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

J Clin Oncol. 2018 Dec 1;36(34):3353-3360. doi: 10.1200/JCO.18.01148. Epub 2018 Oct 20.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02736266.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Academic Medical Centers
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Carcinoma, Transitional Cell / mortality*
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / therapy*
  • Cystectomy / methods*
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Italy
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoadjuvant Therapy / methods
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Prognosis
  • Risk Assessment
  • Survival Analysis
  • Urinary Bladder Neoplasms / mortality*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / therapy*

Substances

  • Antibodies, Monoclonal, Humanized
  • pembrolizumab

Associated data

  • ClinicalTrials.gov/NCT02736266