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
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，
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、
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（查看文献），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（查看文献）。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（查看述评）。
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。
更多阅读
2012 ASCO年会热点预测
ASCO年会讨论区
题目：Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.（Abstract CRA2509）
作者：Suzanne Louise Topalian, Julie R. Brahmer, F. Stephen Hodi, et al
英文摘要
Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression. This study describes the activity and safety of BMS-936558, a fully human mAb blocking PD-1, and highlights the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: Patients (pts) received BMS-936558 IV Q2WK at doses of 0.1 to 10.0 mg/kg during dose-escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each therapy cycle (4 doses). Pts received up to 12 cycles or until PD or CR. Results: As of July 1, 2011, 240 pts with melanoma (MEL, n=95), renal cell (RCC, n=33), colorectal (CRC, n=19), non-small cell lung cancer (NSCLC, n=75), castrate-resistant prostate cancer (CRPC, n=17), and unknown (n=1) were treated. Median duration of therapy was 15 wk (max 120 wk). MTD was not reached. Grade 3-4 related AEs occurred in 13% of pts. AEs of special interest included pneumonitis, hypophysitis, hepatitis, colitis, and thyroiditis. There were 2 related deaths due to pulmonary toxicity. In evaluable pts receiving ≥2 cycles, OR (objective responses; CR or PR) were observed in MEL, RCC, and NSCLC. Aggregate response rates [(OR +unconfirmed PR)/evaluable pts] were: MEL (0.1-10 mg/kg, 20+4/90; 27%), RCC (1-10 mg/kg, 8+2/32; 31%), and NSCLC (1-10 mg/kg, 10+3/73; 18%). OR were durable: among 38 pts with OR, 28 were enrolled ≥1 yr before data lock, and 18 of these had responses lasting ≥1 yr. Ten pts on study <1 yr had ongoing OR with a duration of 1.8 - 5.6 mo. Several pts had prolonged SD. Some had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. To assess PD-1 ligand (PD-L1) as a potential predictive biomarker, IHC was performed on pre-treatment tumor biopsies from 29 pts. Of 16 pts with PD-L1(+) tumors, 50% achieved OR vs. none with PD-L1(-). Conclusions: BMS-936558 produces durable activity in advanced NSCLC, MEL, and RCC. Preliminary data implicate PD-L1 expression on tumor cells as a potential predictive biomarker of response. These findings underscore the importance of the PD-1/PD-L1 pathway and support further clinical development of BMS-936558.
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