Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
J Clin Oncol. 2021 Oct 1;39(28):3140-3148. doi: 10.1200/JCO.21.01003. Epub 2021 Aug 24.
To 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.
Patients 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 once on day 1, and gemcitabine 1,000 mg/m 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 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.
Thirty-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.
Neoadjuvant 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.
评估吉西他滨和顺铂联合免疫检查点抑制剂帕博利珠单抗作为新辅助治疗在根治性膀胱切除术（RC）前治疗肌层浸润性膀胱癌的安全性和疗效。
入组的患者为符合 RC 适应证的临床 T2-4aN0/XM0 肌层浸润性膀胱癌患者。最初的 6 例患者接受了先导帕博利珠单抗 200mg，每 2 周一次，然后是帕博利珠单抗 200mg，第 1 天一次，顺铂 70mg/m2，第 1 天一次，吉西他滨 1000mg/m2，第 1 天和第 8 天一次，每 21 天一次，共 4 个周期。由于毒性原因停止了该方案，随后的患者未接受先导帕博利珠单抗治疗，接受顺铂 35mg/m2，第 1 天和第 8 天一次。主要终点是病理降期（<pT2N0），阴性和阳性假设率分别为 35%和 55%。次要终点包括毒性（包括患者报告的结局）、完全病理缓解（pT0N0）、无事件生存率和总生存率。探索了病理降期与程序性死亡配体 1 染色的关系。
2016 年 6 月至 2020 年 3 月期间入组了 39 例患者（72%为 cT2，23%为 cT3，5%为 cT4a）。患者接受了中位 4 个周期的治疗。除 1 例患者拒绝外，所有患者均接受了 RC。39 例患者中，22 例（56%[95%CI，40%至 72%]）达到<pT2N0，14 例（36%[95%CI，21%至 53%]）达到 pT0N0。任何级别的最常见不良事件（AE）为血小板减少症（74%）、贫血（69%）、中性粒细胞减少症（67%）和低镁血症（67%）。1 例患者出现新诊断的 1 型糖尿病伴与帕博利珠单抗相关的酮症酸中毒，无患者因免疫相关 AE 而需要使用类固醇。与患者相比，临床医生在报告 AE 时始终存在漏报。
新辅助吉西他滨和顺铂联合帕博利珠单抗达到了改善病理降期的主要终点，总体安全性良好。一项围手术期化疗联合帕博利珠单抗或安慰剂的全球研究正在进行中。
