Background

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.

Objective

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.

Intervention

Neoadjuvant pembrolizumab and RC.

Outcome measurements and statistical analysis

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.

Results and limitations

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.

Conclusions

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.

Patient summary

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.

中文翻译：

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PURE-01 与新辅助帕博利珠单抗在具有不同组织学的肌肉浸润性膀胱癌患者中的初步活性的更新结果

背景

膀胱肿瘤的主要变异组织学 (VH) 患者，定义为涉及 >50% 的肿瘤标本，通常被排除在临床试验之外，对于这些患者，标准化疗的功效是有限的。

客观的

为了评估术前 pembrolizumab 在肌肉浸润性膀胱癌 (MIBC) 和 VH 患者中的活性，参加了 PURE-01 研究 (NCT02736266)。

设计、设置和参与者

在开放标签、单臂、2 期 PURE-01 研究中，T2-4aN0M0 MIBC 患者在根治性膀胱切除术 (RC) 前接受了三个疗程的 200 mg pembrolizumab。修改后的研究设计包括以 VH 为主的患者。

干涉

新辅助派姆单抗和 RC。

结果测量和统计分析

意向治疗人群的病理完全缓解（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）和综合基因组分析（FoundationOne 分析）的程序性细胞死亡配体 1 (PD-L1) 表达。多变量逻辑回归分析 (MVA) 评估了与病理反应相关的组织学类别（主要 VH 与非主要 VH 与纯尿路上皮癌）、肿瘤突变负荷 (TMB) 和 CPS。

结果和局限性

2017 年 2 月至 2019 年 6 月，114 名患者入组；其中 34 人 (30%) 出现 VH，其中 19 人 (17%) 以 VH 为主。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）。大多数主要的 VH 患者出现鳞状细胞癌（SCC；N  = 7），7 人中有 6 人（86%）降期至 pT ≤ 1，其中 1 人 pT0；三种淋巴上皮瘤样 (LEL) 变体中的两种具有 pT0 反应。其余九个主要的 VH 都没有反应。在 MVA 上，无论肿瘤组织学如何，TMB 和 CPS 都与 pT0 和 pT ≤ 1 反应相关。

结论

更新的 PURE-01 结果证实了新辅助派姆单抗在 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。CPS 和 TMB 是关键的反应预测因子，与组织学亚型无关。

患者总结

在 PURE-01 研究中，我们初步评估了新辅助派姆单抗在具有主要变异组织学 (VH) 的患者中的活性。在这些患者中，与具有其他主要 VH 的患者相比，具有鳞状细胞癌或淋巴上皮瘤样变异特征的患者具有主要但初步的病理反应。程序性细胞死亡配体 1 的表达和肿瘤突变负荷可以预测对 pembrolizumab 的病理反应，并为根据这些特征而不是组织学膀胱癌亚型选择患者提供基本原理。