NEJM: PD-1单抗对多种癌症有良好疗效

芝加哥(EGMN)——在经过一系列强化预处理的实体肿瘤患者中，近1/4对名为BMS-936558的新型免疫疗法有应答，部分患者的应答持续超过1年。第一作者、约翰霍普金斯大学黑色素瘤项目主任Suzanne Topalian博士在美国临床肿瘤学会(ASCO)年会的新闻发布会上介绍：“该疗法的一个显著特点是，它对其他治疗无效的患者仍可诱导出非常持久的应答。

BMS-936558是一种单克隆抗体，可阻断活化T细胞表面的程序性死亡(PD)-1受体。通过抑制PD-1和PD-1配体(PD-L 1)通路可挽救耗竭的T细胞，增强抗肿瘤免疫力。Topalian博士及其同事招募了296例接受1~5种治疗后出现疾病进展的转移性黑色素瘤、结直肠癌、非小细胞肺癌、前列腺癌或肾癌等患者，对其每2周静脉注射1.0、3.0或10 mg/kg体重的BMS-936558，最多治疗2年。

结果显示，在这项Ⅰ期试验中，236例接受评估的患者的客观应答(定义为完全恢复或明显部分恢复)率为18%~28%。28%的黑色素瘤患者出现客观应答，肾细胞癌患者为27%，二者中分别有6%和27%报告称病情稳定。结直肠癌和胰腺癌患者中未出现肿瘤应答。共有31例患者在至少1年前出现应答，其中20例应答持续时间达1年以上。

对肺癌具有临床活性也是BMS-936558的一大特点，因为一直以来肺癌都对免疫疗法耐药。在这项试验中，肺癌患者的客观应答率为18%，7%病情稳定达到24周或以上。值得一提的是，55%的患者此前已接受了至少前三线疗法。虽然由于患者数量少而须谨慎解读该研究数据，但BMS-936558似乎对鳞状细胞肿瘤更有效，应答率为33%，而对非鳞状细胞肿瘤的应答率为12%。

对42份预处理肿瘤标本进行免疫组化分析的结果提示，PD-L1表达可能成为治疗应答的一种标志物。在所有25例PD-L1阳性肿瘤患者中，9例产生了客观应答，而在17例PD-L1阴性患者中无1例产生客观应答(P=0.006)。

Topalian称，在所有296例患者中，14%观察到严重副作用。他将在ASCO年会上报告这项研究的结果。最常见的不良事件为疲乏、皮疹、腹泻、瘙痒、恶心、食欲或血红蛋白下降，以及发热。3 /4级治疗相关性不良事件在各剂量组中均相似，除了肺炎之外还包括白癜风、结肠炎、肝炎、垂体炎和甲状腺炎。尽管已采取了早期识别、积极治疗肺炎这一治疗副作用的更佳措施，但仍有3例患者应肺炎而死亡。

Topalian博士称，上述结果使BMS-936558有别于其他免疫疗法，如伊匹单抗，后者对转移性黑色素瘤的应答率为10%~15%，然而同时也有20%~30%的患者出现临床显著毒性。BMS-936558最终将可能成为一线药物，或与其他免疫疗法或靶向治疗共同作为进展期疾病的一线疗法。她指出，一项评价伊匹单抗与BMS-936558联合治疗的试验正在纪念斯隆-凯特林癌症中心进行。目前还计划在非小细胞肺癌、黑色素瘤和肾细胞癌患者中开展Ⅲ期试验。

这项早期试验同时发表在《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阻断的研究得出了略低的应答率和不良事件发生率(N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694])。加州大学肿瘤免疫项目主任Antoni Ribas博士在随刊述评中指出，这2项初步研究共同表明，阻断PD-1或PD-L1有可能成为免疫疗法抗肿瘤活性的新基准(doi:10.1056/NEJMe1205943)。

这项研究获得了百时美-施贵宝、Ono制药的支持，并从国立卫生研究院和黑色素瘤研究联盟获得补助金。Topalian博士还报告称为百时美-施贵宝和Amplimmune提供咨询，其合著者报告称与百时美-施贵宝有利益关系。Ribas博士报告称无利益冲突。

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 heavily 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 have 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 intravenous 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 have 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 have 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 analysis 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 have increased likelihood of tumor response – may well have 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.