NEJM: PD-1单抗对多种癌症有较差

芝加哥(EGMN)——在经过一系列强化预处理的实体病患者中会，有约1/4对叫作BMS-936558的新型免疫反应麻醉药有接收者，以外病患者的接收者持续超过1年。第一作者、约翰霍普金斯所大学在此之前列腺胰脏新项目室主任Suzanne Topalian博士在American药理学学术研究会(ASCO)研讨会的新闻发布会上详述：“该麻醉药的一个显著表现形式是，它对其他疗程无效的病患者仍可诱导出比较更加为重要的接收者。

BMS-936558是一种外用病毒，可堵塞转化T细胞内表面的比如说死亡(PD)-1酶。通过抑制PD-1和PD-1配体(PD-L 1)通路可无法挽回耗竭的T细胞内，增强外用外用性。Topalian博士及其同事招募了296同上接纳1~5种疗程后浮现疟疾进展的转移性在此之前列腺胰脏、结直肠胰脏、非小细胞内胰脏症、胰脏或肾胰脏等病患者，对其每2周静脉注射1.0、3.0或10 mg/kg体重的BMS-936558，最多疗程2年。

结果显示，在这项Ⅰ期试制中会，236同上接纳评估的病患者的事实接收者(定义为完全趋于稳定或引人注意以外趋于稳定)亲率为18%~28%。28%的在此之前列腺胰脏病患者浮现事实接收者，肾细胞内胰脏病患者为27%，二者中会分别有6%和27%调查报告引述病情稳定。结直肠胰脏和胰腺胰脏病患者中会未浮现接收者。共有31同上病患者在至少1同一时间浮现接收者，其中会20同上接收者持续时间曾达1年以上。

对胰脏症具有药理学活性也是BMS-936558的正因如此表现形式，因为一直以来胰脏症都对免疫反应麻醉药耐药。在这项试制中会，胰脏症病患者的事实接收者亲率为18%，7%病情稳定超出24周或以上。在在，55%的病患者此在此之前已接纳了至少在此之前三线麻醉药。虽然由于病患者数目少而须谨慎解读该学术研究图表，但BMS-936558似乎对粒状细胞内更加有效，接收者亲率为33%，而对非粒状细胞内的接收者亲率为12%。

对42份预处理标本完成免疫反应组化分析的结果提示，PD-L1表曾达可能踏入疗程接收者的一种标志物。在所有25同上PD-L1阴性病患者中会，9同上产生了事实接收者，而在17同上PD-L1阴性病患者中会无1同上产生事实接收者(P=0.006)。

Topalian引述，在所有296同上病患者中会，14%观察到严重征状。他将在ASCO研讨会上调查报告这项学术研究的结果。最常见的不当惨剧为疲乏、肿胀、腹泻、瘙痒、恶心、肠胃或血红蛋白下降，以及发热。3 /4级疗程相关性不当惨剧在各剂量组中会均相似，除了中会风除此以外还包括白癜风、结肠炎、肝炎、垂体炎和甲状腺炎。尽管已规避了早期识别、努力疗程中会风这一疗程征状的更加佳措施，但仍有3同上病患者应中会风而死亡。

Topalian博士引述，上述结果使BMS-936558有别于其他免疫反应麻醉药，如伊匹单外用，后者对转移性在此之前列腺胰脏的接收者亲率为10%~15%，然而同时也有20%~30%的病患者浮现药理学显著毒性。BMS-936558最终将可能踏入队内药物，或与其他免疫反应麻醉药或抑制剂疗程共同作为进展期疟疾的队内麻醉药。她反驳，一项评价伊匹单外用与BMS-936558联合疗程的试制将要纪念库珀-凯特林胰脏症中会心完成。目在此之前还原计划在非小细胞内胰脏症、在此之前列腺胰脏和肾细胞内胰脏病患者中会推展Ⅲ期试制。

这项早期试制同时发表在《新英格兰医学杂志》上(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690])，同期发表的另一项有关PD-L1堵塞的学术研究得出结论了略低的接收者亲率和不当惨剧发生亲率(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694])。加州所大学免疫反应新项目室主任Antoni Ribas博士在随刊述评中会反驳，这2项更进一步学术研究共同表明，堵塞PD-1或PD-L1有可能踏入免疫反应麻醉药外用活性的新基准(doi:10.1056/NEJMe1205943)。

这项学术研究获取了百时美-施贵宝、Ono制药的全力支持，并从国立卫生学术研究部和在此之前列腺胰脏学术研究联盟获取红利。Topalian博士还调查报告引述为百时美-施贵宝和Amplimmune透过咨询，其月出版者调查报告引述与百时美-施贵宝有利益关系。Ribas博士调查报告引述无利益冲突。

原始史籍:

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.