Necchi Andrea, Raggi Daniele, Gallina Andrea, Madison Russell, Colecchia Maurizio, Lucianò Roberta, Montironi Rodolfo, Giannatempo Patrizia, Farè Elena, Pederzoli Filippo, Bandini Marco, Bianchi Marco, Colombo Renzo, Gandaglia Giorgio, Fossati Nicola, Marandino Laura, Capitanio Umberto, Dehò Federico, Ali Siraj M, Chung Jon H, Ross Jeffrey S, Salonia Andrea, Briganti Alberto, Montorsi Francesco
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Eur Urol. 2020 Apr;77(4):439-446. doi: 10.1016/j.eururo.2019.10.026. Epub 2019 Nov 8.
Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited.
To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266).
DESIGN, SETTING, AND PARTICIPANTS: In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH.
Neoadjuvant pembrolizumab and RC.
Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response.
From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology.
The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes.
In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.
膀胱肿瘤主要组织学变异（VH）患者，即肿瘤标本受累>50%的患者，通常被排除在临床试验之外，并且对于这些患者，标准化疗的疗效有限。
评估术前帕博利珠单抗在参加PURE-01研究（NCT02736266）的肌层浸润性膀胱癌（MIBC）和VH患者中的活性。
设计、设置和参与者：在开放标签、单臂、2期PURE-01研究中，对T2-4aN0M0 MIBC患者在根治性膀胱切除术（RC）前给予三个疗程的200mg帕博利珠单抗。修订后的研究设计纳入了主要VH患者。
新辅助帕博利珠单抗和RC。
意向性治疗人群中的病理完全缓解（pT0）是主要终点。生物标志物分析包括使用联合阳性评分（CPS；Dako 22C3抗体）的程序性细胞死亡配体-1（PD-L1）表达和综合基因组分析（FoundationOne检测）。多变量逻辑回归分析（MVA）评估组织学类别（主要VH与非主要VH与纯尿路上皮癌）、肿瘤突变负荷（TMB）和CPS与病理反应的相关性。
2017年2月至2019年6月，共纳入114例患者；其中34例（30%）存在VH，包括19例（17%）主要VH。总体而言，pT0率为37%（95%置信区间[CI]：28-46），pT≤1率为55%（95%CI：46-65）。大多数主要VH患者表现为鳞状细胞癌（SCC；N=7），7例中有6例（86%）分期降为pT≤1，其中1例为pT（0）；3例淋巴上皮瘤样（LEL）变异中有2例有pT0反应。其余9例主要VH均无反应。在MVA中，无论肿瘤组织学如何，TMB和CPS均与pT0和pT≤1反应相关。
更新后的PURE-01结果证实了新辅助帕博利珠单抗在MIBC中的活性。具有SCC和LEL特征的患者可能适合新辅助免疫治疗试验。无论组织学亚型如何，CPS和TMB都是关键反应预测指标。
在PURE-01研究中，我们初步评估了新辅助帕博利珠单抗在主要组织学变异（VH）患者中的活性。在这些患者中，与其他主要VH患者相比，具有鳞状细胞癌或淋巴上皮瘤样变异特征的患者有主要的（尽管是初步的）病理反应。程序性细胞死亡配体-1的表达和肿瘤突变负荷可能预测对帕博利珠单抗的病理反应，并为根据这些特征而非组织学膀胱癌亚型选择患者提供依据。
