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 Lucianò, 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 ChungRoberto Salvioni, Luigi Mariani, Francesco Montorsi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)JCO1801148
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
DOIs
Publication statusE-pub ahead of print - Oct 20 2018

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Neoadjuvant Therapy
Cystectomy
Urinary Bladder
Carcinoma
Muscles
Tumor Burden
Mutation
Neoplasms
Ligands
pembrolizumab
Gene Expression
Residual Neoplasm
Transaminases
Immunotherapy
Cisplatin
Histology
Biomarkers

Cite this

@article{2e2ded1b7c1444a9ad674addc4ea8ae9,
title = "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",
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.",
author = "Andrea Necchi and Andrea Anichini and Daniele Raggi and Alberto Briganti and Simona Massa and Roberta Lucian{\`o} and Maurizio Colecchia and Patrizia Giannatempo and Roberta Mortarini and Marco Bianchi and Elena Far{\`e} and Francesco Monopoli and Renzo Colombo and Andrea Gallina and Andrea Salonia and Antonella Messina and Ali, {Siraj M} and Russell Madison and Ross, {Jeffrey S} and Chung, {Jon H} and Roberto Salvioni and Luigi Mariani and Francesco Montorsi",
year = "2018",
month = "10",
day = "20",
doi = "10.1200/JCO.18.01148",
language = "English",
pages = "JCO1801148",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",

}

TY - JOUR

T1 - Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01)

T2 - An Open-Label, Single-Arm, Phase II Study

AU - Necchi, Andrea

AU - Anichini, Andrea

AU - Raggi, Daniele

AU - Briganti, Alberto

AU - Massa, Simona

AU - Lucianò, Roberta

AU - Colecchia, Maurizio

AU - Giannatempo, Patrizia

AU - Mortarini, Roberta

AU - Bianchi, Marco

AU - Farè, Elena

AU - Monopoli, Francesco

AU - Colombo, Renzo

AU - Gallina, Andrea

AU - Salonia, Andrea

AU - Messina, Antonella

AU - Ali, Siraj M

AU - Madison, Russell

AU - Ross, Jeffrey S

AU - Chung, Jon H

AU - Salvioni, Roberto

AU - Mariani, Luigi

AU - Montorsi, Francesco

PY - 2018/10/20

Y1 - 2018/10/20

N2 - 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.

AB - 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.

U2 - 10.1200/JCO.18.01148

DO - 10.1200/JCO.18.01148

M3 - Article

C2 - 30343614

SP - JCO1801148

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

ER -