Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations.
Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations.
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DOI：
10.1016/j.jtocrr.2021.100256
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发表时间：
2022-01
影响因子：
--
通讯作者：
Riely GJ
中科院分区：
文献类型：
--
作者：
Arbour KC;Manchado E;Bott MJ;Ahn L;Tobi Y;Ni AA;Yu HA;Shannon A;Ladanyi M;Perron V;Ginsberg MS;Johnson A;Holodny A;Kris MG;Rudin CM;Lito P;Rosen N;Lowe S;Riely GJ
25%的非小细胞肺癌患者发生体细胞KRAS突变。迄今为止，MEK抑制剂单药治疗在临床试验中尚未取得成功。FGFR1的代偿性激活被确定为kras突变型NSCLC中曲美替尼耐药的一种机制，在体外和体内模型中，曲美替尼和波纳替尼联合治疗具有协同作用。本研究旨在评估kras突变型NSCLC患者的这种药物组合。在KRAS突变的晚期NSCLC患者中进行了曲美替尼和波纳替尼的1期剂量递增研究。进行了标准的3 + 3剂量递增。患者接受研究治疗，直到无法忍受的毒性或疾病进展。共有12例kras突变型NSCLC患者接受了治疗（7例使用曲美替尼2mg和波纳替尼15mg， 5例使用曲美替尼2mg和波纳替尼30mg）。常见的毒性为皮疹、腹泻和发热。5例患者报告了可能与治疗相关的严重不良事件，包括1例死亡和4例心血管事件。在两种剂量水平下均观察到严重事件。值得注意的是，75%（12人中有9人）的放射学反应可评估，未观察到证实的部分反应。研究的中位时间为43天。在这项针对kras突变晚期NSCLC患者的1期研究中，曲美替尼和波纳替尼联合治疗与心血管和出血毒性相关。在未来的研究中探索MEK和FGFR1抑制的联合是有可能的，但应该考虑替代药物来提高安全性和耐受性。
Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.
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DOI：
10.1056/nejmoa2103695
发表时间：
2021-06-24
期刊：
The New England journal of medicine
影响因子：
--
作者：
通讯作者：
--
同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
通讯作者：
Riely GJ
影响因子：
1.2
作者：
Modak, Shakeel;Asante-Korang, Alfred;Grana, Nanette
通讯作者：
Grana, Nanette
影响因子：
120.7
作者：
Janne, Pasi A.;van den Heuvel, Michel M.;Vansteenkiste, Johan
通讯作者：
Vansteenkiste, Johan
影响因子：
50.5
作者：
Blumenschein, G. R., Jr.;Smit, E. F.;Jaenne, P. A.
通讯作者：
Jaenne, P. A.