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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

  • Andrea Necchi,
  • Andrea Anichini,
  • Daniele Raggi,
  • Alberto Briganti,
  • Simona Massa,
  • Roberta Luciano,
  • Maurizio Colecchia,
  • Patrizia Giannatempo,
  • Roberta Mortarini,
  • Marco Bianchi,
  • Elena Farè,
  • Francesco Monopoli,
  • Renzo Colombo,
  • Andrea Gallina,
  • Andrea Salonia,
  • Antonella Messina,
  • Siraj M. Ali,
  • Russell Madison,
  • Jeffrey S. Ross,
  • Jon H. Chung,
  • Roberto Salvioni,
  • Luigi Mariani,
  • Francesco Montorsi

Publication: Journal of clinical oncology, Volume 36, December 2018


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.


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.


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.

Commentary by Marco Moschini

The actual standard of care for the treatment for non-metastatic muscle-invasive bladder cancer is the combination of neoadjuvant cisplatin-based chemotherapy and radical cystectomy with concomitant bilateral pelvic lymph node dissection. However, several reports suggest that neoadjuvant chemotherapy is administered in only 20% of eligible patients meaning that 80% of patients are treated with upfront surgery. Promising outcomes have been reported for immune check point inhibitors in the metastatic setting, however their role have not yet been evaluated in the neoadjuvant setting for patients with localized no-metastatic disease.

The authors of this open label, single arm, phase II study, enrolled 50 patients from February 2017 to March 2018 with clinical T≤3bN0M0 stage tumor. All patients received three courses of pembrolizumab 200 mg intravenous every 3 weeks before radical cystectomy and pelvic lymph node dissection. The primary endpoint was to evaluate the rate of complete pathological response defined as a pT0 stage on the radical cystectomy specimen.

The authors report a pT0 rate of 42%, while overall 54% of the patients were down staged (defined as pT<2). Considering complications, one patient experienced a grade 3 transaminase increase and discontinued pembrolizumab. The authors concluded that neoadjuvant administration of pembrolizumab before radical cystectomy and bilateral pelvic lymph node dissection is safe and resulted in 42% of pT0 patients.

The authors of this prospective trial need to be congratulated for testing for the first time the role of immune check point inhibitors in the neoadjuvant setting in MIBC. The results are indeed impressive, where almost half of the patients treated reached a pT0 disease. Moreover, patients with an expression of PD-L1 using the combined positive score (CPS) ≥ 10% which constituted as much as 70% of the patients enrolled, showed excellent response rates, whereas patients with CPS < 10% did not show an efficient antitumor effect of pembrolizumab. These results are in concordance with another study where neoadjuvant atezolizumab in PD-L1 positive patients showed a 40% pT0 rate compared to 16% in PD-L1 negative patients. The ability to predict the response to immunotherapy would be of a huge help if validated in order to select the patients that will benefit the most from the administration of these immune check point inhibitors and avoid cisplatin administration and the related complications.

In conclusion, survival outcomes are awaited but these preliminary pathological results are promising and show us the premises of a changing paradigm.