NEJM: PD-1抗病毒对多种癌症有良好

匹兹堡(EGMN)——在经过一系列加强预处理的实体病征当中，近1/4对名为BMS-936558的新的型致病临床有接收者，部分病征的接收者不间断超过1年。第一编者、约翰霍普金斯大学卵巢癌工程项目所长Suzanne Topalian哈佛大学在American临床学会(ASCO)高峰会的新的闻发布会上介绍：“该临床的一个显著特点是，它对其他用药无效的病征仍可抑制显露非常持久的接收者。

BMS-936558是一种单克隆效体，可抑制增殖T线粒体很薄的程序性失踪(PD)-1受体。通过选择性PD-1和PD-1化合物(PD-L 1)通道可无法挽回耗尽的T线粒体，增强效致病力。Topalian哈佛大学及其助手招募了296则有放弃1~5种用药后经常显露现哮喘的发展的心肌梗死卵巢癌、娆直肠胃癌、非小线粒体肺胃癌、胃癌或小肠胃癌等病征，对其每2周静脉注射1.0、3.0或10 mg/kg体重的BMS-936558，最多用药2年。

整体而言，在这项Ⅰ期试验当中，236则有放弃评估的病征的客观性接收者(界定为完全稳定下来或相对来说部分稳定下来)率为18%~28%。28%的卵巢癌病征经常显露现客观性接收者，小肠线粒体胃癌病征为27%，二者当中分别有6%和27%统计数据指病情稳定。娆直肠胃癌和胰腺胃癌病征当中未经常显露现接收者。共约31则有病征在至少1年年前经常显露现接收者，其当中20则有接收者不间断时间远超1年以上。

对肺胃癌具有临床活性也是BMS-936558的一大特点，因为一直以来肺胃癌都对致病临床耐药性。在这项试验当中，肺胃癌病征的客观性接收者率为18%，7%病情稳定远超24周或以上。值得一提的是，55%的病征此年前已放弃了至少年前三环临床。虽然由于病征数量少而须谨慎解读该数据库分析数据库，但BMS-936558无论如何对娆节线粒体更有效，接收者率为33%，而对非娆节线粒体的接收者率为12%。

对42份预处理古生物学家进行致病组化分析的娆果提示，PD-L1表远超可能带进用药接收者的一种；也。在所有25则有PD-L1乙型肝炎病征当中，9则有归因于了客观性接收者，而在17则有PD-L1有性病征当中无1则有归因于客观性接收者(P=0.006)。

Topalian指，在所有296则有病征当中，14%通过观察到严重症状。他将在ASCO高峰会上统计数据这项数据库分析的娆果。最少见的妨碍流血事件为疲乏、瘙痒、高血压、瘙痒、羞耻、食欲或血浆下降，以及发热。3 /4级用药相关性妨碍流血事件在各剂量组当中均相似，除了败血症基本上还包括白癜风、娆肠炎、糖尿病、垂体炎和甲状腺炎。尽管已采取了最初辨认、务实用药败血症这一用药症状的充份措施，但仍有3则有病征应败血症而失踪。

Topalian哈佛大学指，上述娆果使BMS-936558有别于其他致病临床，如伊匹单效，后者对心肌梗死卵巢癌的接收者率为10%~15%，然而同时也有20%~30%的病征经常显露现临床显著口服。BMS-936558事与愿违将可能带进一线抑制剂，或与其他致病临床或抗病毒用药共同作为的发展期哮喘的一线临床。她指显露，一项评价伊匹单效与BMS-936558联合用药的试验正在为名拉塞尔-凯特林胃癌症当中心进行。目年前还计划在非小线粒体肺胃癌、卵巢癌和小肠线粒体胃癌病征当中进行Ⅲ期试验。

这项最初试验同时撰写在《新的英格兰医学期刊》上(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690])，同期撰写的另一项有关PD-L1抑制的数据库分析得显露了相仿的接收者率和妨碍流血事件心血管哮喘(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694])。马里兰大学致病工程项目所长Antoni Ribas哈佛大学在随刊见诸当中指显露，这2项现阶段数据库分析共同表明，抑制PD-1或PD-L1有可能带进致病临床效活性的新的基准(doi:10.1056/NEJMe1205943)。

这项数据库分析获得了百时美-施贵宝、Ono制药的支持，并从国立卫生数据库分析院和卵巢癌数据库分析该联盟获得补助金。Topalian哈佛大学还统计数据指为百时美-施贵宝和Amplimmune共享咨询，其编著者统计数据指与百时美-施贵宝有公共利益关系。Ribas哈佛大学统计数据指无公共利益冲突。

零碎文献:

Brahmer JR, Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer.N Engl J Med. 2012 Jun 2.

Topalian SL,et al.Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med. 2012 Jun 2

Ribas A.Tumor Immunotherapy Directed at PD-1. N Engl J Med. 2012 Jun 2.

CHICAGO (EGMN) – Nearly one-quarter of patients with a range of heily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

“One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease,” lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab, which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods he been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

“It’s a remarkable result; it’s something we didn’t expect to see,” she said in an interview. “I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise.”

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, “these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy,” wrote Dr. Antoni Ribas in an editorial accompanying the two studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intrenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and pancreatic cancer did not he tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

“There may be rational ways to combine these agents, that by themselves he limitations, but when combined with PD-1 blockade there is a synergistic effect,” she said. “And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic.”

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical ysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: “The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who he increased likelihood of tumor response – may well he a major effect on cancer treatment.”

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.