' m x* c9 Q, P p7 Y ~0 H目前，PD-1/PD-L1免疫竞赛异常激烈。随着各巨头研发项目的推进，竞赛场地也逐渐从黑色素瘤扩大到乳腺癌、肺癌治疗领域。乳腺癌方面，罗氏和默沙东在三阴乳腺癌（TNBC）临床已取得积极数据；肺癌方面，BMS在欧盟提交了全球首个上市申请，默沙东也赢得了FDA突破性疗法认定。
PD-1/PD-L1抗癌免疫疗法市场峰值高达350亿美元，默沙东（Merck & Co）、百时美施贵宝（BMS）、阿斯利康（AZN）、罗氏（Roche）是该领域的佼佼者，均在火速推进各自的临床项目。此次竞赛中，百时美和默沙东稍微领先。百时美的PD-1抑制剂Opdivo（nivolumab）于今年7月获日本批准，是全球批准的首个PD-1抑制剂；而默沙东的PD-1抑制剂Keytruda（pembrolizumab）于今年9月初获FDA批准，是美国批准的首个PD-1抑制剂；这2种药物获批的首个适应症均为黑色素瘤。
乳腺癌、肺癌成竞赛新场地
然而，业界认为，黑色素瘤适应症的市场潜力有限，PD-1/PD-L1免疫疗法的前景仍依赖于其他肿瘤，如非小细胞肺癌（NSCLC）和乳腺癌。乳腺癌方面，罗氏和默沙东上周相继宣布各自PD-1/PD-L1免疫疗法治疗三阴乳腺癌（TNBC）已取得积极数据，并计划于12月9日在第37届圣安东尼奥乳腺癌大会（SABCS）上公布。
而在肺癌领域，百时美已向欧盟提交了Opdivo治疗非小细胞肺癌（NSCLC）适应症的上市申请，标志着PD-1/PD-L1免疫疗法全球首个肺癌适应症申请。本月底，默沙东又扳回一局，FDA已授予Keytruda治疗非小细胞肺癌（NSCLC）的突破性疗法认定，在监管方面将缩短Keytruda肺癌适应症的审查周期。
BMS Opdivo肺癌II期大获成功，股价飙升
近日，百时美公布了Opdivo一项肺癌II期单组开放标签研究（CheckMate-063）的积极数据，该研究涉及117例既往接受过至少2种系统性治疗（有65%患者接受过3种或更多先前治疗）但病情恶化的晚期鳞状细胞非小细胞肺癌（NSCLC）患者。截至目前，随访时间最少11个月，由独立审查委员会（IRC）采用RECIST1.1标准估计的客观缓解率（ORR）为15%（95% CI = 8.7, 22.2），中位缓解持续时间尚未获得；估计的一年生存率为41%（95% CI = 31.6, 49.7），中位总生存期（mOS）为8.2个月（95% CI = 6.05, 10.91）。该研究的详细数据将提交至10月31日举行的2014芝加哥胸部肿瘤跨学科研讨会（2014 Chicago Multidisciplinary Symposium on Thoracic Oncology）。
该项研究的强劲数据远超历史水平，令业界欢呼不已。从历史数据来看，三线鳞状细胞非小细胞肺癌（NSCLC）患者客观缓解率（ORR）仅有个位数，一年存活率仅为5.5%-18%，而该项研究中ORR却达到了15%，一年存活率甚至高达41%。此外，百时美预计，中位总生存期（mOS）8.2个月可能是该群体历史数据的2倍。目前该患者群体在临床上尚无有效的治疗方案。
数据公布后，百时美股价飙升逾8%。根据百时美网站，该公司从今年4月开始向FDA滚动提交Opdivo用于鳞状细胞NSCLC的三线治疗，预计将于今年年底完成申请提交。
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力,有望实质性改善患者总生存期（OS）。而各大制药巨头也正在火速推进各自的项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。' T/ B4 Y( M9 R
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英文原文：Bristol-Myers' nivolumab impresses once again--this time in crucial lung cancer study
Bristol-Myers Squibb's closely watched checkpoint inhibitor nivolumab managed to wow analysts this morning with impressive survival results in a Phase II study of patients with advanced squamous cell non-small cell lung cancer. Of all the patients in the drug arm, 41% were alive at the one-year mark, while investigators tracked an overall response rate of 15%.
Investors loved it. Bristol-Myers' shares ($BMY) soared more than 8% this morning.
Analysts quickly zeroed in on that 41% survival figure for nivolumab (approved as Opdivo). Investigators for the company noted that historically the percentage of these patients still alive at one year hovered between 5% and 18%. ISI's Mark Schoenebaum excitedly noted in an email that company bulls had been looking for a 30% survival rate at the one-year mark, while he thought anything over 35% "would be excellent data." And he went on to note that "landmark OS (overall survival) probably more impt than median given likely late separation of OS curves, in my opinion."
You can also count Leerink's Seamus Fernandez among Bristol-Myers' fan club today. "Our conversation with BMY this morning also highlights median overall survival (OS) of 8.2 mos, which BMY believes could be as much as 2x what would normally be seen in this highly refractory pt population," Fernandez noted. "Furthermore, The fact that duration of response had not been reached at 12 mos adds to our excitement for positive outcomes in both of BMY's 2nd line survival studies."
The cheering section is also likely more than a little relieved. Bristol-Myers had stirred some significant unease earlier in the year after it failed to fully explain why it was delaying a planned regulatory filing for nivo in lung cancer. As Bernstein's Tim Anderson explained in his review, that may have been the result of BMS's need to send along 12-month rather than 6-month results for the single-arm study. The company's historical survival trend number is based on older Medicare patients, which may have skewed it in nivo's favor. And the FDA may have trouble approving a drug based on a single-arm study. Still, he adds, the results are reassuring, easing fears that the numbers may have turned sour.
Bristol-Myers has been investing heavily in lung cancer studies, looking to beat rivals like Merck ($MRK) to the market with a PD-1 drug that can extend the lives of patients. It recently filed for an approval in Europe and now appears well on its way to adding a major market niche to the maiden approvals handed out on skin cancer. Analysts consider lung consider a much larger market, which has driven a frenetic race to the regulatory finish line. Among the leaders in the checkpoint field are Roche ($RHHBY) and AstraZeneca ($AZN).
These PD-1 checkpoint inhibitors are designed to dismantle a stealth mechanism cancer cells rely on to escape detection by the immune system. There's been growing evidence that these drugs will be the first to allow the immune system to marshal its forces to fight cancer, creating a natural combination approach with existing and experimental drugs that can provide a 1-2 punch for even greater efficacy. And a host of follow-up drug candidates are entering the clinic as a broad range of biopharma companies look to stake out a section of what promises to be a megamarket opportunity valued in the tens of billions of dollars.
"The Phase II findings from CheckMate -063 are encouraging as there are no effective treatment options for patients with refractory squamous cell lung cancer after their disease has progressed through two prior therapies," said Emory University's Suresh Ramalingam.
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