Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study

Ondřej Fiala; Sebastiano Buti; Hideki Takeshita; Yohei Okada; Francesco Massari; Georgia Anguera Palacios; Michele Dionese; Sarah Scagliarini; Thomas Büttner; Giuseppe Fornarini; Zin W. Myint; Luca Galli; Vinicius Carrera Souza; Renate Pichler; Ugo De Giorgi; María Natalia Gandur Quiroga; Danielle Gilbert; Lazar Popovic; Enrique Grande; Giulia Mammone; Rossana Berardi; Simon J. Crabb; Javier Molina-Cerrillo; Marcelo Freitas; Murilo Luz; Roberto Iacovelli; Fabio Calabrò; Deniz Tural; Francesco Atzori; Zsófia Küronya; Rita Chiari; Saul Campos; Orazio Caffo; André P. Fay; Jakub Kucharz; Paolo Andrea Zucali; José Augusto Rinck; Annalisa Zeppellini; Diogo Assed Bastos; Gaetano Aurilio; Augusto Mota; Karine Trindade; Cinzia Ortega; Juan Pablo Sade; Mimma Rizzo; Nuno Vau; Patrizia Giannatempo; Allan Barillas; Fernando Sabino Marques Monteiro; Breno Dauster; Carlo Cattrini; Lucas Nogueira; Roni de Carvalho Fernandes; Emmanuel Seront; Luís Garcia Aceituno; Francesco Grillone; Hernan Javier Cutuli; Mauricio Fernandez; Maria Bassanelli; Giandomenico Roviello; Halima Abahssain; Giuseppe Procopio; Michele Milella; Jindrich Kopecky; Angelo Martignetti; Carlo Messina; Manuel Caitano; Eva Inman; Ravindran Kanesvaran; Daniel Herchenhorn; Daniele Santini; Ray Manneh; Renato Bisonni; Roubini Zakopoulou; Alessandra Mosca; Franco Morelli; Fernando Maluf; Andrey Soares; Fernando Nunes; Alvaro Pinto; Anca Zgura; Lorena Incorvaia; Jawaher Ansari; Ignacio Ortego Zabalza; Johannes Landmesser; Alessandro Rizzo; Veronica Mollica; Giulia Sorgentoni; Nicola Battelli; Camillo Porta; Joaquim Bellmunt; Matteo Santoni

doi:10.1007/s00262-023-03518-z

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study

Ondřej Fiala
, Sebastiano Buti
, Hideki Takeshita
, Yohei Okada
, Francesco Massari
, Georgia Anguera Palacios
, Michele Dionese
, Sarah Scagliarini
, Thomas Büttner
, Giuseppe Fornarini
, Zin W. Myint
, Luca Galli
, Vinicius Carrera Souza
, Renate Pichler
, Ugo De Giorgi
, María Natalia Gandur Quiroga
, Danielle Gilbert
, Lazar Popovic
, Enrique Grande
, Giulia Mammone

Rossana Berardi, Simon J. Crabb, Javier Molina-Cerrillo, Marcelo Freitas, Murilo Luz, Roberto Iacovelli, Fabio Calabrò, Deniz Tural, Francesco Atzori, Zsófia Küronya, Rita Chiari, Saul Campos, Orazio Caffo, André P. Fay, Jakub Kucharz, Paolo Andrea Zucali, José Augusto Rinck, Annalisa Zeppellini, Diogo Assed Bastos, Gaetano Aurilio, Augusto Mota, Karine Trindade, Cinzia Ortega, Juan Pablo Sade, Mimma Rizzo, Nuno Vau, Patrizia Giannatempo, Allan Barillas, Fernando Sabino Marques Monteiro, Breno Dauster, Carlo Cattrini, Lucas Nogueira, Roni de Carvalho Fernandes, Emmanuel Seront, Luís Garcia Aceituno, Francesco Grillone, Hernan Javier Cutuli, Mauricio Fernandez, Maria Bassanelli, Giandomenico Roviello, Halima Abahssain, Giuseppe Procopio, Michele Milella, Jindrich Kopecky, Angelo Martignetti, Carlo Messina, Manuel Caitano, Eva Inman, Ravindran Kanesvaran, Daniel Herchenhorn, Daniele Santini, Ray Manneh, Renato Bisonni, Roubini Zakopoulou, Alessandra Mosca, Franco Morelli, Fernando Maluf, Andrey Soares, Fernando Nunes, Alvaro Pinto, Anca Zgura, Lorena Incorvaia, Jawaher Ansari, Ignacio Ortego Zabalza, Johannes Landmesser, Alessandro Rizzo, Veronica Mollica, Giulia Sorgentoni, Nicola Battelli, Camillo Porta, Joaquim Bellmunt, Matteo Santoni

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

Original language	English
Pages (from-to)	3665-3682
Number of pages	18
Journal	Cancer Immunology, Immunotherapy
Volume	72
Issue number	11
DOIs	https://doi.org/10.1007/s00262-023-03518-z
State	Published - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Funding

The authors would like to thank all patients voluntarily taking part in the study.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ARON-2 study
Immunotherapy
Metformin
Proton pump inhibitors
Statins
Urothelial cancer

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Oncology
Cancer Research

Access to Document

10.1007/s00262-023-03518-z

Cite this

Fiala, O., Buti, S., Takeshita, H., Okada, Y., Massari, F., Palacios, G. A., Dionese, M., Scagliarini, S., Büttner, T., Fornarini, G., Myint, Z. W., Galli, L., Souza, V. C., Pichler, R., De Giorgi, U., Quiroga, M. N. G., Gilbert, D., Popovic, L., Grande, E., ... Santoni, M. (2023). Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study. Cancer Immunology, Immunotherapy, 72(11), 3665-3682. https://doi.org/10.1007/s00262-023-03518-z

@article{bea3ea2b457c47ac8d8d8e03af5b63c7,

title = "Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study",

abstract = "Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.",

keywords = "ARON-2 study, Immunotherapy, Metformin, Proton pump inhibitors, Statins, Urothelial cancer",

author = "Ond{\v r}ej Fiala and Sebastiano Buti and Hideki Takeshita and Yohei Okada and Francesco Massari and Palacios, \{Georgia Anguera\} and Michele Dionese and Sarah Scagliarini and Thomas B{\"u}ttner and Giuseppe Fornarini and Myint, \{Zin W.\} and Luca Galli and Souza, \{Vinicius Carrera\} and Renate Pichler and \{De Giorgi\}, Ugo and Quiroga, \{Mar{\'i}a Natalia Gandur\} and Danielle Gilbert and Lazar Popovic and Enrique Grande and Giulia Mammone and Rossana Berardi and Crabb, \{Simon J.\} and Javier Molina-Cerrillo and Marcelo Freitas and Murilo Luz and Roberto Iacovelli and Fabio Calabr{\`o} and Deniz Tural and Francesco Atzori and Zs{\'o}fia K{\"u}ronya and Rita Chiari and Saul Campos and Orazio Caffo and Fay, \{Andr{\'e} P.\} and Jakub Kucharz and Zucali, \{Paolo Andrea\} and Rinck, \{Jos{\'e} Augusto\} and Annalisa Zeppellini and Bastos, \{Diogo Assed\} and Gaetano Aurilio and Augusto Mota and Karine Trindade and Cinzia Ortega and Sade, \{Juan Pablo\} and Mimma Rizzo and Nuno Vau and Patrizia Giannatempo and Allan Barillas and Monteiro, \{Fernando Sabino Marques\} and Breno Dauster and Carlo Cattrini and Lucas Nogueira and \{de Carvalho Fernandes\}, Roni and Emmanuel Seront and Aceituno, \{Lu{\'i}s Garcia\} and Francesco Grillone and Cutuli, \{Hernan Javier\} and Mauricio Fernandez and Maria Bassanelli and Giandomenico Roviello and Halima Abahssain and Giuseppe Procopio and Michele Milella and Jindrich Kopecky and Angelo Martignetti and Carlo Messina and Manuel Caitano and Eva Inman and Ravindran Kanesvaran and Daniel Herchenhorn and Daniele Santini and Ray Manneh and Renato Bisonni and Roubini Zakopoulou and Alessandra Mosca and Franco Morelli and Fernando Maluf and Andrey Soares and Fernando Nunes and Alvaro Pinto and Anca Zgura and Lorena Incorvaia and Jawaher Ansari and Zabalza, \{Ignacio Ortego\} and Johannes Landmesser and Alessandro Rizzo and Veronica Mollica and Giulia Sorgentoni and Nicola Battelli and Camillo Porta and Joaquim Bellmunt and Matteo Santoni",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2023",

month = nov,

doi = "10.1007/s00262-023-03518-z",

language = "English",

volume = "72",

pages = "3665--3682",

number = "11",

}

Fiala, O, Buti, S, Takeshita, H, Okada, Y, Massari, F, Palacios, GA, Dionese, M, Scagliarini, S, Büttner, T, Fornarini, G, Myint, ZW, Galli, L, Souza, VC, Pichler, R, De Giorgi, U, Quiroga, MNG, Gilbert, D, Popovic, L, Grande, E, Mammone, G, Berardi, R, Crabb, SJ, Molina-Cerrillo, J, Freitas, M, Luz, M, Iacovelli, R, Calabrò, F, Tural, D, Atzori, F, Küronya, Z, Chiari, R, Campos, S, Caffo, O, Fay, AP, Kucharz, J, Zucali, PA, Rinck, JA, Zeppellini, A, Bastos, DA, Aurilio, G, Mota, A, Trindade, K, Ortega, C, Sade, JP, Rizzo, M, Vau, N, Giannatempo, P, Barillas, A, Monteiro, FSM, Dauster, B, Cattrini, C, Nogueira, L, de Carvalho Fernandes, R, Seront, E, Aceituno, LG, Grillone, F, Cutuli, HJ, Fernandez, M, Bassanelli, M, Roviello, G, Abahssain, H, Procopio, G, Milella, M, Kopecky, J, Martignetti, A, Messina, C, Caitano, M, Inman, E, Kanesvaran, R, Herchenhorn, D, Santini, D, Manneh, R, Bisonni, R, Zakopoulou, R, Mosca, A, Morelli, F, Maluf, F, Soares, A, Nunes, F, Pinto, A, Zgura, A, Incorvaia, L, Ansari, J, Zabalza, IO, Landmesser, J, Rizzo, A, Mollica, V, Sorgentoni, G, Battelli, N, Porta, C, Bellmunt, J & Santoni, M 2023, 'Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study', Cancer Immunology, Immunotherapy, vol. 72, no. 11, pp. 3665-3682. https://doi.org/10.1007/s00262-023-03518-z

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study. / Fiala, Ondřej; Buti, Sebastiano; Takeshita, Hideki et al.
In: Cancer Immunology, Immunotherapy, Vol. 72, No. 11, 11.2023, p. 3665-3682.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma

T2 - data from the ARON-2 retrospective study

AU - Fiala, Ondřej

AU - Buti, Sebastiano

AU - Takeshita, Hideki

AU - Okada, Yohei

AU - Massari, Francesco

AU - Palacios, Georgia Anguera

AU - Dionese, Michele

AU - Scagliarini, Sarah

AU - Büttner, Thomas

AU - Fornarini, Giuseppe

AU - Myint, Zin W.

AU - Galli, Luca

AU - Souza, Vinicius Carrera

AU - Pichler, Renate

AU - De Giorgi, Ugo

AU - Quiroga, María Natalia Gandur

AU - Gilbert, Danielle

AU - Popovic, Lazar

AU - Grande, Enrique

AU - Mammone, Giulia

AU - Berardi, Rossana

AU - Crabb, Simon J.

AU - Molina-Cerrillo, Javier

AU - Freitas, Marcelo

AU - Luz, Murilo

AU - Iacovelli, Roberto

AU - Calabrò, Fabio

AU - Tural, Deniz

AU - Atzori, Francesco

AU - Küronya, Zsófia

AU - Chiari, Rita

AU - Campos, Saul

AU - Caffo, Orazio

AU - Fay, André P.

AU - Kucharz, Jakub

AU - Zucali, Paolo Andrea

AU - Rinck, José Augusto

AU - Zeppellini, Annalisa

AU - Bastos, Diogo Assed

AU - Aurilio, Gaetano

AU - Mota, Augusto

AU - Trindade, Karine

AU - Ortega, Cinzia

AU - Sade, Juan Pablo

AU - Rizzo, Mimma

AU - Vau, Nuno

AU - Giannatempo, Patrizia

AU - Barillas, Allan

AU - Monteiro, Fernando Sabino Marques

AU - Dauster, Breno

AU - Cattrini, Carlo

AU - Nogueira, Lucas

AU - de Carvalho Fernandes, Roni

AU - Seront, Emmanuel

AU - Aceituno, Luís Garcia

AU - Grillone, Francesco

AU - Cutuli, Hernan Javier

AU - Fernandez, Mauricio

AU - Bassanelli, Maria

AU - Roviello, Giandomenico

AU - Abahssain, Halima

AU - Procopio, Giuseppe

AU - Milella, Michele

AU - Kopecky, Jindrich

AU - Martignetti, Angelo

AU - Messina, Carlo

AU - Caitano, Manuel

AU - Inman, Eva

AU - Kanesvaran, Ravindran

AU - Herchenhorn, Daniel

AU - Santini, Daniele

AU - Manneh, Ray

AU - Bisonni, Renato

AU - Zakopoulou, Roubini

AU - Mosca, Alessandra

AU - Morelli, Franco

AU - Maluf, Fernando

AU - Soares, Andrey

AU - Nunes, Fernando

AU - Pinto, Alvaro

AU - Zgura, Anca

AU - Incorvaia, Lorena

AU - Ansari, Jawaher

AU - Zabalza, Ignacio Ortego

AU - Landmesser, Johannes

AU - Rizzo, Alessandro

AU - Mollica, Veronica

AU - Sorgentoni, Giulia

AU - Battelli, Nicola

AU - Porta, Camillo

AU - Bellmunt, Joaquim

AU - Santoni, Matteo

PY - 2023/11

Y1 - 2023/11

N2 - Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

AB - Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

KW - ARON-2 study

KW - Immunotherapy

KW - Metformin

KW - Proton pump inhibitors

KW - Statins

KW - Urothelial cancer

UR - https://www.scopus.com/pages/publications/85169897836

UR - https://www.scopus.com/pages/publications/85169897836#tab=citedBy

U2 - 10.1007/s00262-023-03518-z

DO - 10.1007/s00262-023-03518-z

M3 - Article

C2 - 37676282

AN - SCOPUS:85169897836

SN - 0340-7004

VL - 72

SP - 3665

EP - 3682

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

IS - 11

ER -

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this