醫學界致力於開發對藥品可受益人羣的檢測

New drugs that boost the immune system’s ability to fight tumors may be one of the greatest medical advances in years, cancer doctors say, pulling some patients from death’s door and keeping them in remission for years.

增強免疫系統對抗癌細胞能力的新型藥物有可能是近年來最大的醫學進步之一，癌症醫生說，它能將病人從鬼門關上拉回來，延長數年的壽命。

But the truth is that this happens for only a minority of patients. Now, doctors say, there is a new imperative to develop a test that will identify in advance which patients will benefit, sparing others the cost and possible side effects.

但事實是，這種情況只會發生在一小部分病人身上。現在，醫生說，開發一項能提前鑑定出哪些病人能受益的檢測是當務之急，它能省去其他病人大筆的費用和可能出現的副作用。

The drugs currently cost about $150,000 a year per patient — even more for higher doses used in some cases — and the health system is eventually expected to spend billions or even tens of billions of dollars on the drugs each year.

目前，這種藥物每個病人每年要花費約15萬美元——在一些需要更大劑量的病例中甚至更多——預計醫療體系最終每年將在這種藥物上投入數十億、甚至是上百億美元資金。

“We don’t want to give these to 100 percent of the patients if only 59 percent or 20 percent will benefit,” said Dr. David R. Gandara, a professor and lung cancer specialist at the University of California, Davis. Being able to test for a biomarker that could predict the drugs’ efficacy “would make this new class of drugs easier on the wallet, the national health wallet,” he said.

“如果只有59%或者20%的病人能從中受益，我們不希望將這種藥物開給100%的病人，”加州大學戴維斯分校的教授、肺癌專家大衛·R·甘德拉醫生(Dr. David R. Gandara)說。如果有一項技術可以通過檢測生物標誌物來展示藥物有效與否，“將使這種新型藥物對錢包造成的壓力減小，我說的是國家醫療體系的錢包。”他說。

But developing such a test has proved tricky so far, for ethical as well as scientific reasons. Some doctors said it would be unfair to withhold the new drugs from patients based on a test if there was still even a slight chance that the drugs would help.

但迄今爲止，出於道德倫理和科學技術的原因，對這樣一種檢測手段的開發一直步履維艱。一些醫生認爲，哪怕只存在一絲這種藥物發揮作用的機會，僅因爲一項檢測就不把藥物給予病人都是不公平的。

“We don’t want to be wrong, because these medicines have an effect that, in some cases, is durable for years,” said Dr. Jedd D. Wolchok, chief of the melanoma and immunotherapeutics service at the Memorial Sloan Kettering Cancer Center. “We don’t want to have an imperfect biomarker.”

“我們不想犯錯，因爲這些藥物在某些病例中，藥效會持續數年，”紀念斯隆-凱特琳癌症中心(Memorial Sloan Kettering Cancer Center)黑色素瘤和免疫療法服務部(melanoma and immunotherapeutics service)負責人傑德·D·沃夏克博士（ D. Wolchok）說。“我們不希望有一個不完美的生物標誌物。”

The need for such biomarkers is illustrated in a study led by Dr. Wolchok that is to be presented on Sunday in Chicago at the annual meeting of the American Society of Clinical Oncology. The study is being published online by the New England Journal of Medicine.

沃夏克領導的一項研究說明了對於這樣的生物標誌物的需求，研究將在芝加哥週日的美國臨牀腫瘤學會(American Society of Clinical Oncology)年度會議上獲得展示。《新英格蘭醫學期刊》(New England Journal of Medicine)也將在其網站上發表這項研究。

The 945-patient study shows that the combination of two immune-boosting drugs from Bristol-Myers Squibb — Opdivo and Yervoy — is more effective than either drug alone in treating advanced melanoma. Patients treated with both drugs went a median of 11.5 months before their disease worsened, a longer reprieve than the 6.9 months for those who received only Opdivo and 2.9 months for those who took Yervoy.

這項覆蓋945名病人的研究表明，兩種來自百時美施貴寶(Bristol-Myers Squibb)的提高免疫力的藥物——納武單抗(Opdivo)和伊匹單抗(Yervoy)——搭配在一起，在治療晚期黑色素瘤中比任意一種更有效。同時使用這兩種藥物的病人在病情惡化前有平均11.5個月的時間，相較只使用納武單抗的6.9個月和只使用伊匹單抗的2.9個月，病人獲得了更長的壽命。

But the combination also caused serious side effects like diarrhea and colitis in 55 percent of patients, compared with only 16.3 percent for Opdivo alone and 27.3 percent for Yervoy alone.

但藥物搭配在一起也導致了嚴重的副作用，如55%的病人出現腹瀉和結腸炎，而只使用納武單抗的病人中這一比例只有16.3%，只使用伊匹單抗的病人中這一比例只有27.3%。

Dr. Antoni Ribas, a melanoma specialist at the University of California, Los Angeles, who was not involved in the study, said Opdivo alone might be just as good as the combination for many patients, with far fewer side effects, but that a biomarker test was needed.

加州大學洛杉磯分校的黑色素瘤專家安東尼·瑞巴斯醫生(Dr. Antoni Ribas)沒有參與到這項研究當中，他說，對於許多病人來說，只使用納武單抗的療效也許和藥物組合一樣好，它遠沒有那麼多副作用，只是需要一項生物標誌物檢測。

“The combination is outstanding, but we have to figure out who needs the combination as opposed to the single agent,” he said.

“藥物組合很出色，但我們必須搞清楚哪些病人需要它們，而不是隻需要某一種藥物。”他說。

The main test being explored is for PD-L1, a protein produced by cancer cells that, in effect, orders the immune system to stand down and not attack.

現在正在研發的主要檢測針對的是PD-L1，一種由癌細胞產生的蛋白質，它能使免疫系統“解除戒備”、不攻擊癌細胞。

The Merck drug Keytruda, Opdivo and other similar treatments work by keeping this “stand down” order from being received by the immune cells. So it makes sense that the drugs work best against tumors that are issuing such an order and that they may not work at all against tumors that are not issuing the order.

納武單抗和默克(Merck)的Keytruda等類似藥物，通過阻止免疫細胞接收到“解除戒備”的命令來發揮作用。因此一種合情合理的想法是，這類藥品最擅長對抗發佈這類指令的腫瘤，而不是那些不會發出相關指令的腫瘤。

Studies by Bristol-Myers and Merck as well as Roche, which is also developing such a drug, have shown that there was a much greater success rate using the drugs to treat tumors that were positive for PD-L1.

百時美施貴寶、默克與羅氏(Roche)等研發此類藥物的公司的研究顯示，此類藥物在治療PD-L1呈陽性的腫瘤時有着大得多的成功率。

Still, at least a small number of patients whose tumors do not produce meaningful amounts of PD-L1 also seem to benefit from these drugs. So some doctors say it is wrong to withhold the drugs from patients whose tumors test negative for PD-L1.

然而，仍有少數體內腫瘤甚少釋放PD-L1的患者可以受益於此類藥物，因此一些醫生表示，不應拒絕給出這些藥物，不讓PD-L1呈陰性反應的患者用藥。

In the melanoma study, patients whose tumors were positive for PD-L1 did as well on Opdivo alone as with the combination, as measured by the delay before their cancer worsened. One implication might be that those patients should get only Opdivo, while others should get the combination.

針對黑色素瘤的研究中，就延遲癌症惡化時間這個標準而言，PD-L1呈陽性反應的病患在只服用納武單抗時，與服用藥物組合效果相同。這可能顯示這些病患應當單獨使用納武單抗治療，其他病患則服用藥物組合。

But Dr. Michael B. Atkins, deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, said that even for PD-L1-positive tumors, the combination was better at shrinking the abnormalities.

但喬治城大學隆巴底綜合癌症中心(Georgetown Lombardi Comprehensive Cancer Center)的副主任邁可‧B‧埃特金斯博士(Dr. Michael B. Atkins)表示，即便是PD-L1呈陽性反應的腫瘤，藥物組合在縮小腫瘤上的表現仍然更佳。

“The biomarker isn’t good enough to make any decisions on it,” said Dr. Atkins, who was not involved in the study.

“這個生物標誌物不足以成爲治療決策的根據，”未參與研究的埃特金斯博士表示。

PD-L1 is not the only possible biomarker. Scientists are finding that the drugs work best against tumors with lots of mutations. Researchers reported on Friday that a genetic signature could identify a small subset of patients with colorectal and other types of cancer who would be likely to benefit from Keytruda.

PD-L1不是唯一可能帶來幫助的生物標誌物。科學家發現，這些藥物在對抗有着多種突變的腫瘤時效果最好。研究者週五公佈，一種標記基因可以指認出一小部分結腸癌及可能會受益於藥物Keytruda的其他癌症類型。

Dr. Ribas and colleagues suggest examining tumor samples to see if immune cells are present. The drugs appear to work best when immune cells are already in or near the tumor, ready to attack when the “stand down” order is lifted by a drug. If the immune cells are not present, then merely lifting the order may not be enough.

瑞巴斯博士及同僚指出，需要檢驗腫瘤樣本中是否存有免疫細胞。如果免疫細胞已經位於腫瘤內或鄰近部位，可以在“解除戒備”的指令被移除時進行攻擊，這些藥物就能達到最佳效果。倘若免疫細胞不存在，那移除指令也很難產生效果。

Merck is working with a diagnostic company, NanoString Technologies, to develop a test that measures activity levels in genes associated with immune response.

默克正在與診斷技術公司“奈米序列科技(NanoString Technologies)合作，研發一種測試，用以測量與免疫反應相關的基因的活躍程度。

A downside for drug companies is that a test can narrow the market for a drug.

對製藥公司不利的是，測試會縮減一種藥物的市場。

Shares of Bristol-Myers fell nearly 7 percent on Friday based on what would seem to be positive clinical trial results showing that Opdivo could prolong the lives of patients with the most common form of lung cancer.

百時美施貴寶的股票在週五下跌了近百分之七，儘管一項臨牀實驗結果似乎帶來了好消息，顯示納武單抗可以延長罹患主要類型肺癌的病患的生命。

But there was a big survival difference in patients with PD-L1-positive tumors and patients whose tumors test negative for the protein. For those with PD-L1-negative tumors, there was no real difference between Opdivo and the generic chemotherapy drug docetaxel. This information dashed investors’ hopes that Opdivo might be used by all patients with that form of lung cancer.

但PD-L1這種蛋白質呈陽性與否意味着患者存活時間上的很大差異。對於PD-L1呈陰性的腫瘤患者而言，納武單抗與化療仿製藥多西他賽(docetaxel)的效果無異。投資者曾希望此類肺癌的所有病患都會使用納武單抗，但這個消息讓他們希望破滅。

Opdivo did cause fewer side effects than docetaxel, but insurers might not be willing to pay so much more for that reason alone.

納武單抗的副作用仍比多西他賽要少，但保險業者並不願意僅爲這個理由支付其高額費用。

Docetaxel costs $6,000 for six cycles of treatment; Opdivo used for the same length of time costs about $60,000, said Dr. Patrick W. Cobb, an oncologist in Billings, Mont.

蒙大拿州比靈斯的腫瘤科醫生派崔克‧W‧柯布(Partrick W. Cobb)表示，多西他賽六次療程要價6千美元（約合3萬7千人民幣），同樣時長療程的納武單抗則需6萬美元。

“The cost of treating these patients will be far higher than in the past,” Dr. Cobb said on a webinar sponsored by Kantar Health, a consulting firm. “We really need a way of determining which patients are likely to benefit from these agents.”

“治療這些病患的支出會遠超以往，”柯布醫生在由諮詢公司坎達健康(Kantar Health)贊助的網絡研討會中表示。“我們真的需要找到一個方法，來分辨哪些病患可能從這些藥物獲得益處。”