Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, USA; Harvard Medical School, Boston, USA.
Department of Medicine, Georgetown University, Washington, USA.
Ann Oncol. 2020 Dec;31(12):1725-1733. doi: 10.1016/j.annonc.2020.09.015. Epub 2020 Sep 29.
Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.
This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.
We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.
RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
重排基因融合是治疗非小细胞肺癌（NSCLC）的有效靶点。RET 选择性抑制剂塞普替尼（LOXO-292）和普拉替尼（BLU-667）最近在晚期 RET 融合阳性 NSCLC 中显示出良好的抗肿瘤活性和安全性，均已获得美国食品药品监督管理局（FDA）的批准。目前对选择性 RET 抑制剂耐药机制的了解仍然有限。
本研究在五家机构进行。对接受塞普替尼或普拉替尼治疗的 RET 融合阳性 NSCLC 患者的组织和/或无细胞 DNA 进行检测，采用下一代测序（NGS）或 MET FISH 进行评估。
共分析了 18 例接受 RET 选择性抑制剂（塞普替尼 10 例，普拉替尼 7 例，普拉替尼序贯塞普替尼 1 例，每例抑制剂治疗后均进行活检）治疗的 RET 融合阳性患者的 23 例治疗后组织和/或血浆活检。3 例患者有配对的组织和血浆样本，其中 1 例还有 2 份连续的耐药组织标本。RET 抑制剂的中位无进展生存期为 6.3 个月（95%置信区间 3.6-10.8 个月）。在 2 例患者（10%）中发现了获得性 RET 突变，均影响激酶溶剂前沿的 RET G810 残基。3 例耐药病例（15%）存在获得性 MET 扩增，无同时发生的 RET 耐药突变，1 例标本存在获得性 KRAS 扩增。NGS 未发现其他经典驱动基因突变。在 16 例耐药肿瘤标本中，均无鳞状或小细胞组织学转化的证据。
RET 溶剂前沿突变是 RET 抑制剂耐药的一种常见机制，尽管其发生率相对较低。选择性 RET 抑制的大多数耐药可能是由 RET 非依赖性耐药引起的，如获得性 MET 或 KRAS 扩增。需要具有针对 RET 耐药突变的下一代 RET 抑制剂和联合策略来有效克服这些患者的耐药性。
