Effect of Acid‐Suppressive Strategies on Pazopanib Efficacy in Patients With Soft‐Tissue Sarcoma

Abstract

Pazopanib (PAZ), a tyrosine kinase inhibitor used in the treatment of soft tissue sarcoma (STS), should not be administered with acid‐suppressive medications (ASMs) due to decreased drug solubility. Common practice for patients requiring ASM with PAZ is to separate administration by 12 hours; however, there is little real‐world evidence describing clinical outcomes using this strategy. The aim of this study was to determine whether concomitant ASM impacted efficacy and adverse event rates in patients with STS receiving PAZ. Medical records were retrospectively reviewed for patients with STS who received PAZ from June 2011 to July 2017. Patients were stratified into two groups, PAZ with or without ASM (PAZ + ASM or PAZ only). The primary objective was to determine whether progression‐free survival (PFS) differed between groups. Secondary objectives were to determine overall survival (OS) and occurrence of grade 3/4 toxicities. Ninety‐one patients were included in the study, 42 patients in the PAZ + ASM group and 49 in the PAZ only group. Median PFS was significantly shorter in the PAZ + ASM group than the PAZ only group (5.3 vs. 6.7 months). The PAZ + ASM group also had a 74% higher relative risk of progression or death than the PAZ only group, but there was no difference in OS. Regarding adverse events, the PAZ + ASM group trended toward lower levels of grade 3/4 hypertension (19% vs. 37%). These results suggest that ASM should be avoided in patients with STS receiving PAZ. Larger studies are needed to further elucidate the impact of ASM use with PAZ in clinical practice.

Effect of Concomitant Proton Pump Inhibitors with Pazopanib on Cancer Patients: A Retrospective Analysis

“…A retrospective analysis of two prospective studies of pazopanib in STS (EORTC 62,043 and 62072) demonstrated that gastric-acid suppressive agents (GAS) concomitantly administrated (in 17.7% of the 333 eligible patients) was associated with shorter mPFS (2.8 vs. 4.6 months (HR, 1.49; 95% CI, 1.11-1.99; p = 0.01)), and mOS (8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; p < 0.01)); these effects were not observed in placebo-treated patients [9]. This was also shown in another series of patients treated for STS [10]. Surprisingly, two retrospective series analyzing pazopanib in advanced RCC patients gave negative results, with only minor differences in prognosis between patients receiving PPIs or not receiving them [11,12].…”

“…A pooled retrospective analysis, comparing patients treated for STS in two prospective trials with pazopanib or placebo, with or without the associated PPIs, showed a reduction in PFS and overall survival (OS) in patients who were concomitantly on PPIs and pazopanib (no effect was observed in the placebo arm), suggesting a detrimental role for this combination [9]. Another retrospective study from medical records, in a cohort of 91 patients treated with pazopanib for STS, demonstrated that the 42 patients taking concomitant acid-suppressive medications had shorter PFS and a trend toward less hypertension [10]. Conversely, two retrospective studies of patients on pazopanib for advanced RCC did not show any change in survival when pazopanib was combined with PPIs [11,12].…”

Proton Pump Inhibitors and Cancer: Current State of Play

“…Several studies have investigated the DDIs between PPIs and TKIs; the results are contradictory concerning PPI interaction with the bioavailability and activity of TKIs. A summary of these DDIs is presented in Table 3 ( Rugo et al, 2005 ; Egorin et al, 2009 ; Yin et al, 2010 ; Yin et al, 2012 ; Takahashi et al, 2012 ; Hilton et al, 2013 ; Abbas et al, 2013 ; Musib et al, 2013 ; Tan et al, 2013 ; Johansson et al, 2014 ; Narasimhan et al, 2014 ; Chu et al, 2015 ; Kletzl et al, 2015 ; Ha et al, 2015 ; Iurlo et al, 2016 ; Kumarakulasinghe et al, 2016 ; Lam et al, 2016 ; Zenke et al, 2016 ; Chu et al, 2017 ; Lalani et al, 2017 ; Lacy et al, 2017 ; Lau et al, 2017 ; Morcos et al, 2017 ; Yokota et al, 2017 ; de Jong et al, 2018 ; Nieves Sedano et al, 2018 ; Ohgami et al, 2018 ; Fang et al, 2019 ; Mir et al, 2019 ; Vishwanathan et al, 2018 ; Pisano et al, 2019 ; de Man et al, 2019 ; Koutake et al, 2020 ; Ruanglertboon et al, 2020 ; Van De Sijpe et al, 2020 ; Chen et al, 2021 ; Rassy et al, 2021 ). Table 4 summarizes the main studies reporting reductions in the survival of patients receiving this combination of medication ( Chu et al, 2015 ; Ha et al, 2015 ; Fang et al, 2019 ; Mir et al, 2019 ).…”

Managing Drug Interactions With Oral Anticancer Treatments

“…A study following patients who were prescribed erlotinib while also taking a proton pump inhibitor (PPI) or a histamine-2 receptor antagonist (H 2 RA) concomitantly found a reduced progression-free survival compared with the group taking erlotinib alone (5.3 months vs. 11.0 months, p = .029; Lam et al, 2016 ). Pazopanib (Votrient) is another example of an OC that is impacted by pH ( Pisano et al, 2019 ). Patients with soft-tissue sarcoma taking concomitant GAS agents and pazopanib therapy experienced a shorter progression-free survival relative to patients taking pazopanib alone (5.3 months vs. 6.7 months; Pisano et al, 2019 ).…”

“…Pazopanib (Votrient) is another example of an OC that is impacted by pH ( Pisano et al, 2019 ). Patients with soft-tissue sarcoma taking concomitant GAS agents and pazopanib therapy experienced a shorter progression-free survival relative to patients taking pazopanib alone (5.3 months vs. 6.7 months; Pisano et al, 2019 ). Patients taking an H 2 RA were counseled to take their pazopanib dose 2 hours before or 10 hours after their H 2 RA dose, but pazopanib efficacy was still decreased ( Pisano et al, 2019 ).…”