Department of Medicine II, Hematology and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
Department of Medicine II, Hematology and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
Clin Lung Cancer. 2024 Dec;25(8):672-682.e5. doi: 10.1016/j.cllc.2024.07.012. Epub 2024 Jul 23.
MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification.
This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2).
A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54).
In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.
MET 扩增是 EGFR 突变型非小细胞肺癌（NSCLC）中对 EGFR 抑制的常见耐药机制。几项试验显示了联合 EGFR 和 MET 抑制（EGFRi/METi）的令人鼓舞的结果。然而，MET 扩增的定义不一致，并且经常包括多倍体和真正的扩增。
这是一项多中心、真实世界的分析，纳入了 EGFR 抑制后疾病进展且 MET 拷贝数增加（CNG）的患者，定义为真正的扩增（MET 与染色体 7 着丝粒的比值 [MET-CEP7]≥2）或多倍体（基因拷贝数≥5，MET-CEP7<2）。
共纳入 43 例 MET CNG 患者，其中 42 例通过 FISH 检测到。分别有 23、7 和 14 例患者接受了 EGFRi/METi、METi 和 SoC 治疗。EGFRi/METi 组的真实世界临床获益率（定义为疾病稳定或更好）明显更高，为 82%（95%置信区间 [CI]，60-95），而 METi 组为 29%（4-71），SoC 组为 50%（23-77）。EGFRi/METi 组的真实世界无进展生存期更长，中位值分别为 9.8 个月和 4.3 个月（METi 组的 HR，0.19，95%CI，0.06-0.57）和 3.7 个月（SoC 组的 HR，0.41，0.18-0.91）。总生存期也有改善的趋势。与治疗和 CNG 类型（扩增与多倍体）的交互分析表明，差异仅由接受 EGFRi/METi 治疗的 MET 扩增患者驱动（OS 的 HR，0.09，0.01-0.54）。
在这项真实世界的研究中，EGFRi/METi 与 METi 和 SoC 相比显示出临床获益。未来的研究应重点关注 MET CNG 类型的差异影响，特别关注真正的 MET 扩增作为反应预测因子。
