2014年10月28日讯 /生物谷BIOON/ --目前，PD-1/PD-L1免疫竞赛异常激烈，该领域的佼佼者——默沙东（Merck & Co）、百时美施贵宝（BMS）、阿斯利康（AZN）、罗氏（Roche）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。阿斯利康和罗氏的PD-L1抑制剂也已处于III期临床。
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。与黑色素瘤相比，肺癌是非常有利可图的治疗领域，而百时美似乎已经抢得先机，将夺取新市场的主要份额。
近日，默沙东又扳回了一局，FDA已授予Keytruda突破性药物（BTD）认定，用于经含铂化疗方案治疗后病情恶化的表皮生长因子受体（EGFR）突变阴性和间变性淋巴瘤激酶（ALK）重排阴性非小细胞肺癌（NSCLC）患者的治疗。而突破性疗法（BTD）认定，可以帮助缩短Keytruda肺癌适应症申请的审查时间表，尤其是FDA已明确表示，计划尽可能快地审批通过。
今年9月底，默沙东在2014年全球第二大肿瘤盛会——第39届欧洲临床肿瘤学会（ESMO）年会上公布了Keytruda治疗非小细胞肺癌（NSCLC）的一项Ib期临床研究的数据，该研究取得了较好的无进展生存期（PFS）数据和总生存期（OS）数据，数据同时表明，Keytruda的抗肿瘤活性与患者的PD-L1水平直接相关。默沙东便是根据该项Ib期的积极数据，向FDA申请了突破性药物认定（BTD）。
目前，业界还很难估量Keytruda对默沙东的重要性。受益于肿瘤学领域的迅速进展，默沙东庞大的研发部门在经历长达5年的临床干旱期后，已部分恢复了往日的风采。在美国，Keytruda获批的首个适应症为黑色素瘤，而百时美Opdivo今年年初获日本批准黑色素瘤适应症，可以说，在美国市场中，默沙东已击败了百时美。但业界认为，与黑色素瘤相比，肺癌才是PD-1/PD-L1免疫疗法最大的市场机会之一。目前，该治疗领域，百时美已计划在今年年底向FDA滚动提交Opdivo肺癌适应症申请。
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。
近日，默沙东公布第三季度销售数据，由于仿制药进一步侵蚀，与去年同期相比，第三季度销售下降4%。默沙东也迫切需要诸如Keytruda的重磅新产品恢复增长。
英文原文：Merck grabs another 'breakthrough' in PD-1 lung cancer race with Bristol-Myers
With the goal line for lung cancer in sight at the FDA as it races with an ambitious R&D team at Bristol-Myers Squibb ($BMY), Merck ($MRK) has grabbed bragging rights to the agency's breakthrough drug designation for the checkpoint inhibitor pembrolizumab (Keytruda) for that golden market opportunity--helping to ease the sting of falling Q3 pharma sales.
The pharma giant put out word that the agency has granted its BTD title for epidermal growth factor receptor (EGFR) mutation-negative, and anaplastic lymphoma kinase (ALK) rearrangement-negative non-small cell lung cancer "whose disease has progressed on or following platinum-based chemotherapy."
Backing up earlier immuno-oncology research on the topic, investigators reported at European Society for Medical Oncology meeting a few weeks ago that pembrolizumab's antitumor activity for NSCLC directly correlated to levels of PD-L1 in patients, a closely linked target for the disease. Better progression-free survival and overall survival times were recorded in that Phase Ib study, which Merck says was used for their BTD application with the feds.
It's hard to overestimate the importance of Keytruda for Merck. The pharma giant's huge R&D division has regained a considerable portion of its lost luster following a grim 5-year drought in the clinic based on its rapid progress with the cancer treatment. The drug was the first approved in the U.S. for melanoma, beating out Bristol-Myers Squibb--which grabbed the first global approval for a checkpoint inhibitor in Japan earlier this year. Bristol-Myers is determined to be the first to get an OK in lung cancer, which is considered one of the largest market opportunities for these drugs. Bristol-Myers has completed its European application for lung cancer and expects to wrap a rolling app at the FDA by the end of this year.
A breakthrough designation could help Merck shave some time off its regulatory timeline, particularly as regulators have made it clear that they plan to push through approvals as quickly as possible.
PD-1 and PD-L1 both play a significant role in cancer. By blocking those two IO targets investigators have found that the immune system can begin to recognize cancer cells and mount an attack that can make a significant difference in terms of survival expectations. And the leaders in the field--which includes Roche ($RHHBY) and AstraZeneca ($AZN)--are scrambling to stake out positions as early leaders.
Merck needs all the good news it can get on the R&D front. Long a laggard among the Big 10 drug developers, Merck reported that its Q3 pharma sales dropped 4% year-over-year as generics took a deeper bite into sales revenue. The prospect that big new products like Keytruda can point those numbers back north is the company's main defense now against unhappy investors.