See article, p. 963

In drug development for rare molecular targets, the limited number of patients can prevent sequential testing of first- and second-generation inhibitors. The TRK kinases represent one such target, and NTRK gene rearrangements can be targeted by the recently developed selective TRK tyrosine kinase inhibitor (TKI) larotrectinib. To combat acquired resistance, Drilon and colleagues developed LOXO-195, a TRK TKI designed to overcome resistance conferred by secondary TRK kinase domain mutations, in parallel with the early clinical development of larotrectinib. In vitro, LOXO-195 potently inhibited wild-type NTRK1/2/3 and several TRK kinase domain mutants that reduced larotrectinib sensitivity. Further, LOXO-195 suppressed the growth of tumors driven by oncogenic NTRK1/3 in mice. Based on these preclinical findings, the first two patients to develop larotrectinib resistance were treated with LOXO-195 using rapid safety- and pharmacokinetic-guided intrapatient dose-escalation study designs. An adult patient with LMNA–NTRK1-rearranged colorectal cancer who developed larotrectinib resistance due to an NTRK1 G595R acquired resistance mutation responded rapidly to LOXO-195 and achieved an ongoing partial response. After treatment the G595R allele was no longer detectable in cell-free DNA. A pediatric patient with ETV6–NTRK3-rearranged infantile fibrosarcoma with a G623R acquired resistance mutation also experienced rapid tumor regression, though her cancer recurred. In addition to demonstrating that LOXO-195 may overcome resistance to larotrectinib in patients with NTRK-rearranged tumors, this study illustrates the utility of a drug development approach that anticipates resistance to first-generation kinase inhibitors and enables parallel generation of next-generation kinase inhibitors, particularly in a rare patient population.

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在针对稀有分子靶标的药物开发中，数量有限的患者可以阻止对第一代和第二代抑制剂进行顺序测试。TRK激酶代表了一个这样的靶标，而最近开发的选择性TRK酪氨酸激酶抑制剂（TKI）larotrectinib可以靶向NTRK基因重排。为了对抗获得性耐药，Drilon和同事开发了LOXO-195，这是一种TRK TKI，旨在克服Latrrectinib的早期临床开发，以克服继发性TRK激酶结构域突变赋予的耐药性。体外，LOXO-195有效地抑制了野生型NTRK1 / 2/3和一些TRK激酶结构域突变体，这些突变体降低了larotrectinib的敏感性。此外，LOXO-195在小鼠中抑制了由致癌NTRK1 / 3驱动的肿瘤的生长。基于这些临床前研究结果，使用快速安全性和药代动力学指导的患者剂量递增研究设计，使用LOXO-195对前两名发展为larotrectinib耐药性的患者进行了治疗。一名成年LMNA-NTRK1重排的大肠癌患者由于NTRK1 G595R获得性耐药突变而对larotrectinib产生耐药性，因此对LOXO-195的反应迅速，并取得了持续的部分应答。治疗后，在无细胞DNA中不再可检测到G595R等位基因。一名ETV6-NTRK3患儿复发的具有G623R获得性耐药突变的婴儿纤维肉瘤也经历了肿瘤的快速消退，尽管她的癌症复发了。除了证明LOXO-195可以克服NTRK重排肿瘤患者对larotrectinib的耐药性外，这项研究还说明了一种药物开发方法的实用性，该方法可预测对第一代激酶抑制剂的耐药性，并能够并行产生下一代激酶抑制剂，尤其是在罕见的患者人群中。