抗PD-1单克隆抗体pembrolizumab在转移性
Ronald Levy教授
研究内容
KEYNOTE-012研究纳入了39位肿瘤有PD-L1表达的患者。在供筛选的162位经治的胃癌患者中，40%表达了配体。采用原型免疫组化分析手段来评估肿瘤样本中的PD-L1表达和22C3抗体。定义阳性为间质内或有≥1%的肿瘤细胞染色。
患者接受每2周10 mg/kg的pembrolizumab治疗，持续24个月或直到完全缓解，疾病进展，或出现不可接受的毒性。研究的首要终点为由独立中心评估的客观缓解率。
“随访到第8.8个月时，就出现了抗肿瘤活性的有力证据。” 日本Aichi癌症中心医院的Kei Muro博士在2014年的ESMO大会上报告了该研究的初始分析结果。
按RECIST v.1标准评估的Pembrolizumab的客观缓解率是22.2% (95% CI, 10.1-39.2)，研究人员评估的客观缓解率为33.3% (95% CI, 19.1-50.2)。有应答的8位患者均为部分应答；另5位患者疾病保持稳定。亚洲和非亚洲人群的应答相似。
有4位患者的应答无法评估或测定。将近53%的患者有某种程度的肿瘤缩小。
Muro 强调，“8位有应答患者中的6位在分析时仍有应答”。从用药到有应答的中位时间为8周，中位应答持续时间为24周（范围，8周-33周以上）。
Muro在报告中说，中位无进展生存时间(PFS)为1.9个月 (95% CI, 1.8-3.5)。在第6个月时，PFS率为24%，总生存（OS）率为69%。中位OS还没有达到。
研究者们终结说pembrolizumab的安全性和耐受性对于这类人群是可以接受的。4位患者（10.3%）发生了药物相关的3-5级不良反应事件。有一位患者由于缺氧死亡。
“我们发现高水平的PD-L1表达可以改善结果。”Muro补充道，这一点在ORR，PFS及OS中都能观察到。但是他同时也表示，目前的这一趋势很微弱，而且需要更进一步的研究。
Association Between PD-L1 Expression and Pembrolizumab Efficacy
KEYNOTE-059试验的2期试验将探索pembrolizumab单独治疗，或联用
Ronald Levy教授在报告中，表示了对肿瘤免疫治疗的信心。他表示：“我们发现可以利用免疫系统杀死癌症，这也适用于胃肠道肿瘤。”
他特别对KEYNOTE-012研究评论到，“不需要许多肿瘤细胞表达配体来使药物发挥作用”，然而，他承认只有40%的患者有1%的必要这么做，大多数患者都没有应答。
Levy表示，研究人员正在努力通过组合疗法来增大应答率，可能会通过提高靶点——PD-1配体的表达来达到这一目的。
医脉通编译自：Updated KEYNOTE-012 Shows Activity for Pembrolizumab in Gastric Cancer, Onclive, January 15, 2015
英文摘要
Background: Tumors use the PD-1 pathway to evade immune surveillance. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumor activity in advanced cancers. We assessed the safety and efficacy of pembrolizumab in patients with advanced gastric cancer in KEYNOTE-012 (Clinicaltrials.gov identifier NCT01848834).
Methods: Archival tumor samples from patients from Asia-Pacific (AP) and rest of the world (ROW) with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction were screened for PD-L1 expression using a prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, progression, or unacceptable toxicity. Imaging was performed every 8 weeks. Primary efficacy end point is ORR assessed per RECIST v1.1 by independent central review. Secondary end points include duration of response, PFS, and OS.
Results: Of the 162 patientts screened, 65 (40%) were PD-L1+. Of these 65 patients, 39 enrolled (19 from AP, 20 from ROW; median age, 63 years [range 33-78]). The number of prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remain on therapy. Four patients experienced 5 total grade 3-5 drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to response was 8 weeks (range 7-16), with a median response duration of 24 weeks (range 8+ to 33+). PD-L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 24%. The 6-month OS rate was 69%.
Conclusions: Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer.
查看会议专题》》》2015 ASCO胃肠肿瘤(GI)研讨会
(本网站所有内容，凡注明来源为“医脉通”，版权均归医脉通所有，未经授权，任何媒体、网站或个人不得转载，否则将追究法律责任，授权转载时须注明“来源：医脉通”。本网注明来源为其他媒体的内容为转载，转载仅作观点分享，版权归原作者所有，如有侵犯版权，请及时联系我们。)
