萝卜和小周的故事之一：MAPK抑制剂曲美替尼和司美替尼的高下之争
萝卜是晚期胰腺癌患者， 他的妻子小周在我眼里就是一个现代版的新白娘子， 为了救自己的丈夫， 带著丈夫远渡重洋来到美国，先是去了妖界第一门派MD Anderson治疗无效，后来小周又找到NIH的不死神仙Steve Rosenberg为萝卜做了KRAS TCR-T, 还是进展， 于是小周带著萝卜回国治疗， 国内的医生都觉得没有治疗的必要， 建议姑息治疗，小周不想放弃，找到了我，然后我答应指点一番。
今天是萝卜吃药的第6天，之前不能走路，现在可以走几步，整个人的体感有改善，医院检验科说CA199高于1000就无法给出准确数值，所以我无法监控CA199的数值下降趋势， 影像检测还太早。这就是前情提要。
话说小周今晚问了我几个问题，第一个问题是我上周五参加本系住院医的院长论坛的时候特意问UCSF的RAS专家Kevin Shannon的问题，那就是FDA批准了好几个MAPK抑制剂， 临床治疗的时候该如何选择， Shannon博士给我的回答是根据具体的病症和每个MAPK抑制剂的体内药物动力学特性来决定。
在说曲美替尼之前，我先给你们一个样本：
这篇文章做的就是MAPK抑制剂PD-0325901在 1期临床试验的病人中的PK和PD.
不同剂量下药物在血液中浓度的时间曲线：
不同癌症病人的治疗效果与MAPK抑制剂效果(副作用）的关系：
简单说活性抑制>60% 的病人活得更久，有皮炎副作用的也活得更久。
下面看曲美替尼PK/PD的动物试验数据:
下面是第一天和第七天血液和肿瘤中曲美替尼的活性检测， read out是磷酸化的ERK激酶， 这是MEK的底物。
24小时内都可以有效抑制。
下面是1期临床的结果：
Lancet Oncol. 2012 Aug;13(8):773-81. doi: 10.1016/S1470-2045(12)70270-X. Epub 2012 Jul 16.
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.
Infante JR1, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA.
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Abstract
BACKGROUND:Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinibis a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.METHODS:We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.FINDINGS:We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.INTERPRETATION:The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinibs inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.这个临床试验结果决定了现在销售的曲美替尼剂量是每日2毫克。
最后是2期的临床试验数据：
J Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17.
Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.
Kim KB1, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD.
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Abstract
PURPOSE:BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.PATIENTS AND METHODS:This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.
RESULTS:In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.CONCLUSION:Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.司美替尼的问题是血液半衰期显著短于曲美替尼， 无法做到24小时压制全身多器官转移的胰腺癌细胞， 这就是为什么对于胰腺癌患者曲美替尼是更好的选择的原因。
我在电话里跟小周说，你的好奇心也太强了， 这你也要问。
萝卜，现在你能明白为什么你体感会改善了吧？ 因为曲美替尼24小时不休息的在你体内工作著。
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