ASCO呼吁开展规模更小、设计更精的癌症试验

美国临床肿瘤学会(ASCO)呼吁癌症研究人员重新思考四种常见癌症的临床试验设计，以期获得更大的收获。

经过数月的研究审议以及公开征求意见，最终的推荐意见试图寻求一个最佳平衡点，一方面避免提出无法达到因而被忽视的指南，另一方面确保目标远大且仍然现实可行。ASCO推荐意见已于3月17日发表于《临床肿瘤学杂志》(Journal of Clinical Oncology)(J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009])。

以胰腺癌为例，专家建议临床试验应以中位总生存率提高50%为目标，或者对于适合接受FOLFIRINOX方案(亚叶酸钙+氟尿嘧啶+伊立替康+奥沙利铂)的患者，使中位总生存期延长4~5个月；对于适合接受吉西他滨(健择)加或不加白蛋白结合型紫杉醇(凯素)治疗的患者，中位总生存期延长3~4个月。

建议选择总生存期(OS)而非无进展生存期(PFS)作为主要终点，不过专家也承认OS可能带来多方面的挑战，比如需要更长时间的随访，研究后治疗的潜在混杂效应，以及在一线靶向治疗期间针对疾病进展后发现的继发性突变采取二线治疗。

最终，中位OS延长2.5~6个月(取决于具体临床情况)被视为相对于标准治疗的最低改善要求，以此来定义具有临床意义的结局。

推荐意见指出，获得这种改善的同时还必须确保治疗毒性相对于现有治疗没有增加或仅有少量增加，毒性较高的治疗方案必须获得最大程度的OS改善才能被视为具有临床意义。

专家委员会主席、美国德克萨斯大学MD安德森癌症中心的外科学教授Lee M. Ellis博士在接受采访时表示：“我们希望试验申办方能够理解提高临床试验目标的必要性，但他们在使用这些推荐意见时可能会比较保守。设计目标不那么高的试验如果能达到试验终点，如果能找到办法识别出那些最可能从干预措施中获益的患者，那么对于个别患者仍然可能是有益的。”

ASCO专家委员会所期望的“规模更小、设计更精” 的试验有赖于根据肿瘤的分子驱动因素来选择适合接受靶向治疗的患者的能力，而非纳入所有愿意参加试验的患者。遗憾的是，很多时候仍然是在没有全面了解药物靶点的情况下就开发靶向治疗药物，所以也就没有配套的诊断方法来帮助选择患者。

美国俄勒冈健康与科学大学卫生保健管理研究中心主任David M. Dilts博士对此表示赞同，他在随刊述评中写道：“当不确定靶点的位置或者靶点是否有用时，是很难击中靶点的。随着大型临床研究机构纷纷建立了标本库，其中一些标本已被详细定性，加之这些标本的分析技术也发展得越来越快、越来越好、越来越便宜，我们相信这一真实存在的风险会在不久的将来得到解决。”(J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277])。

为此，专家委员会还呼吁试验申办方针对每项试验都建立综合性生物标本库。

Ellis博士说：“建立这类标本库的障碍包括成本以及试验申办方是否愿意或是否有能力为此买单。不过，我们相信这笔投入会得到回报，它将有助于我们了解癌症的分子驱动因素，从而为癌症患者开发出更恰当的靶向治疗药物。”

生活质量

虽然在所有工作组的讨论中生活质量(QOL)都是经常被提及的话题，但推荐意见在这方面并没有硬性要求。取而代之的是，工作组引用了2011年批准Janus激酶1/2抑制剂ruxolitinib(Jakavi)治疗骨髓纤维化这个例子，来说明如何连续评估特定的癌症相关症状来定义具有临床意义的患者结局。

长期从事转移性乳腺癌患者倡导工作的Musa Mayer女士在接受采访时说：“仅仅提及生活质量有多么重要是不够的。临床试验必须设计一套经过深思熟虑的、可行的、经确证的、患者自我报告的结局指标，以反映临床效益。试验观察到的不良事件绝不可能完全反映患者对某种治疗的真实体验。”

乳腺癌

对于乳腺癌，专家委员会选择的是之前没有针对疾病转移接受过治疗的转移性三阴性乳腺癌。专家建议临床试验以OS延长4.5~6个月为目标，但也指出乳腺癌工作组没能就可以视为具有临床意义的效应量达成共识。目前，这个预后较差的患者人群的中位OS为18个月。

肺癌

专家委员会提到了两个肺癌人群：非鳞状细胞癌和鳞状细胞癌。专家建议临床试验以这两个人群的OS分别延长3.25~4个月和2.5~3个月为目标。目前，这两个患者人群的基线中位OS分别为13个月和10个月。

结肠癌

有关结肠癌的推荐意见针对的是先前经过所有治疗后疾病仍然进展的患者，或者不适合接受标准二线或三线治疗的患者。对于这类患者，临床试验的目标是较之目前4~6个月的基线中位OS，OS延长3~5个月。

值得注意的是，专家委员会并没有提及达到所有四种癌症的推荐治疗目标所需的成本。不过，ASCO癌症治疗价值工作组已经开始着手评估特定肿瘤治疗的疗效、毒性和治疗成本。

作为一名乳腺癌幸存者，美国国防部国会指导乳腺癌研究项目整合小组前任主席/现任委员Patricia Haugen女士在接受采访时表示：“虽然具体的推荐意见比较有限，但工作组对于其所涉及的问题的确提供了经过深思熟虑的推荐意见。”

Haugen女士希望新的推荐意见能被切实遵守，但她也表示要获得更有意义的临床效益，需要广泛的支持和改变现状的决心。她说：“这种决心必须是真实的，必须来自参与临床试验过程的各方机构。只有这样，那些不符合所推荐的高标准的临床试验才不会被设计、被资助或者被实施。”

评论员Dilts博士对此表示赞同，要达到所推荐的目标，需要来自各个领域的有力倡导。他建议，可以采取“美国国防部高级研究计划署(DARPA)的方法，以解决高危问题为重点并予以支持。”

Ellis博士声明担任了基因泰克、罗氏、Imclone、礼来和安进公司的顾问/咨询委员会委员。Mayer女士、Haugen女士和Dilts博士声明无相关利益冲突。

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By: PATRICE WENDLING, Oncology Practice

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.