NEJM: PD-1单抗对多种癌症有极好

芝加哥(EGMN)——在经过一系列提升示举例的实体病变里面，有数1/4对名为BMS-936558的最初型免疫系统疗法有；也，部分病变的；也持续最多1年。第一作者、约翰霍普金斯大学卵巢胃癌单项主任Suzanne TopalianDr在美国医学学会(ASCO)年会的最初闻发布会上讲解：“该疗法的一个显著表现形式是，它对其他疗法单方面的病变仍可游离不止更加更为重要的；也。

BMS-936558是一种化学合成，可抑制转化T细胞内表面的一般而言丧命(PD)-1酶。通过抑制PD-1和PD-1配体(PD-L 1)通路可保住耗竭的T细胞内，增强抗免疫系统力。TopalianDr及其同事征募了296举例接受1~5种疗法后浮现疾病进展的转移性卵巢胃癌、拢肝胃癌、非小细胞内肝胃癌、胃癌或肝胃癌等病变，对其每2周静脉注射1.0、3.0或10 mg/kg体型的BMS-936558，最多疗法2年。

拢果显示，在这项Ⅰ期次测试里面，236举例接受评估的病变的合理；也(定义为完全维持或明显部分维持)率为18%~28%。28%的卵巢胃癌病变浮现合理；也，肝细胞内胃癌病变为27%，二者里面分别有6%和27%年度报告说是病状保持稳定。拢肝胃癌和胰腺胃癌病变里面未浮现；也。总计31举例病变在数1年前浮现；也，其里面20举例；也持续时间达1年以上。

对肝胃癌具有医学活性也是BMS-936558的造就表现形式，因为一直以来肝胃癌都对免疫系统疗法病毒性。在这项次测试里面，肝胃癌病变的合理；也率为18%，7%病状保持稳定超越24周或以上。值得一提的是，55%的病变此前已接受了数前三线疗法。虽然由于病变数量少而须谨慎说明了该学术研究资料，但BMS-936558似乎对点状细胞内更有效，；也率为33%，而对非点状细胞内的；也率为12%。

对42份示举例标本进行免疫系统组化分析的拢果提示，PD-L1强调或许带入疗法；也的一种多种类型。在所有25举例PD-L1阴性病变里面，9举例产生了合理；也，而在17举例PD-L1阴性病变里面无1举例产生合理；也(P=0.006)。

Topalian说是，在所有296举例病变里面，14%观察到严重药物。他将在ASCO年会上年度报告这项学术研究的拢果。最常见的不当政治事件为疲乏、皮疹、腹泻、瘙痒、恶心、食欲或血红蛋白回升，以及头痛。3 /4级疗法相关性不当政治事件在各血糖组里面均雷同，除了白血病之外还包括白癜风、拢肠尘、肝尘、小脑尘和甲状腺尘。尽管已规避了早期辨识、积极疗法白血病这一疗法药物的极佳措施，但仍有3举例病变应白血病而丧命。

TopalianDr说是，上述拢果使BMS-936558大相迳庭其他免疫系统疗法，如伊匹单抗，后者对转移性卵巢胃癌的；也率为10%~15%，然而同时也有20%~30%的病变浮现医学显著毒性。BMS-936558最终将或许带入里面卫药物，或与其他免疫系统疗法或靶向疗法共同作为进展期疾病的里面卫疗法。她宣说是，一项评价伊匹单抗与BMS-936558联合疗法的次测试准备纪念斯隆-凯特林胃癌症里面心进行。以外还计划在非小细胞内肝胃癌、卵巢胃癌和肝细胞内胃癌病变里面筹划Ⅲ期次测试。

这项早期次测试同时发表在《最初英格兰医学杂志》上(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690])，同期发表的另一项有关PD-L1抑制的学术研究断定了略低的；也率和不当政治事件发生率(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694])。康奈尔大学免疫系统单项主任Antoni RibasDr在随刊概述里面宣说是，这2项可行性学术研究共同确实，抑制PD-1或PD-L1有或许带入免疫系统疗法抗活性的最初标准(doi:10.1056/NEJMe1205943)。

这项学术研究获得了百时美-施贵宝、Ono制药的支持，并从国立卫生学术研究所和卵巢胃癌学术研究联盟获得补偿金。TopalianDr还年度报告说是为百时美-施贵宝和Amplimmune提供政府部门，其编著者年度报告说是与百时美-施贵宝有利益关系。RibasDr年度报告说是无不法行为。

原始文献:

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.