Zhang, Jiarong Tan, Chengping Hu, Pengbo Deng, Nong Yang
Abstract
Background MET proto-oncogene amplification (amp) is an important mechanism underlying acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the optimal treatment strategy after acquiring MET- amp-mediated EGFR-TKI resistance remains controversial. Our study compared three treatment strategies for patients with EGFR -mutant non-small-cell lung cancer (NSCLC) who were detected with MET- amp at EGFR-TKI progression using next-generation sequencing. Methods Of the 70 patients included in the study, 38 received EGFR-TKI + crizotinib, 10 received crizotinib monotherapy, and 22 received chemotherapy. Clinical outcomes and molecular profiles were analyzed. Results The objective response rate was 48.6% for EGFR-TKI + crizotinib group, 40.0% for crizotinib monotherapy group, and 18.2% for chemotherapy group. Patients who received EGFR-TKI + crizotinib had significantly longer progression-free survival than those who received crizotinib or chemotherapy (5.0 vs . 2.3 vs . 2.9 months, p = 0.010), but overall survival was comparable (10.0 vs . 4.1 vs . 8.5 months, p = 0.088). TP53 mutation (58.5%) and EGFR- amp (42.9%) were frequent concurrent mutations of the cohort. Progression-free survival was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs . 2.3 vs . 2.9 months, p = 0.009) or EGFR- amp (n = 13) (5.0 vs . 1.2 vs . 2.4 months, p = 0.016) in the EGFR-TKI + crizotinib group than the other two regimen. Potential acquired resistance mechanisms to EGFR-TKI + crizotinib included EGFR -T790M (n = 2), EGFR- L718Q (n = 1), EGFR -S645C (n = 1), MET -D1228H (n = 1), BRAF -V600E (n = 1), NRAS -Q61H (n = 1), KRAS- amp (n = 1), ERBB2- amp (n = 1), CDK4- amp (n = 1), and MYC- amp (n = 1). Conclusion Our study provides real-world clinical evidence from a large cohort that simultaneous inhibition of EGFR and MET could be a more effective therapeutic strategy for patients with MET- amp acquired from EGFR-TKI therapy.