帕博利珠单抗作为肌层浸润性尿路上皮膀胱癌根治性切除术的新辅助治疗（PURE-01）：一项开放标签、单臂、Ⅱ期研究。
Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study.
机构信息
Andrea Necchi, Andrea Anichini, Daniele Raggi, Simona Massa, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Elena Farè, Francesco Monopoli, Antonella Messina, Roberto Salvioni, and Luigi Mariani, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; Alberto Briganti, Roberta Lucianò, Marco Bianchi, Renzo Colombo, Andrea Gallina, Andrea Salonia, and Francesco Montorsi, Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy; Siraj M. Ali, Russell Madison, Jeffrey S. Ross, and Jon H. Chung, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.
出版信息
J Clin Oncol. 2018 Dec 1;36(34):3353-3360. doi: 10.1200/JCO.18.01148. Epub 2018 Oct 20.
PURPOSE
To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used.
PATIENTS AND METHODS
In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay.
RESULTS
Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors.
CONCLUSION
Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.
目的
评估帕博利珠单抗作为新辅助免疫疗法在根治性膀胱切除术（RC）前治疗肌层浸润性膀胱癌（MIBC）的疗效，MIBC 患者对标准顺铂类化疗反应不佳。
方法
在 PURE-01 研究中，患者的主要组织学类型为尿路上皮癌，且临床（c）T≤3bN0 期肿瘤。患者在 RC 前接受三个周期的 200mg 帕博利珠单抗每 3 周一次的治疗。在意向治疗人群中，主要终点为病理完全缓解（pT0）。生物标志物分析包括使用组合阳性评分（CPS；Dako 22C3 pharmDx 检测）评估程序性死亡配体 1（PD-L1）表达、基因组测序（FoundationONE 检测）和免疫基因表达检测。
结果
2017 年 2 月至 2018 年 3 月共招募了 50 名患者。27 名患者（54%）的肿瘤为 cT3 期，21 名（42%）为 cT2 期，2 名（4%）为 cT2-3N1 期。1 名患者（2%）出现 3 级转氨酶升高并停止使用帕博利珠单抗。所有患者均接受了 RC；21 名患者（42%；95%CI，28.2%至 56.8%）达到 pT0。作为次要终点，27 名患者（54%；95%CI，39.3%至 68.2%）降期为 pT<2。在 PD-L1 CPS≥10%（n=35）的 54.3%患者中，RC 结果为 pT0，而 CPS<10%（n=15）的患者中仅 13.3%为 pT0。观察到肿瘤突变负荷（TMB）与 pT0 之间存在显著的非线性关联，截断值为 15 个突变/Mb。pT0 患者和非 pT0 患者的术前病变中存在几个基因的表达存在显著差异。在残余肿瘤中观察到 TMB 的显著治疗后变化和免疫抵抗的适应性机制的证据。
结论
新辅助帕博利珠单抗治疗 MIBC 的患者，42%的患者达到 pT0，且安全性良好。该研究表明，在 PD-L1 阳性或高 TMB 肿瘤患者中，帕博利珠单抗可能是 MIBC 有价值的新辅助治疗药物。
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