Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer
Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer
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DOI：
10.1200/jco.21.01003
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发表时间：
2021-10-01
影响因子：
45.3
通讯作者：
Milowsky, Matthew I.
中科院分区：
文献类型：
--
作者：
Rose, Tracy L.;Harrison, Michael R.;Milowsky, Matthew I.
目的评价吉西他滨、顺铂联合免疫检查点抑制剂派姆单抗作为肌层浸润性膀胱癌根治性化疗（RC）前新辅助治疗的安全性和有效性。最初的6名患者接受了Pembrolizumab 200 mg，2周一次的导入治疗，然后是Pembrolizumab 200 mg，第1天一次，顺铂70 mg/m2，第1天一次，吉西他滨1,000 mg/m2，第1天和第8天一次，每21天一次，共4个周期。该方案因毒性而停止，随后患者在第1天和第8天接受顺铂35 mg/m2，不使用Pembrolizumab。主要终点为病理分期下降（<pT 2N 0），无效假设率和备择假设率分别为35%和55%。次要终点是毒性反应，包括患者报告的结局、完全病理学缓解（pT 0 N 0）、无事件生存期和总生存期。探索了病理分期下调与程序性细胞死亡配体1染色的相关性。在2016年6月至2020年3月期间，共招募了39名患者（72%cT2，23%cT3和5%cT4a）。患者接受中位4个周期的治疗。除1例患者拒绝接受外，所有患者均接受了RC。39例患者中有22例（56% [95% CI，40 - 72]）达到<pT 2N 0，39例患者中有14例（36% [95% CI，21 - 53]）达到pT 0 N 0。最常见的任何级别的不良事件（AE）为血小板减少（74%）、贫血（69%）、中性粒细胞减少（67%）和低镁血症（67%）。1例患者发生与帕博利珠单抗相关的新发1型糖尿病伴酮症酸中毒，无患者需要类固醇治疗免疫相关AE。临床医生一致报告的AE相比patients.CONCLUSIONNEoadjuvant吉西他滨和顺铂加帕博利珠单抗达到其主要终点，改善病理分期下降，一般是安全的。一项关于围手术期化疗加派姆单抗或安慰剂的全球研究正在进行中。新辅助#pembrolizumab + GC治疗#MIBC -正在进行的III期试验有望实现56%的病理分期下调率
PURPOSETo evaluate the safety and efficacy of gemcitabine and cisplatin in combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant therapy before radical cystectomy (RC) in muscle-invasive bladder cancer.METHODSPatients with clinical T2-4aN0/XM0 muscle-invasive bladder cancer eligible for RC were enrolled. The initial six patients received lead-in pembrolizumab 200 mg once 2 weeks prior to pembrolizumab 200 mg once on day 1, cisplatin 70 mg/m(2) once on day 1, and gemcitabine 1,000 mg/m(2) once on days 1 and 8 every 21 days for four cycles. This schedule was discontinued for toxicity and subsequent patients received cisplatin 35 mg/m(2) once on days 1 and 8 without lead-in pembrolizumab. The primary end point was pathologic downstaging (< pT2N0) with null and alternative hypothesis rates of 35% and 55%, respectively. Secondary end points were toxicity including patient-reported outcomes, complete pathologic response (pT0N0), event-free survival, and overall survival. Association of pathologic downstaging with programmed cell death ligand 1 staining was explored.RESULTSThirty-nine patients were enrolled between June 2016 and March 2020 (72% cT2, 23% cT3, and 5% cT4a). Patients received a median of four cycles of therapy. All patients underwent RC except one who declined. Twenty-two of 39 patients (56% [95% CI, 40 to 72]) achieved < pT2N0 and 14 of 39 (36% [95% CI, 21 to 53]) achieved pT0N0. Most common adverse events (AEs) of any grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%). One patient had new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Clinicians consistently under-reported AEs when compared with patients.CONCLUSIONNeoadjuvant gemcitabine and cisplatin plus pembrolizumab met its primary end point for improved pathologic downstaging and was generally safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo is ongoing. Neoadjuvant #pembrolizumab plus GC in #MIBC - promising 56% pathologic downstaging rate with ongoing phase 3 trial