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Clinical Trials: Targeted Therapy

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 Litière, 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 and Alessandro Gronchi
Olivier Mir
1Gustave Roussy, Sarcoma Group, Villejuif, France.
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  • For correspondence: olivier.mir@gustaveroussy.fr
Nathan Touati
2European Organization for Research and Treatment of Cancer, Brussels, Belgium.
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Michela Lia
2European Organization for Research and Treatment of Cancer, Brussels, Belgium.
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Saskia Litière
2European Organization for Research and Treatment of Cancer, Brussels, Belgium.
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Axel Le Cesne
1Gustave Roussy, Sarcoma Group, Villejuif, France.
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Stefan Sleijfer
3Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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Jean-Yves Blay
4Léon Bérard Cancer Center, Lyon, France.
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Michael Leahy
5The Christie NHS Foundation Trust, Manchester, United Kingdom.
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Robin Young
6Weston Park Hospital, Sheffield, United Kingdom.
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Ron H.J. Mathijssen
3Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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Nielka P. Van Erp
7Radboud University Medical Centre, Nijmegen, the Netherlands.
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Hans Gelderblom
8Leiden University Medical Center, Leiden, the Netherlands.
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Winette T. Van der Graaf
7Radboud University Medical Centre, Nijmegen, the Netherlands.
9The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, United Kingdom.
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Alessandro Gronchi
10Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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DOI: 10.1158/1078-0432.CCR-18-2748 Published March 2019
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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 = 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 = 0.43 for PFS and HR, 0.84; 95% CI, 0.48–1.48; P = 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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received August 22, 2018.
  • Revision received November 5, 2018.
  • Accepted December 14, 2018.
  • Published first February 14, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 25 (5)
March 2019
Volume 25, Issue 5
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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 Litière, 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 and Alessandro Gronchi
Clin Cancer Res March 1 2019 (25) (5) 1479-1485; DOI: 10.1158/1078-0432.CCR-18-2748

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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 Litière, 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 and Alessandro Gronchi
Clin Cancer Res March 1 2019 (25) (5) 1479-1485; DOI: 10.1158/1078-0432.CCR-18-2748
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