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. 2023 Nov;72(11):3665-3682.
doi: 10.1007/s00262-023-03518-z. Epub 2023 Sep 7.

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 #  1   2 , Sebastiano Buti #  3   4 , Hideki Takeshita  5 , Yohei Okada  5 , Francesco Massari  6 , Georgia Anguera Palacios  7 , Michele Dionese  8 , Sarah Scagliarini  9 , Thomas Büttner  10 , Giuseppe Fornarini  11 , Zin W Myint  12 , Luca Galli  13 , Vinicius Carrera Souza  14   15 , Renate Pichler  16 , Ugo De Giorgi  17 , María Natalia Gandur Quiroga  15   18 , Danielle Gilbert  19 , Lazar Popovic  20 , Enrique Grande  21 , Giulia Mammone  22 , Rossana Berardi  23 , Simon J Crabb  24 , Javier Molina-Cerrillo  25 , Marcelo Freitas  15   26 , Murilo Luz  15   27 , Roberto Iacovelli  28 , Fabio Calabrò  29 , Deniz Tural  30 , Francesco Atzori  31 , Zsófia Küronya  32 , Rita Chiari  33 , Saul Campos  15   34 , Orazio Caffo  35 , André P Fay  15   36 , Jakub Kucharz  37 , Paolo Andrea Zucali  38   39 , José Augusto Rinck  15   40 , Annalisa Zeppellini  41 , Diogo Assed Bastos  15   42 , Gaetano Aurilio  43 , Augusto Mota  15   44 , Karine Trindade  15   45 , Cinzia Ortega  46 , Juan Pablo Sade  47 , Mimma Rizzo  48 , Nuno Vau  49 , Patrizia Giannatempo  50 , Allan Barillas  15   51 , Fernando Sabino Marques Monteiro  15   52 , Breno Dauster  15   53 , Carlo Cattrini  54 , Lucas Nogueira  15   55 , Roni de Carvalho Fernandes  56 , Emmanuel Seront  57 , Luís Garcia Aceituno  15   58 , Francesco Grillone  59 , Hernan Javier Cutuli  60 , Mauricio Fernandez  15   61 , Maria Bassanelli  62 , Giandomenico Roviello  63 , Halima Abahssain  64 , Giuseppe Procopio  50   65 , Michele Milella  66 , Jindrich Kopecky  67 , Angelo Martignetti  68 , Carlo Messina  69 , Manuel Caitano  15   70 , Eva Inman  15   71 , Ravindran Kanesvaran  72 , Daniel Herchenhorn  15   73 , Daniele Santini  74 , Ray Manneh  75 , Renato Bisonni  76 , Roubini Zakopoulou  77 , Alessandra Mosca  78 , Franco Morelli  79 , Fernando Maluf  80   81 , Andrey Soares  15   81   82 , Fernando Nunes  15   83 , Alvaro Pinto  84 , Anca Zgura  85 , Lorena Incorvaia  86 , Jawaher Ansari  87 , Ignacio Ortego Zabalza  21 , Johannes Landmesser  88 , Alessandro Rizzo  89 , Veronica Mollica  6 , Giulia Sorgentoni  90 , Nicola Battelli  90 , Camillo Porta  91 , Joaquim Bellmunt #  92 , Matteo Santoni #  90
Affiliations

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 et al. Cancer Immunol Immunother. 2023 Nov.

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.

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Conflict of interest statement

O. Fiala received honoraria from Roche, Janssen, GSK and Pfizer for consultations and lectures unrelated to this project. S. Buti received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, AstraZeneca, Merck, all unrelated to this project. M. Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas and Bayer, all unrelated to this project. R. Kanesvaran has received fees for speaker bureau and advisory board activities from the following companies; Pfizer, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Merck, Amgen, Astellas and Bayer, all unrelated to this project. E. Grande has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific and has received research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals, all unrelated to this project. F. S. M. Monteiro has received research support from Janssen, Merck Sharp Dome and honoraria from Janssen, Ipsen, Bristol Myers Squibb and Merck Sharp Dome, all unrelated to this project. C. Porta has received honoraria from Angelini Pharma, Astra Zeneca, BMS, Eisai, General Electric, Ipsen and MSD and acted as a Protocol Steering Committee Member for BMS, Eisai and MSD, all unrelated to this project. Z. Myint has received research support from Merck unrelated to this project. J. Molina-Cerrillo declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS and has received research grants from Pfizer, IPSEN and Roche, all unrelated to this project. P. Giannatempo has received research support from Ipsen, Astra Zeneca, MSD and honoraria for speaker engagements, advisory roles from Astellas, MSD, Janssen, Pfizer, all unrelated to this project. E. T. Lam has received institutional research funding from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Bristol-Myers Squibb, Pfizer, and F. Hoffmann-La Roche Ltd. The other authors declare to have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Overall survival and progression-free survival according to the use of concomitant proton pump inhibitors (PPIs), statins or metformin
Fig. 2
Fig. 2
Forest plots showing hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) according to the use of concomitant proton pump inhibitors (PPIs), statins and metformin
Fig. 3
Fig. 3
Overall survival according to concomitant use of proton pump inhibitors (PPIs) stratified by sex, smoking status and age
Fig. 4
Fig. 4
Overall survival according to concomitant use of proton pump inhibitors (PPIs) stratified by tumor histology, primary tumor site, metachronous disease, lymph node or bone metastases and pembrolizumab setting (second-line therapy after progression on first-line platinum-based chemotherapy, Cohort A)
Fig. 5
Fig. 5
Progression-free survival according to concomitant use of proton pump inhibitors (PPIs) stratified by sex, age, smoking status, tumor histology and primary tumor site
Fig. 6
Fig. 6
Progression-free survival according to concomitant use of proton pump inhibitors (PPIs) stratified by synchronous metastatic disease, lymph node metastases and pembrolizumab setting (second-line therapy after progression on first-line platinum-based chemotherapy, Cohort A)
Fig. 7
Fig. 7
Forest plots showing hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) according to the PPI use in all patient subgroups
See this image and copyright information in PMC

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