腎癌首選藥物是舒尼替尼還是索拉非尼？

Motzer教授接受媒體採訪
Question: 1st question is we know that you’ve dedicated yourself in treatment of renal cancer and testicular cancer for over 20 years, so can you briefly talk about the latest development in treating kidney cancer?
Motzer:
Kidney cancer has been considered to be a very resistant cancer to treatment for many years. It’s actually considered a model for a cancer that’s resistant to chemotherapy. It’s been a very difficult cancer to treat, because it is often diagnosed at a late stage. There aren’t early warning signs for kidney cancer. So about 1 out of 2 of the times that someone’s been diagnosed with the cancer they have spread to other areas.
Until recently, there have been very few treatment options to treat people with kidney cancer in that setting so that it has been considered to be a cancer with a poor outlook. The only 2 treatments that have yield to any benefit until recently are cytokines or immunotherapy with 2 commonly used cytokines been IFN-α or Interleukin-2. They only resulted in response in 1 out of 10 patients and the average survival for people with metastatic cancer was about 12 months. Both of those medicines were discovered in the mid 1980’s, and it’s been the main state of treatment with no progress at all until just recently with the discovery of the targeted therapies.
We’re basically in the era now of targeted therapies for cancer where it is recognized that most cancers arise from some sort of genetic mutation cancer. And so the targeted therapies have been available largely as a result of a better understanding of tumor biology, plus the development of molecules or medicines largely through industry. It was recognized about 10 years ago that there is a gene mutated that causes most cases of kidney cancer called the Von Hippel-Lindau gene. Also in parallel different targeted medicines were developed in laboratory and it was recognized that they matched very well with kidney cancer. So the 2 medications that were developed earliest and proven to be beneficial to patients are sorafenib which is made by Bayer and sunitinib which is made by Pfizer. They are both pills that people take that can treat kidney cancer.
There’s other etcetera coming. There’s another drug called temsirolimus which is made by Wyeth, is also a targeted therapy that’s proven beneficial. Avastin (Bevacizumab) was studied in a large phase III trial and that proved to be beneficial as well. Most recently, another orally administrative medicine called everolimus, which is made by a company called Novartis, is proving effective for kidney cancer patients.
From the stand point of medical studies, these targeted therapy medicines have replaced the cytokines with interferon; they have been swept away and patients are treated with the targeted therapies. They rarely result in a complete remission of a cancer. For the most part, the medicines are used to control or contain the cancer as long as possible. When the cancer breaks through, we will try a different medicine. So they are all important steps in terms of the cancer care for people with kidney cancer. But when you add them all together, they are resulting in a much better outcome and a much longer survival for people with metastatic kidney cancer.
Question: you mean combined?
Motzer:
No, they are not given combined but given in sequence.
The paradigm in the United States and Europe is in most patients to go with the sunitinib first, because that’s felt to be the most effective. Then if the person progresses after the sunitinib, until recently we have always given the sorafenib as the second line. With the temsirolimus available, temsirolimus or sorafenib is given and then the third. So there is the first line, second line and third line. We’re trying to sort out with clinical trials which are kind of the best sequence to give out the medicines.
Question: So just now you mention that you use the sunitinib as the 1st line?
Motzer:
That’s the first-line in the United States
Question: And others are the second-line？
Motzer:
The second and third line is sorafenib or temsirolimus. As far as which one is the best order, it’s being addressed in a large phase 3 international trial where the patients are randomized to temsirolimus or sorafenib as the second line. So we don’t know which one is the better line, but for the most part, our patients wind up getting all three.
Question: And I know that sunitinib has been used to treat advanced kidney cancer. And I want to know how about its future for other tumors?
Motzer:
My focus is on renal cell carcinoma, so my understanding is that sunitnib is being studied in a broad spectrum of other solid tumors as well, including lung cancer, breast cancer and others. In those cancers, it’s often given in combination in chemotherapy. It’s also proven to be effective and approved by many regulatory authorities for GIST as well.
Question: we all know that you have been in charge of many international multi-center trials. Some of the trials have been recommended by NCCN as the evidence. Can you describe the most recently progress in the clinical trials?
Motzer:
In a renal cell carcinoma, the large pivotal phase 3 trials that establish sunitinib are the first line treatment for patients with metastatic cancer which was a randomized comparison of sunitinib to IFN-. It was targeted to a relatively general population of patients. We have a system that we kind of use to estimate the prognosis (the Motzer System). It’s a 3-period system that differentiates patients as favorable, intermediate and poor. In that trial, the majority of people have a favourable of intermediate. And a study showed that the progression free survival which was the primary endpoint was longer for sunitinib compared to IFN, and the survival was also longer as well. The overall survival endpoint was more difficult to assess because many of the patients on interferon arm had access to the new targeted therapies which lengthened their survival. But that’s the main study that defined sunitinib as the first line treatment in U.S and Europe. However, some new data released in this year’s ASCO do show that sunitinib can prolong patients overall survival to over 2 years to 26.4 months, which is the first time achievement in mRCC treating history.
There was also another study that was done of Bevacizumab or Avastin plus interferon compared to interferon that was also a positive study and has resulted of approval of that combination in many countries of Europe. But it has not approved in the United States. So that’s considered to be a second option.
Temsirolimus which has a unique mechanism of action which is called an mTOR hyperactive specifically tailored to very poorly prognosis patients. It was studies in a head to head comparison to interferon and patients in that small minority of people of very poor outcome. It showed increase survival in that group. So the nomogram in the United Stats and Europe as well is for the first line treatment, for the favorable and intermediate, sunitinib is the main option. And a second option is Bevacizumab plus interferon. In the poorest population, the largest group of evidence is for temsirolimus based on the phase 3 trial, but sunitinib is an option as well.
For the most part, sorafenib was studied in a second line setting compared to placebo in patients who have had old treatments. Its use hasn’t been as successful in first line when it was compared to interferon in first line and a smaller trial but it wasn’t better than interferon. So mostly in our country, sorafenib is used in selected instances in patients who maybe would not tolerate the others but it’s more used in second and third line in our country.
Question: what do you think about the most significant difference between eastern and western countries in these trials using sunitinib or sorafenib?
Motzer:
I think since these agents are used globally and patients in different countries can tolerate medicines differently. It’s very important that there be extensive clinical trial experience in a while spectrum of countries around the world. I think that is very important. My understanding is that as some of these studies had been represented from people from all different countries. If there are gaps for areas with less experience, it will be important for the companies to do trials specifically in that country so that the doctors can get experiences with their own patient population. So that’s why I think it’s very important that you do study in China with sunitinib or temsirolimus specifically in your patient population with your experts.
Question: what’s you opinion on the cost-effectiveness of these multi-targeted therapies?
Motzer:
I think that the striking fact with these drugs would be improved efficacy and outlook for the patients with this disease. That really has to be the emphasis. The fact is that patients with this disease really had little or no options 5 years ago. And it’s a lethal tumor with a rather quick death. So now there are multiple medications that improve the outlook and be proved the prognosis to lengthen survival. So I think that the countries and their sponsoring companies have to come up with ways so that they can offer them to their own patients with this disease. It’s critical.
Question: I have another question, I want to find the Motzer scoring system, but I could not find any material on that. Can you give me some suggestions for finding that?
Motzer:
Years back when we were treating patients with mostly chemotherapy or cytokines, what we did was investigating a way to see if we could predict the outcome for people with metastatic cancer. The reason we did this is that we could counsel all the patients and also it would help clinical trial designed an interpretation when medicines did become available that looked like they were useful. So it was an underrepresented area that really wasn’t any system for people with metastatic renal cell cancer. The point of fact is that the medications were so poor and the course was so dismal and there were very few doctors that focused at renal cell cancer before. So we’ve had an extensive record for over 20 years of trying all different medications for this disease at Memorial Sloan-kettering Cancer Center. That’s what we do. And it was initiated by another doctor that was there before me who’s a very well known gastrointestinal stromal tumors oncologist. But when he left, I picked up the kidney cancer and done it ever since, so I establish a large database of close to 700 people that have been treated on our trial, and we setted up that rich system. It’s called the Memorial Sloan-Kettering (MSKCC) Risk System. It was initially published in the Journal of Clinical Ocology in 1996 which was the primary model. There have been 2 other publications where we kind of refined it, one to the first line and the other is to the second line. But the primary model was in 1996 in the Journal of Clinical Oncology.
記者: 您致力於腎細胞癌與睾丸癌治療工作已逾20年，是否能簡述一下在腎細胞癌治療領域的最新進展？
Motzer: 腎細胞癌一直被認爲是一種非常容易發生耐藥的腫瘤，事實上，它是一個化療耐藥的癌症模型。由於通常到了晚期才被診斷髮現，其治療的艱難性不言而喻。腎癌沒有早期預警指標，因此大約 1/2的患者在被診斷爲癌症時，癌細胞已經擴散到其他部位。直到最近，晚期腎癌病人治療的選擇也很有限，因此腎癌的前景仍是不好的。近期依然只有兩種有一定療效的治療方案——細胞因子或免疫治療，常用的兩種細胞因子是IFN-α 或IL-2。然而只有1/10的患者能產生響應，而轉移性腎癌患者的中位生存期大約僅爲12個月。這兩種藥物是在80年代中期研發的，此後腎癌治療的研究始終進展緩慢，直至靶向療法的出現。
意識到大多數癌症是由基因突變引起的我們已經站在了癌症靶向治療的新紀元，靶向治療因爲對腫瘤生物學深入瞭解與通過工業界推動而得以長足發展的分子醫學發展的結果而成爲可能。10年前我們發現了VHL基因突變是導致大多數腎癌的原因，與此同時，許多靶向型藥物經藥物實驗室研發確證用於腎癌治療。拜耳生產的索拉非尼與輝瑞生產的舒尼替尼是兩種較早研發成功的靶向藥物，這兩種藥劑被用於治療轉移性腎癌。更多的新型藥物接踵而來，由惠氏研發的temsirolimus 作爲靶向治療具有良好的療效。阿瓦斯丁（貝伐單抗）也進行了大型階段三試驗，同樣具有確證的療效。最近又一種新葯everolimus由諾華研發成功，它們都對腎癌有良好治療效果。
從醫學研究角度而言，它們已全面替代了細胞因子干擾素的治療，病人開始接受了新的靶向型藥物治療。雖然這些藥物很少能夠完全清除癌細胞，但卻能夠儘可能的控制腫瘤，延長其無疾病進展期。當腫瘤開始進展，我們可嘗試使用不同的藥物，因此在對於腎癌患者治療階段，每一種藥物的運用都是一個非常重要的步驟。它們結合起來，將可以產生更好的治療結果，延長轉移性腎癌患者的生存期。
記者: 您的意思是聯合用藥？
Motzer: 不，我指的是按照一定的順序給藥。在歐美國家大多數病患首先使用舒尼替尼，這被認爲是最有效的治療方案。若患者使用舒尼替尼治療仍發生疾病進展，我們將temsirolimus 或索拉非尼作爲二線治療藥物，緊接着進行三線治療。我們正試圖通過臨牀試驗以歸納出最好的給藥順序。
記者: 您剛纔指出舒尼替尼是一線用藥？
Motzer：在美國是這樣。
記者: 您能對其他的二線治療做一些介紹嗎？
Motzer: 索拉非尼或temsirolimus作爲二、三線治療方案。至於哪種給藥順序更爲恰當，我們正在進行temsirolimus或索拉非尼隨機二線治療的大樣本三期國際臨牀試驗。這依舊處於研究階段，但大多數病人通常會接受從一線直到三線的治療。
記者: 舒尼替尼已經被用於治療晚期腎癌， 那麼您對它在其他腫瘤領域的治療前景作何理解？
Motzer: 我的專業領域是腎細胞癌，就我所知，舒尼替尼正在被研究用於更爲寬泛的腫瘤治療領域，包括肺癌、乳腺癌以及其他實體腫瘤。在這些癌症治療中，它通常與化療相結合。而目前已批准的適應症中，還包括胃腸道間質瘤。
記者: 您負責了多個國際多中心試驗，一些試驗已經由NCCN作爲臨牀證據。您能否與我們分享一下這些研究的最新進展？
Motzer: 在腎細胞癌的分子靶向治療領域，奠定了舒尼替尼一線治療地位的關鍵性研究是一項大樣本Ⅲ期隨機臨牀試驗，該試驗比較了舒尼替尼與干擾素-α（IFN-α）一線治療腎細胞癌的療效。我們運用Motzer評分系統來評估預後效果，這是個將患者分爲低、中危、高危三級的系統。在試驗中，大部分爲低或中危患者。研究顯示了在患者無疾病進展生存期方面的進展(該試驗的主要終點)，使用舒尼替尼的患者比使用干擾素的患者生存期顯著延長。總生存期這一終點較難評價，因爲很多使用干擾素的患者隨後交叉到了舒尼替尼組，這樣他們的生存期得以延長。該研究是支持舒尼替尼在歐美國家獲批用於腎細胞癌一線治療的主要研究。而最近在ASCO上發佈的這項研究的最新數據顯示，舒尼替尼組患者的總體生存期可超過兩年（26.4個月）。這在晚期腎癌治療史上還是首次。
還有另一項研究使用貝伐單抗或阿瓦斯丁結合干擾素與干擾素的比較，也獲得了陽性結果。從而使該聯合用藥方案在多個歐洲國家被批准應用，但在美國尚未被批准，目前作爲第二選擇。
Temsirolimus是一種機制獨特的雷帕黴素靶蛋白劑，特別用於預後不良患者。另一項比較貝伐單抗+IFN與單用IFN療效的研究也取得陽性結果，對它的研究是在少數預後差的人羣中進行的與IFN的頭對頭研究，結果發現能提高這一組人羣的生存。因此，在美國和歐洲是這樣分類治療的：對於預後較好或中等的患者，一線治療主要選擇舒尼替尼，第二選擇爲貝伐單抗+IFN；對於預後較差患者，主要循證醫學證據是temsirolimus的Ⅲ期臨牀研究，但舒尼替尼也可選擇。
較多的研究中，索拉非尼被用於接受過傳統治療的病人與安慰劑做對照。小樣本臨牀試驗比較了索拉非尼與IFN在一線治療中的療效，顯示索拉非尼不優於IFN，提示它在一線治療並不成功。因此，在美國，索拉非尼選擇性用於不耐受其它治療者，但更多地用於二線或三線治療。
記者: 您認爲東西方國家在舒尼替尼或索拉非尼的臨牀試驗方面存在哪些顯著差別？
Motzer: 分子靶向藥物在全球範圍內廣泛應用，而不同國家的患者對藥物耐受性不同。因此，開展廣泛納入多國家患者的臨牀試驗就非常重要。若不同國家之間用藥經驗有差異，在相對缺乏用藥經驗國家開展的臨牀試驗，就有利於該國臨牀醫生積累對患者治療的經驗，我認爲在中國開展舒尼替尼治療的臨牀試驗有重要意義。
記者: 您如何看待靶向治療藥物的效益支出比？
Motzer: 首先我必須強調靶向藥物治療這些癌症的療效和前景是很令人振奮的。五年前此類患者幾乎無藥可治，現在多種新型藥物可改善預後、延長生存。我認爲，國家和製藥公司應設法使這類藥物的治療費用可負擔，使本國腫瘤患者可得到這類藥物治療，這非常關鍵。
記者:我想了解一下Motzer評分系統，您能介紹一下它的誕生過程麼？？
Motzer: 過去當我們還在使用化療或細胞因子治療患者時，我們研究了一種分析轉移癌症病人的預後的方法。這樣可以幫助我們針對不同患者設計治療方案，並且更好的解釋臨牀試驗所得到的藥品有效性數據。而在轉移性腎癌患者的治療中，當時並沒有一個這樣的系統。原因則是當時的治療方案匱乏、治療前景不明朗，因此專注於腎癌研究的醫學研究人員有限。在斯隆-凱特林紀念癌症中心，我們有超過20年的大量針對這一疾病的各種藥物試驗記錄，那就是我們所做的。這是由在我之前的另一名知名胃腸間質腫瘤學家所啓動的工作，之後由我接任並着手於腎癌的研究直到今日。我們建立起一個由近700名經我們試驗治療的患者所組成大型數據庫，稱爲斯隆-凱特林(MSKCC)風險分組。最初與最主要的模型發佈於1996年的《臨牀腫瘤學》期刊，並通過另2個刊物發佈了其完善後的一線、二線研究成果。