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

• Published in: Clinical cancer research 2019-03, Vol.25 (5), p.1479-1485
• Main Authors: Mir, Olivier, Touati, Nathan, Lia, Michela, Litière, Saskia, Le Cesne, Axel, Sleijfer, Stefan, Blay, Jean-Yves, Leahy, Michael, Young, Robin, Mathijssen, Ron H J, Van Erp, Nielka P, Gelderblom, Hans, Van der Graaf, Winette T, Gronchi, Alessandro
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Female; Gastric Acid - metabolism; Humans; Male; Middle Aged; Neoplasm Grading; Prognosis; Pyrimidines - administration & dosage; Sarcoma - diagnosis; Sarcoma - drug therapy; Sarcoma - metabolism; Sarcoma - mortality; Sulfonamides - administration & dosage; Survival Analysis; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-18-2748

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. 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. 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; = 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; < 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; = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; = 0.54 for OS). 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.