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.

临床研究表明，根据患者的分子分布情况，可以更好更快地进行药物审批。去年12月，一项针对试验性药物neratinib的乳腺癌试验引起了业界的关注，但这不仅仅是药物的问题。

With standard treatments being replaced by more personalized ones, trial design needs to change, too.

随着标准治疗被更个性化的治疗所取代，试验设计也需要改变。

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.

不同寻常的是试验本身。它被称为“I-SPY 2”，它可以并行地评估多个候选药物，而不是一次只进行一个。这种方法是一波努力的一部分，旨在改革昂贵且耗时的药物审批过程，而这往往不被考虑到癌症生物学当中的复杂现实。

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，每一种药物都在肿瘤具有特定分子特征的患者中进行筛选。试验“学习”，如它所积累的数据，它不是随机分配新病人来治疗或控制，而是利用早期的结果来调整补充。neratinib是由美国加州洛杉矶的Puma生物技术公司制造的，它只是五种被测试的靶向化合物中的一种，它们都被设计成选择性地阻断肿瘤生长的信号通路。

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.

药物审批的标准途径包括在第一阶段展示安全性，第二阶段的临床效果，然后是第三阶段的随机对照试验(RCT)，以确认实验治疗是否对目前的护理标准具备统计学意义上的改善。RCTs使人们发现了宝贵的治疗方法，可以提高生存时间和生活质量。英国医学研究委员会(UK medical Research Council)伦敦临床试验部门的医学肿瘤学家理查德?卡普兰(Richard Kaplan)说，我们在早期就像儿童白血病一样，取得了一些显著的成功，我们看到各种药物的微小改进，直到疾病转化为通常治愈的疾病。

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，癌症的进展减缓了，但是许多肿瘤学家希望它能再次加速。由于对遗传学和细胞生物学的深入了解，细胞毒性化学疗法的钝性工具，不加区分地瞄准所有快速分裂的细胞，现在正在为具有特定分子特征的肿瘤药物或生物标志物补充药物。但临床研究设计并没有跟上步伐。许多RCTs仍然倾向于广泛的观点，在两个大致相同的患者群体中对药物表现进行比较简单的比较。但是，他们无法解释个体遗传学，这就意味着他们会产生误导的结果。

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（译者：吉非替尼）的故事吧。gefitinib是由阿斯利康在伦敦开发的一种靶向药物，并以Iressa（译者：艾瑞莎）的营销方式销售。在一些非小细胞肺癌患者(NSCLC)的早期确诊后，该药物在2005年的第三阶段试验中失败(参考文献1)。该试验的近1700名患者并没有根据他们的肿瘤突变谱进行选择。德克萨斯州休斯顿的MD安德森癌症中心的生物统计学家Donald Berry说，该公司采取了尝试获取所有NSCLC的策略。“我们希望它在这个小子集中可得到推进。”这项试验所导致的糟糕结果使得美国食品和药物管理局(FDA)对开具该药实施严格的限制。然而，经过后来的分析发现，该种药物在特定的患者中收效甚佳，而gefitinib目前在欧洲可以恰如其分的运用于突变患者。

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.

批评人士指出，gefitinib吉非替尼的故事是新药物与旧试验设计的碰撞。他们断言，传统的随机试验代价太大，延迟了好的治疗方法的鉴定，并掩盖了只针对小部分患者有效的好药。

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).

张开双臂

然而，在某种程度上，gefitinib是一个让患者更快地获得药物的例子。它是FDA通过加速审批程序批准使用的众多肿瘤药物之一。如果它们在第二阶段的研究中显示出强有力的临床效果证据，只要在第三阶段进行试验以确认效果，那么该方案允许该种药物上市。(这就是吉非替尼的后果，受到严格的限制)。

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.

在众多的候选企业中，制药公司必须就如何进行资源投资做出艰难的决定。当许多单独的试验并行进行时，他们会争夺有限的患者资源。一项研究显示，2011年在美国进行的所有胰脏癌试验都需要83%的患者参与手术治疗。然而，根据美国癌症协会的数据，只有大约5%的病人自愿接受试验。

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.

多重防卫适应性试验，如I-SPY 2和FOCUS4，在1月份开始招募的结直肠癌试验，提供了一种方法来解决对公司资源和可用病人数量的限制。这些二期试验同时研究了几个标记和候选药物，通过扩大对有前景的治疗的研究，并停止对那些没有显示效果的药物进行研究，从而对结果做出反应。

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根据肿瘤的分子轮廓将乳腺癌患者分为10个子群体。然后将每个子群体分为治疗组和对照组。对每种药物的反应与单一控制臂进行比较。未来的患者招募并不是严格的随机的，而是由即将到来的试验数据告知的。这种方法，药物生物标志物与早期的承诺被分配更多的患者具有相同的生物标志物。加州大学旧金山分校的乳腺癌专家Laura Esserman共同组织了这次试验，Berry说:“这是在你根据这些知识去修改你的行为时更新知识的过程。”I-SPY 2已经有了第二名“毕业生”进入第三阶段，在伊利诺斯州北芝加哥的AbbVie公司进行药物聚合酶抑制剂的试验。其他五种化合物仍在测试中。

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正在给四个治疗臂招募病人。与I-SPY 2不同的是，患者被分配到治疗中，他们的生物标志物被认为是一种匹配。每个治疗组都有自己的对照组，由具有相同生物标记的病人组成。在他们的生物标志物组中表现良好的药物也将被给予那些肿瘤缺乏该标记的人来测试更广泛的影响。另一种单独的化疗只会治疗那些由于某种原因不能参与其他组的病人，以及那些没有对试验的治疗作出反应的患者，但是他们可能会受益于那些针对肿瘤亚型的未来药物。

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.

与往常一样，I-SPY 2的重点是最初的治疗，而不是局限于那些预后较差的晚期、转移性或耐药性疾病患者。贝瑞说，关注转移性疾病总是首先发生在癌症中，如果没有发生任何事情，你就不会继续下去。我们得早点看。“I-SPY 2”中的女性接受“新辅助”治疗，目的是在切除肿瘤之前缩小肿瘤。试验设计人员倾向于回避早期的患者，他们可能已经可以通过标准的治疗方法治愈，但是早期肿瘤的突变更少，而且更均匀，所以可能更容易达到目标。

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%.”

加州大学圣地亚哥分校(University of California, San Diego)个体化癌症治疗中心(Center for个性化Cancer Therapy)主任Razelle Kurzrock说，这样的早期测试已经改善了慢性粒细胞白血病(CML)的结果。目前已经有一种针对CML的有效靶向药物:imatinib（伊马替尼），诺华公司将其作为Gleevec（译者：甲磺酸伊玛替尼胶囊）或Glivec（译者：格列卫）。当医生们只使用这种药物作为最后的手段时，伊马替尼的回报是有限的。但是Kurzrock说，当医生开始给病人诊断时，他们的表现会有很大的改善。她说，回复率不再只有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.

令人感到兴奋的是，FDA在2012年中期宣布，它将考虑加快对乳腺癌药物的审批，这些药物可以在没有手术的情况下消除可检测的肿瘤组织，这部分是基于像I-SPY 2这样的试验数据。2013年9月，该机构首次批准使用pertuzumab（译者：帕托珠单抗），这是罗氏市场的Perjeta（帕托珠单抗）。

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.

这些试验设计提供了更多的机会，让患者参与到几乎所有患者的治疗组中，而不是简单地拒绝那些不符合单一生物标记标准的患者。此外，相对于每一种治疗都有一个控制组的费用，I-SPY 2的唯一控制臂会有相当大的节省。FOCUS4和I-SPY 2也提供了更大的成本削减的潜力，通过从药物中获得更大的收益，而不是通常在临床试验中寻求的，在治疗药物上没有肿瘤进展的存活率要比对照组高出一倍。这减少了需要获得健康的三期数据的患者数量，并确保只有高性能的候选人才能继续前进。卡普兰说，如果一种药物在中期分析过程中不能达到预先设定的结果，我们会将其关闭。

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.

从I-SPY 2中获得成功需要一种预测:一种药物有85%的机会在300个病人的第三阶段试验中成功，如果参与公司选择继续，FOCUS4中的治疗可以无缝地进入第三阶段。这也是肺癌主治方案的一个特点，这是一种在华盛顿DC癌症研究组织的支持者的支持下开发的一种针对squamt细胞肺癌的适应性试验。预计该试验将很快开始。

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.

疾病的重新定义

随着基因组学研究开始提供关于不同癌症的突变谱的进一步信息，更多的生物标记出现，研究人员正在重新评估癌症的分类(参见“第二次机会”)。举例来说，与两种不同突变的乳腺癌相比，与乳腺癌相同的结直肠癌可能有更多的共同点。如果事实证明是这样，那么这些应该是告知药物测试的相似之处。

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.

第二次机会：对过去药物决策的新视角

药品到诊所的旅程并不一定会随着监管机构的决定而结束。当临床肿瘤学家了解到病人对药物的反应和他或她的基因之间的相互作用时，很明显，一些失败的药物，可以通过观察一小部分参与者所表现出显著的益处的这种实例来恢复。

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.

以诺华公司开发的everolimus（译者：依维莫司）为例。这种药物在转移性膀胱癌的第二期试验中失败了，但是一名患者的癌症消失了，并在那里停留了两年多。纽约纪念斯隆-凯特灵癌症中心的研究人员随后发现，约8%患有膀胱癌的人携带一种突变，使他们的肿瘤容易受到药物的影响。美国国家癌症研究所正在通过其特殊的反应者计划，检查其他罕见但重要的药物反应的报告，这些报告可能会发现一些失败的药物重新投入开发。该研究所癌症诊断项目副主任芭芭拉·康利(Barbara Conley)说，我们研究了一些在过去几年中没有得到批准的二期试验，其中有多达10%的人有例外的反应。

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，即使药物被批准，它的成功也只能在现实世界中得到评估。加拿大多伦多玛格丽特癌症中心的肿瘤学研究员伊恩·坦诺克说，试验对象没有心脏或肾脏疾病。但这样的结果就会被带到一个没有选择的病人社区，那里有很多的并发症。结果，小的好处可能消失，罕见的毒性可能变得明显。Tannock提倡大规模的研究，以追踪药物在获得批准后的表现。但是，这种观察性研究需要临床中心的密切协作，至少在美国，由于缺乏中央国家癌症登记处，这一过程变得困难。

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.”

美国临床肿瘤学协会希望通过将患者治疗和结果数据整合在一起来纠正这一问题。这将允许我们为一组患者查询一组特定的分子特征数据，看看这些患者所接受的哪种治疗在子群体患者中最有效。我们现在可以提出一些在标准临床试验中无法回答的问题。

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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.

更多说法

Kurzrock是倾向于分子分析而非基于组织的定义的人之一。她说，如果你有一种针对某一特定异常的药物，你会希望看到异常，而不是你是否在治疗乳腺癌。支持这个模型的证据越来越多。例如，尽管FDA已经批准了crizotinib(译者：克里唑蒂尼。辉瑞公司将其作为Xalkori进行销售)，但临床研究表明，这种药物对患有侵袭性脑瘤的儿童也同样有效。

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”.

现在必须通过对不同疾病的试验逐步获得该项批准。为了加快这一进程，几家公司正在进行一项“篮子”试验，对多种癌症的治疗方法进行测试，这些癌症有常见的遗传干扰。葛兰素史克公司正在测试两种黑色素瘤药物，dabrafenib（译者：达拉非尼）和trametinib（译者：曲美替尼），在包括大脑、甲状腺和肠道在内的9种癌症中，它们在基因BRAF中共享突变，从而使它们容易受到这些药物的影响。该公司负责肿瘤研究和发展的高级副总裁拉斐尔?阿马多认为，这种方法为那些可能会从缝隙中钻出来的罕见癌症患者提供了希望。通过对来自不同肿瘤组的数据进行分析，即使是很小的一组阳性结果也有统计学意义。因此，Amado说，我们不需要在这些极其稀少的人群中进行非常大规模的随机试验。

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.

美国国家癌症研究所正在通过分子分析探索这一方法，利用靶向基因测序，将各种药物与有实体肿瘤或淋巴瘤的人配对，后者的疾病已在现有治疗中取得进展。该研究所癌症诊断项目副主任芭芭拉·康利(Barbara Conley)说，我们将有大约20个配置用来启动，针对你可能在癌症中发现的常见的可疑突变。如果我们能让35%或更多的肿瘤患者存活六个月以上，这是一个有趣的信号。这些基本上是第二阶段的试验，寻找可以证明进入第三期的适应症，但监管机构表示，他们愿意正式承认交叉肿瘤疗效的有力证据。FDA肿瘤学和血液学产品办公室主任Richard Pazdur说，FDA可能会批准一种基于分子定义人群的药物，而不是针对特定疾病的适应症。

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，额外的复杂性可能会混淆这一广泛的生物标记研究。例如，在某些黑色素瘤中起作用的BRAF抑制剂在结直肠癌中是无效的，具有相同的突变。但Kurzrock坚持认为，普遍的有效性是不切实际的期望。她说，如果你看看那些被批准用于肺癌的药物，反应率通常在15%到20%之间。我们不能期望100%的患者在基因组分类的基础上作出反应。

“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.”

“我们需要测试一种新的定制策略。”

事实上，肿瘤通常包含多种突变，这可能会导致药物耐药性成为靶向制剂的共同障碍，这表明每个患者的癌症可能需要一种特殊的药物混合物。Kurzrock说，我们将需要对每个病人和病人中心的护理进行一个新的定制策略，而不仅仅是测试药物或药物组合的旧方法。

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.”

这种复杂性将意味着研究人员和肿瘤学家的学习曲线陡然上升。Berry认为，肿瘤学将最终经历一个广泛的转变，将药物测试作为一个机会来深入了解疾病，而不仅仅是验证现有的假设。他说，未来真的是结合临床实践和临床试验，在试验中有学习和确认的概念。这将意味着一个完全不同的监管视角和一个完全不同的企业商业模式。