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Clinical studies that group patients according to their molecular profile can make for better and faster drug approval decisions. In December last year, a breast-cancer trial for the experimental drug neratinib captured industry attention — but the buzz was not just about the drug.
臨床研究表明，根據(jù)患者的分子分布情況，可以更好更快地進(jìn)行藥物審批。去年12月，一項(xiàng)針對(duì)試驗(yàn)性藥物neratinib的乳腺癌試驗(yàn)引起了業(yè)界的關(guān)注，但這不僅僅是藥物的問題。
With standard treatments being replaced by more personalized ones, trial design needs to change, too.
隨著標(biāo)準(zhǔn)治療被更個(gè)性化的治療所取代，試驗(yàn)設(shè)計(jì)也需要改變。
What was unusual was the trial itself. Known as I-SPY 2, it assesses multiple drug candidates in parallel, instead of the usual practice of one at a time. The approach is part of a wave of efforts to reform the costly and time-consuming process of drug approval that often fails to take into account the complex realities of cancer biology.
不同尋常的是試驗(yàn)本身。它被稱為“I-SPY 2”，它可以并行地評(píng)估多個(gè)候選藥物，而不是一次只進(jìn)行一個(gè)。這種方法是一波努力的一部分，旨在改革昂貴且耗時(shí)的藥物審批過程，而這往往不被考慮到癌癥生物學(xué)當(dāng)中的復(fù)雜現(xiàn)實(shí)。
In I-SPY 2, each drug is screened in patients whose tumours have specific molecular profiles. The trial 'learns' as it accumulates data, so rather than randomly assigning new patients to just treatment or control, it uses early results to adjust recruitment. Made by Puma Biotechnology in Los Angeles, California, neratinib was just one of five targeted compounds being tested, and all were designed to selectively block signalling pathways involved in tumour growth.
在I-SPY 2中，每一種藥物都在腫瘤具有特定分子特征的患者中進(jìn)行篩選。試驗(yàn)“學(xué)習(xí)”，如它所積累的數(shù)據(jù)，它不是隨機(jī)分配新病人來治療或控制，而是利用早期的結(jié)果來調(diào)整補(bǔ)充。neratinib是由美國(guó)加州洛杉磯的Puma生物技術(shù)公司制造的，它只是五種被測(cè)試的靶向化合物中的一種，它們都被設(shè)計(jì)成選擇性地阻斷腫瘤生長(zhǎng)的信號(hào)通路。
The standard road to drug approval involves demonstrating safety in phase I, clinical effect in phase II and then a phase III randomized controlled trial (RCT) to confirm whether the experimental treatment provides a statistically meaningful improvement over the current standard of care. RCTs have enabled the discovery of valuable treatments that bolster both survival time and quality of life. “We actually had some outstanding successes early on — like childhood leukaemia, where we saw small improvements from various drugs stack up until the disease turned into something that is usually cured,” says Richard Kaplan, a medical oncologist at the UK Medical Research Council's Clinical Trials Unit in London.
藥物審批的標(biāo)準(zhǔn)途徑包括在第一階段展示安全性，第二階段的臨床效果，然后是第三階段的隨機(jī)對(duì)照試驗(yàn)(RCT)，以確認(rèn)實(shí)驗(yàn)治療是否對(duì)目前的護(hù)理標(biāo)準(zhǔn)具備統(tǒng)計(jì)學(xué)意義上的改善。RCTs使人們發(fā)現(xiàn)了寶貴的治療方法，可以提高生存時(shí)間和生活質(zhì)量。英國(guó)醫(yī)學(xué)研究委員會(huì)(UK medical Research Council)倫敦臨床試驗(yàn)部門的醫(yī)學(xué)腫瘤學(xué)家理查德?卡普蘭(Richard Kaplan)說，我們?cè)谠缙诰拖駜和籽∫粯�，取得了一些顯著的成功，我們看到各種藥物的微小改進(jìn)，直到疾病轉(zhuǎn)化為通常治愈的疾病。
Progress against cancer has since slowed down, but many oncologists are hopeful that it is poised to accelerate once more. Thanks to a deeper knowledge of genetics and cell biology, the blunt instrument of cytotoxic chemotherapy — which indiscriminately targets all rapidly dividing cells — is now being supplemented by drugs created for tumours with specific molecular features, or biomarkers. But clinical-study design has not kept pace. Many RCTs still tend to take a broad view, making relatively simple comparisons of drug performance in two roughly identical patient groups. But their failure to account for individual genetics means that they can give rise to misleading results.
自那以后，癌癥的進(jìn)展減緩了，但是許多腫瘤學(xué)家希望它能再次加速。由于對(duì)遺傳學(xué)和細(xì)胞生物學(xué)的深入了解，細(xì)胞毒性化學(xué)療法的鈍性工具，不加區(qū)分地瞄準(zhǔn)所有快速分裂的細(xì)胞，現(xiàn)在正在為具有特定分子特征的腫瘤藥物或生物標(biāo)志物補(bǔ)充藥物。但臨床研究設(shè)計(jì)并沒有跟上步伐。許多RCTs仍然傾向于廣泛的觀點(diǎn)，在兩個(gè)大致相同的患者群體中對(duì)藥物表現(xiàn)進(jìn)行比較簡(jiǎn)單的比較。但是，他們無法解釋個(gè)體遺傳學(xué)，這就意味著他們會(huì)產(chǎn)生誤導(dǎo)的結(jié)果。
Witness the tale of gefitinib, a targeted drug developed by AstraZeneca in London and marketed as Iressa. After showing early promise in some patients with non-small-cell lung cancer (NSCLC), the drug failed in a phase III trial in 2005 (ref. 1). The trial's nearly 1,700 patients had not been selected on the basis of their tumour mutational profile. “The company took the tack of trying to get all of NSCLC,” says Donald Berry, a biostatistician at the MD Anderson Cancer Center in Houston, Texas. “It hoped that the benefit in this small subset would drive things.” The poor results of the trial led the US Food and Drug Administration (FDA) to put severe restrictions on who could be prescribed the drug. Later analyses2, however, revealed that the drug was effective in a specific subset of patients, and gefitinib is now available in Europe to patients with the appropriate mutations.
看看gefitinib（譯者：吉非替尼）的故事吧。gefitinib是由阿斯利康在倫敦開發(fā)的一種靶向藥物，并以Iressa（譯者：艾瑞莎）的營(yíng)銷方式銷售。在一些非小細(xì)胞肺癌患者(NSCLC)的早期確診后，該藥物在2005年的第三階段試驗(yàn)中失敗(參考文獻(xiàn)1)。該試驗(yàn)的近1700名患者并沒有根據(jù)他們的腫瘤突變譜進(jìn)行選擇。德克薩斯州休斯頓的MD安德森癌癥中心的生物統(tǒng)計(jì)學(xué)家Donald Berry說，該公司采取了嘗試獲取所有NSCLC的策略�！拔覀兿Ｍ谶@個(gè)小子集中可得到推進(jìn)�！边@項(xiàng)試驗(yàn)所導(dǎo)致的糟糕結(jié)果使得美國(guó)食品和藥物管理局(FDA)對(duì)開具該藥實(shí)施嚴(yán)格的限制。然而，經(jīng)過后來的分析發(fā)現(xiàn)，該種藥物在特定的患者中收效甚佳，而gefitinib目前在歐洲可以恰如其分的運(yùn)用于突變患者。
Critics point to the gefitinib story as a collision between new drugs and old trial design. They assert that conventional randomized trials are too costly, delay the identification of good therapies and mask the benefits of good drugs that work in only a subset of patients.
批評(píng)人士指出，gefitinib吉非替尼的故事是新藥物與舊試驗(yàn)設(shè)計(jì)的碰撞。他們斷言，傳統(tǒng)的隨機(jī)試驗(yàn)代價(jià)太大，延遲了好的治療方法的鑒定，并掩蓋了只針對(duì)小部分患者有效的好藥。
Open arms
In one way, however, gefitinib is an example of progress in getting drugs to patients more quickly. It is one of a number of oncology drugs to be approved for use by the FDA through its accelerated approval programme. The programme allows drugs to be marketed if they show strong evidence of clinical effect in a phase II study as long as a subsequent phase III trial is done to confirm the effect. (This is where gefitinib fell down and gained its tight restrictions).
張開雙臂
然而，在某種程度上，gefitinib是一個(gè)讓患者更快地獲得藥物的例子。它是FDA通過加速審批程序批準(zhǔn)使用的眾多腫瘤藥物之一。如果它們?cè)诘诙A段的研究中顯示出強(qiáng)有力的臨床效果證據(jù)，只要在第三階段進(jìn)行試驗(yàn)以確認(rèn)效果，那么該方案允許該種藥物上市。(這就是吉非替尼的后果，受到嚴(yán)格的限制)。
With numerous candidates in their pipelines, pharmaceutical companies must make difficult decisions about how to invest their resources. When many separate trials are done in parallel, they compete for a limited pool of patients. One study3 showed that filling all pancreatic-cancer trials in the United States in 2011 would have required the participation of 83% of patients with surgically treatable tumours. Yet only about 5% of patients volunteer for trials, according to the American Cancer Society.
在眾多的候選企業(yè)中，制藥公司必須就如何進(jìn)行資源投資做出艱難的決定。當(dāng)許多單獨(dú)的試驗(yàn)并行進(jìn)行時(shí)，他們會(huì)爭(zhēng)奪有限的患者資源。一項(xiàng)研究顯示，2011年在美國(guó)進(jìn)行的所有胰臟癌試驗(yàn)都需要83%的患者參與手術(shù)治療。然而，根據(jù)美國(guó)癌癥協(xié)會(huì)的數(shù)據(jù)，只有大約5%的病人自愿接受試驗(yàn)。
Multi-armed adaptive trials such as I-SPY 2 and FOCUS4 — a colorectal cancer trial that started recruitment in January — offer a way to tackle limits on both company resources and the number of available patients. These phase II trials study several markers and drug candidates at once, responding to results by expanding studies for promising treatments and discontinuing them for those that are not showing any effect.
多重防衛(wèi)適應(yīng)性試驗(yàn)，如I-SPY 2和FOCUS4，在1月份開始招募的結(jié)直腸癌試驗(yàn)，提供了一種方法來解決對(duì)公司資源和可用病人數(shù)量的限制。這些二期試驗(yàn)同時(shí)研究了幾個(gè)標(biāo)記和候選藥物，通過擴(kuò)大對(duì)有前景的治療的研究，并停止對(duì)那些沒有顯示效果的藥物進(jìn)行研究，從而對(duì)結(jié)果做出反應(yīng)。
I-SPY 2 divides patients with breast cancer into ten subgroups on the basis of their tumour's molecular profile. Each subgroup is then divided among the treatment and control groups. Responses to each drug are compared against a single control arm. Future recruitment is not strictly randomized, but rather is informed by incoming trial data. This way, drug–biomarker combinations with early promise are allocated more patients with the same biomarker profile.“This is about updating knowledge as you go and modifying your actions on the basis of that knowledge,” says Berry, who co-organized the trial with breast-cancer specialist Laura Esserman from the University of California, San Francisco. I-SPY 2 has a second graduate moving on to phase III trials — the drug veliparib from AbbVie in North Chicago, Illinois. Five other compounds are still being tested.
I-SPY 2根據(jù)腫瘤的分子輪廓將乳腺癌患者分為10個(gè)子群體。然后將每個(gè)子群體分為治療組和對(duì)照組。對(duì)每種藥物的反應(yīng)與單一控制臂進(jìn)行比較。未來的患者招募并不是嚴(yán)格的隨機(jī)的，而是由即將到來的試驗(yàn)數(shù)據(jù)告知的。這種方法，藥物生物標(biāo)志物與早期的承諾被分配更多的患者具有相同的生物標(biāo)志物。加州大學(xué)舊金山分校的乳腺癌專家Laura Esserman共同組織了這次試驗(yàn)，Berry說:“這是在你根據(jù)這些知識(shí)去修改你的行為時(shí)更新知識(shí)的過程�！盜-SPY 2已經(jīng)有了第二名“畢業(yè)生”進(jìn)入第三階段，在伊利諾斯州北芝加哥的AbbVie公司進(jìn)行藥物聚合酶抑制劑的試驗(yàn)。其他五種化合物仍在測(cè)試中。
FOCUS4 is recruiting patients to four treatment arms. Unlike in I-SPY 2, patients are assigned to the treatment for which their biomarker profile is thought to be a match. Each treatment arm has its own control group, made up of patients with the same biomarkers. Drugs that perform well in their biomarker-matched group will also be given to individuals whose tumours lack that marker to test for broader effects. A separate chemotherapy-only arm will treat patients who, for whatever reason, cannot participate in the other groups, as well as those who have not responded to the treatment on trial but might benefit from future drugs that target their tumour subtype.
FOCUS4正在給四個(gè)治療臂招募病人。與I-SPY 2不同的是，患者被分配到治療中，他們的生物標(biāo)志物被認(rèn)為是一種匹配。每個(gè)治療組都有自己的對(duì)照組，由具有相同生物標(biāo)記的病人組成。在他們的生物標(biāo)志物組中表現(xiàn)良好的藥物也將被給予那些腫瘤缺乏該標(biāo)記的人來測(cè)試更廣泛的影響。另一種單獨(dú)的化療只會(huì)治療那些由于某種原因不能參與其他組的病人，以及那些沒有對(duì)試驗(yàn)的治療作出反應(yīng)的患者，但是他們可能會(huì)受益于那些針對(duì)腫瘤亞型的未來藥物。
In another shift from business as usual, I-SPY 2 is focusing on initial treatment, rather than limiting itself to patients facing poor prognoses from advanced, metastatic or drug-resistant disease. “Looking at metastatic disease is always first in cancer, and if nothing happens you don't continue,” says Berry. “We have to look earlier.” Women in I-SPY 2 receive 'neoadjuvant' treatment that is intended to shrink their tumours before they are removed. Trial designers have tended to shy away from early-stage patients who might already be curable with standard treatments, but early-stage tumours often have fewer mutations and are more homogeneous, so could be easier to target.
與往常一樣，I-SPY 2的重點(diǎn)是最初的治療，而不是局限于那些預(yù)后較差的晚期、轉(zhuǎn)移性或耐藥性疾病患者。貝瑞說，關(guān)注轉(zhuǎn)移性疾病總是首先發(fā)生在癌癥中，如果沒有發(fā)生任何事情，你就不會(huì)繼續(xù)下去。我們得早點(diǎn)看。“I-SPY 2”中的女性接受“新輔助”治療，目的是在切除腫瘤之前縮小腫瘤。試驗(yàn)設(shè)計(jì)人員傾向于回避早期的患者，他們可能已經(jīng)可以通過標(biāo)準(zhǔn)的治療方法治愈，但是早期腫瘤的突變更少，而且更均勻，所以可能更容易達(dá)到目標(biāo)。
Such early-stage testing has led to improved outcomes in chronic myelogenous leukaemia (CML), says Razelle Kurzrock, director of the Center for Personalized Cancer Therapy at the University of California, San Diego. There is already an effective targeted drug for CML: imatinib, which Novartis markets as Gleevec or Glivec. When physicians were using this drug only as a last resort, imatinib offered limited returns. But Kurzrock says that when doctors started giving it to patients upon diagnosis, the improvement in performance was dramatic. “The response rate is no longer just 10%,” she says. “It's close to 100%.”
加州大學(xué)圣地亞哥分校(University of California, San Diego)個(gè)體化癌癥治療中心(Center for個(gè)性化Cancer Therapy)主任Razelle Kurzrock說，這樣的早期測(cè)試已經(jīng)改善了慢性粒細(xì)胞白血病(CML)的結(jié)果。目前已經(jīng)有一種針對(duì)CML的有效靶向藥物:imatinib（伊馬替尼），諾華公司將其作為Gleevec（譯者：甲磺酸伊瑪替尼膠囊）或Glivec（譯者：格列衛(wèi)）。當(dāng)醫(yī)生們只使用這種藥物作為最后的手段時(shí)，伊馬替尼的回報(bào)是有限的。但是Kurzrock說，當(dāng)醫(yī)生開始給病人診斷時(shí)，他們的表現(xiàn)會(huì)有很大的改善。她說，回復(fù)率不再只有10%，而是接近100%。
Encouragingly, the FDA declared in mid-2012 that it would consider accelerated approval for breast-cancer drugs that can eliminate detectable tumour tissue without surgery4, based in part on data from trials such as I-SPY 2. In September 2013, the agency issued its first such approval for the neoadjuvant use of pertuzumab, which Roche markets as Perjeta.
令人感到興奮的是，F(xiàn)DA在2012年中期宣布，它將考慮加快對(duì)乳腺癌藥物的審批，這些藥物可以在沒有手術(shù)的情況下消除可檢測(cè)的腫瘤組織，這部分是基于像I-SPY 2這樣的試驗(yàn)數(shù)據(jù)。2013年9月，該機(jī)構(gòu)首次批準(zhǔn)使用pertuzumab（譯者：帕托珠單抗），這是羅氏市場(chǎng)的Perjeta（帕托珠單抗）。
These trial designs offer greater opportunities for patient participation by creating treatment groups for almost all comers, rather than simply rejecting patients who do not match a single-biomarker criterion. Furthermore, I-SPY 2's sole control arm yields considerable savings relative to the expense of having a control group for each treatment. Both FOCUS4 and I-SPY 2 also offer the potential for even greater cost-cutting by seeking stronger gains from the drugs than those generally sought in clinical trials — typically, a doubling of survival without tumour progression on the treatment drug than on the control. This reduces the number of patients needed to obtain robust phase III data and ensures that only high-performance candidates move forward. “If a drug doesn't meet its prespecified outcome during interim analysis, we're going to close that arm,” says Kaplan.
這些試驗(yàn)設(shè)計(jì)提供了更多的機(jī)會(huì)，讓患者參與到幾乎所有患者的治療組中，而不是簡(jiǎn)單地拒絕那些不符合單一生物標(biāo)記標(biāo)準(zhǔn)的患者。此外，相對(duì)于每一種治療都有一個(gè)控制組的費(fèi)用，I-SPY 2的唯一控制臂會(huì)有相當(dāng)大的節(jié)省。FOCUS4和I-SPY 2也提供了更大的成本削減的潛力，通過從藥物中獲得更大的收益，而不是通常在臨床試驗(yàn)中尋求的，在治療藥物上沒有腫瘤進(jìn)展的存活率要比對(duì)照組高出一倍。這減少了需要獲得健康的三期數(shù)據(jù)的患者數(shù)量，并確保只有高性能的候選人才能繼續(xù)前進(jìn)。卡普蘭說，如果一種藥物在中期分析過程中不能達(dá)到預(yù)先設(shè)定的結(jié)果，我們會(huì)將其關(guān)閉。
Successful graduation from I-SPY 2 requires a projection that a drug has an 85% chance of succeeding in a 300-patient phase III trial, and treatment arms in FOCUS4 can move seamlessly into phase III if participating companies opt to continue. This is also a feature of the Lung Cancer Master Protocol, an adaptive trial for squamous-cell lung cancer developed with support from the advocacy group Friends of Cancer Research in Washington DC. The trial is expected to start recruiting soon.
從I-SPY 2中獲得成功需要一種預(yù)測(cè):一種藥物有85%的機(jī)會(huì)在300個(gè)病人的第三階段試驗(yàn)中成功，如果參與公司選擇繼續(xù)，F(xiàn)OCUS4中的治療可以無縫地進(jìn)入第三階段。這也是肺癌主治方案的一個(gè)特點(diǎn)，這是一種在華盛頓DC癌癥研究組織的支持者的支持下開發(fā)的一種針對(duì)squamt細(xì)胞肺癌的適應(yīng)性試驗(yàn)。預(yù)計(jì)該試驗(yàn)將很快開始。
Disease redefined
As genomic studies start to provide further information about the mutation profiles of different cancers and as more biomarkers emerge, researchers are re-evaluating cancer classification (see 'Second chance'). A colorectal cancer that shares a mutation with a breast carcinoma may have more in common than two breast carcinomas with different mutations, for example. If this proves to be the case, then these should be the similarities that inform drug testing.
疾病的重新定義
隨著基因組學(xué)研究開始提供關(guān)于不同癌癥的突變譜的進(jìn)一步信息，更多的生物標(biāo)記出現(xiàn)，研究人員正在重新評(píng)估癌癥的分類(參見“第二次機(jī)會(huì)”)。舉例來說，與兩種不同突變的乳腺癌相比，與乳腺癌相同的結(jié)直腸癌可能有更多的共同點(diǎn)。如果事實(shí)證明是這樣，那么這些應(yīng)該是告知藥物測(cè)試的相似之處。
Second Chance: A new perspective for past drug decisions
A drug's journey to the clinic doesn't necessarily end with a regulator's decision. As clinical oncologists learn more about the interplay between a patient's response to a drug and his or her genetics, it is becoming clear that some failed drugs might be rehabilitated by looking at instances in which a small subgroup of participants showed significant benefit.
第二次機(jī)會(huì)：對(duì)過去藥物決策的新視角
藥品到診所的旅程并不一定會(huì)隨著監(jiān)管機(jī)構(gòu)的決定而結(jié)束。當(dāng)臨床腫瘤學(xué)家了解到病人對(duì)藥物的反應(yīng)和他或她的基因之間的相互作用時(shí)，很明顯，一些失敗的藥物，可以通過觀察一小部分參與者所表現(xiàn)出顯著的益處的這種實(shí)例來恢復(fù)。
Take everolimus, developed by Novartis. This drug failed a phase II trial for metastatic bladder cancer — but one patient's cancer went away and stayed away for more than two years. Researchers at the Memorial Sloan-Kettering Cancer Center in New York subsequently found that about 8% of people with bladder cancer carry a mutation that makes their tumour susceptible to the drug6. The US National Cancer Institute is now examining other reports of rare but significant drug responses through its Exceptional Responders programme, which might see some failed drugs put back into development. “We've looked at some of the phase II trials that didn't get approval over the past few years, and in lots of them as many as 10% of the people had exceptional responses,” says Barbara Conley, associate director of the institute's cancer-diagnosis programme.
以諾華公司開發(fā)的everolimus（譯者：依維莫司）為例。這種藥物在轉(zhuǎn)移性膀胱癌的第二期試驗(yàn)中失敗了，但是一名患者的癌癥消失了，并在那里停留了兩年多。紐約紀(jì)念斯隆-凱特靈癌癥中心的研究人員隨后發(fā)現(xiàn)，約8%患有膀胱癌的人攜帶一種突變，使他們的腫瘤容易受到藥物的影響。美國(guó)國(guó)家癌癥研究所正在通過其特殊的反應(yīng)者計(jì)劃，檢查其他罕見但重要的藥物反應(yīng)的報(bào)告，這些報(bào)告可能會(huì)發(fā)現(xiàn)一些失敗的藥物重新投入開發(fā)。該研究所癌癥診斷項(xiàng)目副主任芭芭拉·康利(Barbara Conley)說，我們研究了一些在過去幾年中沒有得到批準(zhǔn)的二期試驗(yàn)，其中有多達(dá)10%的人有例外的反應(yīng)。
Conversely, even when a drug is approved, its success can only really be assessed in the real world. “Trial subjects don't have cardiac or renal disease,” says Ian Tannock, an oncology researcher at Princess Margaret Cancer Centre in Toronto, Canada. “But then that result is taken out into a community of unselected patients where there is a lot of comorbidity.” As a result, small benefits may disappear and rare toxicities may become apparent. Tannock advocates large-scale research to track the performance of drugs after they have been approved. But such observational studies require close collaboration across clinical centres — a process made difficult in the United States, at least, by the lack of a central national cancer registry.
相反，即使藥物被批準(zhǔn)，它的成功也只能在現(xiàn)實(shí)世界中得到評(píng)估。加拿大多倫多瑪格麗特癌癥中心的腫瘤學(xué)研究員伊恩·坦諾克說，試驗(yàn)對(duì)象沒有心臟或腎臟疾病。但這樣的結(jié)果就會(huì)被帶到一個(gè)沒有選擇的病人社區(qū)，那里有很多的并發(fā)癥。結(jié)果，小的好處可能消失，罕見的毒性可能變得明顯。Tannock提倡大規(guī)模的研究，以追蹤藥物在獲得批準(zhǔn)后的表現(xiàn)。但是，這種觀察性研究需要臨床中心的密切協(xié)作，至少在美國(guó)，由于缺乏中央國(guó)家癌癥登記處，這一過程變得困難。
The American Society for Clinical Oncology hopes to rectify this problem with CancerLinQ, which integrates patient treatment and outcome data. “This would allow us to query data for a group of patients with a particular set of molecular characteristics, look at what treatments those patients received and identify the treatment that seemed to work the best in that subset of patients,” says Neal Meropol, a medical oncologist at Case Western Reserve University in Cleveland, Ohio, and a member of society's board of directors. “We can now ask questions that simply could not be answered in a standard clinical trial.”
美國(guó)臨床腫瘤學(xué)協(xié)會(huì)希望通過將患者治療和結(jié)果數(shù)據(jù)整合在一起來糾正這一問題。這將允許我們?yōu)橐唤M患者查詢一組特定的分子特征數(shù)據(jù)，看看這些患者所接受的哪種治療在子群體患者中最有效。我們現(xiàn)在可以提出一些在標(biāo)準(zhǔn)臨床試驗(yàn)中無法回答的問題。
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Kurzrock is among many who favour molecular profiling over tissue-based definitions. “If you have a drug that targets a specific abnormality, you would want to look at that abnormality — not whether you're dealing with breast cancer,” she says. Evidence to support this model is mounting. For example, although the FDA has approved crizotinib (marketed by Pfizer as Xalkori) for NSCLC, clinical studies suggest that the drug could also be effective for children with aggressive brain tumours that have the same mutation5.
更多說法
Kurzrock是傾向于分子分析而非基于組織的定義的人之一。她說，如果你有一種針對(duì)某一特定異常的藥物，你會(huì)希望看到異常，而不是你是否在治療乳腺癌。支持這個(gè)模型的證據(jù)越來越多。例如，盡管FDA已經(jīng)批準(zhǔn)了crizotinib(譯者：克里唑蒂尼。輝瑞公司將其作為Xalkori進(jìn)行銷售)，但臨床研究表明，這種藥物對(duì)患有侵襲性腦瘤的兒童也同樣有效。
Such approvals must now be won gradually through trials on different diseases. To speed things up, several companies are pursuing 'basket' trials that test treatments on multiple cancers with common genetic disruptions. GlaxoSmithKline is testing two melanoma drugs, dabrafenib and trametinib, in nine cancers — including brain, thyroid and intestine — that share mutations in the gene BRAF that could render them susceptible to these drugs. Rafael Amado, senior vice-president for oncology research and development at the firm, argues that this approach offers hope to patients with rare cancers who might otherwise slip through the cracks. By performing analyses that take data from across tumour groups, even small sets of positive outcomes can become statistically meaningful. As a result, says Amado, “we don't have to run very large randomized trials in these ultra-rare populations”.
現(xiàn)在必須通過對(duì)不同疾病的試驗(yàn)逐步獲得該項(xiàng)批準(zhǔn)。為了加快這一進(jìn)程，幾家公司正在進(jìn)行一項(xiàng)“籃子”試驗(yàn)，對(duì)多種癌癥的治療方法進(jìn)行測(cè)試，這些癌癥有常見的遺傳干擾。葛蘭素史克公司正在測(cè)試兩種黑色素瘤藥物，dabrafenib（譯者：達(dá)拉非尼）和trametinib（譯者：曲美替尼），在包括大腦、甲狀腺和腸道在內(nèi)的9種癌癥中，它們?cè)诨駼RAF中共享突變，從而使它們?nèi)菀资艿竭@些藥物的影響。該公司負(fù)責(zé)腫瘤研究和發(fā)展的高級(jí)副總裁拉斐爾?阿馬多認(rèn)為，這種方法為那些可能會(huì)從縫隙中鉆出來的罕見癌癥患者提供了希望。通過對(duì)來自不同腫瘤組的數(shù)據(jù)進(jìn)行分析，即使是很小的一組陽性結(jié)果也有統(tǒng)計(jì)學(xué)意義。因此，Amado說，我們不需要在這些極其稀少的人群中進(jìn)行非常大規(guī)模的隨機(jī)試驗(yàn)。
The US National Cancer Institute is exploring this approach through its Molecular Analysis for Therapy Choice programme, using targeted gene sequencing to match various drugs to people with solid tumours or lymphomas whose disease has progressed on existing treatments. “We'll have about 20 arms to start with, targeting the usual suspect mutations that you might find in cancer,” says Barbara Conley, associate director of the institute's cancer-diagnosis programme. “If we can get 35% or more patients across tumour types to survive six months or more, that's an interesting signal.” These are essentially phase II trials looking for indications that could justify a move to phase III, but regulators say that they are willing to formally recognize robust evidence of cross-tumour efficacy. “The FDA could approve a drug based on a molecularly defined population rather than a disease-site-specific indication,” says Richard Pazdur, director of the agency's Office of Oncology and Hematology Products.
美國(guó)國(guó)家癌癥研究所正在通過分子分析探索這一方法，利用靶向基因測(cè)序，將各種藥物與有實(shí)體腫瘤或淋巴瘤的人配對(duì)，后者的疾病已在現(xiàn)有治療中取得進(jìn)展。該研究所癌癥診斷項(xiàng)目副主任芭芭拉·康利(Barbara Conley)說，我們將有大約20個(gè)配置用來啟動(dòng)，針對(duì)你可能在癌癥中發(fā)現(xiàn)的常見的可疑突變。如果我們能讓35%或更多的腫瘤患者存活六個(gè)月以上，這是一個(gè)有趣的信號(hào)。這些基本上是第二階段的試驗(yàn)，尋找可以證明進(jìn)入第三期的適應(yīng)癥，但監(jiān)管機(jī)構(gòu)表示，他們?cè)敢庹匠姓J(rèn)交叉腫瘤療效的有力證據(jù)。FDA腫瘤學(xué)和血液學(xué)產(chǎn)品辦公室主任Richard Pazdur說，F(xiàn)DA可能會(huì)批準(zhǔn)一種基于分子定義人群的藥物，而不是針對(duì)特定疾病的適應(yīng)癥。
Additional complexity could confound this broad biomarker-informed research, however. For instance, BRAF inhibitors that work in some melanomas are ineffective in colorectal tumours with the same mutations. But Kurzrock maintains that universal effectiveness is an unrealistic expectation. “If you look at drugs that were approved for lung cancer, the response rates were usually in the range of 15–20% of patients,” she says. “We cannot expect 100% of patients treated on the basis of a genomic classification to respond.”
然而，額外的復(fù)雜性可能會(huì)混淆這一廣泛的生物標(biāo)記研究。例如，在某些黑色素瘤中起作用的BRAF抑制劑在結(jié)直腸癌中是無效的，具有相同的突變。但Kurzrock堅(jiān)持認(rèn)為，普遍的有效性是不切實(shí)際的期望。她說，如果你看看那些被批準(zhǔn)用于肺癌的藥物，反應(yīng)率通常在15%到20%之間。我們不能期望100%的患者在基因組分類的基礎(chǔ)上作出反應(yīng)。
“We will need to test a new strategy of customization.”
Indeed, tumours often contain multiple mutations that might drive drug resistance — a common roadblock for targeted agents suggesting that each patient's cancer may require a specialized cocktail of agents. “We will need to test a new strategy of customization per patient and patient-centric care,” says Kurzrock, “rather than just the old way of testing a drug or combination of drugs.”
“我們需要測(cè)試一種新的定制策略�！�
事實(shí)上，腫瘤通常包含多種突變，這可能會(huì)導(dǎo)致藥物耐藥性成為靶向制劑的共同障礙，這表明每個(gè)患者的癌癥可能需要一種特殊的藥物混合物。Kurzrock說，我們將需要對(duì)每個(gè)病人和病人中心的護(hù)理進(jìn)行一個(gè)新的定制策略，而不僅僅是測(cè)試藥物或藥物組合的舊方法。
This complexity will mean a steep learning curve for researchers and oncologists. Berry believes that oncology will ultimately undergo a broad transformation — approaching drug testing as an opportunity to gain insight into the disease rather than merely validate existing hypotheses. “The future really is combining clinical practice and clinical trials, and having a notion of both learning and confirming in the trial,” he says. “It will mean a completely different regulatory perspective and an entirely different business model for companies.”
這種復(fù)雜性將意味著研究人員和腫瘤學(xué)家的學(xué)習(xí)曲線陡然上升。Berry認(rèn)為，腫瘤學(xué)將最終經(jīng)歷一個(gè)廣泛的轉(zhuǎn)變，將藥物測(cè)試作為一個(gè)機(jī)會(huì)來深入了解疾病，而不僅僅是驗(yàn)證現(xiàn)有的假設(shè)。他說，未來真的是結(jié)合臨床實(shí)踐和臨床試驗(yàn)，在試驗(yàn)中有學(xué)習(xí)和確認(rèn)的概念。這將意味著一個(gè)完全不同的監(jiān)管視角和一個(gè)完全不同的企業(yè)商業(yè)模式。
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