蘿蔔和小周的故事之一：MAPK抑製劑曲美替尼和司美替尼的高下之爭
蘿蔔是晚期胰腺癌患者， 他的妻子小周在我眼裡就是一個現代版的新白娘子， 為了救自己的丈夫， 帶著丈夫遠渡重洋來到美國，先是去了妖界第一門派MD Anderson治療無效，後來小周又找到NIH的不死神仙Steve Rosenberg為蘿蔔做了KRAS TCR-T, 還是進展， 於是小周帶著蘿蔔回國治療， 國內的醫生都覺得沒有治療的必要， 建議姑息治療，小周不想放棄，找到了我，然後我答應指點一番。
今天是蘿蔔吃藥的第6天，之前不能走路，現在可以走幾步，整個人的體感有改善，醫院檢驗科說CA199高於1000就無法給出準確數值，所以我無法監控CA199的數值下降趨勢， 影像檢測還太早。這就是前情提要。
話說小周今晚問了我幾個問題，第一個問題是我上周五參加本系住院醫的院長論壇的時候特意問UCSF的RAS專家Kevin Shannon的問題，那就是FDA批准了好幾個MAPK抑製劑， 臨床治療的時候該如何選擇， Shannon博士給我的回答是根據具體的病症和每個MAPK抑製劑的體內藥物動力學特性來決定。
在說曲美替尼之前，我先給你們一個樣本：
這篇文章做的就是MAPK抑製劑PD-0325901在 1期臨床試驗的病人中的PK和PD.
不同劑量下藥物在血液中濃度的時間曲線：
不同癌症病人的治療效果與MAPK抑製劑效果(副作用）的關係：
簡單說活性抑制>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的動物試驗數據:
下面是第一天和第七天血液和腫瘤中曲美替尼的活性檢測， read out是磷酸化的ERK激酶， 這是MEK的底物。
24小時內都可以有效抑制。
下面是1期臨床的結果：
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.這個臨床試驗結果決定了現在銷售的曲美替尼劑量是每日2毫克。
最後是2期的臨床試驗數據：
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.司美替尼的問題是血液半衰期顯著短於曲美替尼， 無法做到24小時壓制全身多器官轉移的胰腺癌細胞， 這就是為什麼對於胰腺癌患者曲美替尼是更好的選擇的原因。
我在電話里跟小周說，你的好奇心也太強了， 這你也要問。
蘿蔔，現在你能明白為什麼你體感會改善了吧？ 因為曲美替尼24小時不休息的在你體內工作著。
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