Impact of concomitant administration of gastric acid–suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials

Olivier Mir*, Nathan Touati, Michela Lia, Saskia Litiere, Axel Le Cesne, Stefan Sleijfer, Jean Yves Blay, Michael Leahy, Robin Young, Ron H.J. Mathijssen, Nielka P. Van Erp, Hans Gelderblom, Winette T. Van der Graaf, Alessandro Gronchi

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

63 Citations (Scopus)

Abstract

Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid–suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects. Patients and Methods: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for 80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients. Results: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11–1.99; P ¼ 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31–2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51–1.34; P ¼ 0.43 for PFS and HR, 0.84; 95% CI, 0.48–1.48; P ¼ 0.54 for OS). Conclusions: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.

Original languageEnglish
Pages (from-to)1479-1485
Number of pages7
JournalClinical Cancer Research
Volume25
Issue number5
DOIs
Publication statusPublished - 1 Mar 2019

Bibliographical note

Funding Information:
This study was supported by EORTC Soft Tissue and Bone Sarcoma Group, EORTC staff, and Fonds Cancer (FOCA) from Belgium.

Publisher Copyright:
© 2019 American Association for Cancer Research.

Research programs

  • EMC MM-03-86-08

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