Pazopanib Sarcoma Outcomes Worse With Concomitant Acid Suppressant Use

Co-administration of pazopanib and gastric acid suppressive therapy may have a detrimental effect on the progression-free and overall survival of soft tissue sarcoma patients

medwireNews: Researchers caution against the use of gastric acid suppressive (GAS) agents alongside pazopanib in patients with soft tissue sarcoma, after finding poorer survival outcomes among concomitant users than nonusers. 

“If patients have good medical reasons to stay on, or to start, GAS medication, therapeutic drug monitoring of pazopanib plasma concentrations could be helpful to optimally adjust the pazopanib dose”, they write in Clinical Cancer Research

From the EORTC 62043 and 62072 trials – a phase II single-arm and phase III placebo-controlled trial of pazopanib, respectively – the team identified 333 patients, 17.7% of whom had taken either proton pump inhibitors or histamine H2-receptor antagonists for over 80% of the duration of treatment with the multikinase tyrosine kinase inhibitor. 

Progression-free survival (PFS) was significantly worse for concomitant users than nonusers, at a median of 2.8 and 4.6 months, respectively, and a hazard ratio (HR) of 1.49 after adjusting for age at randomisation, gender, performance status and tumour grade. 

This was also the case for overall survival (OS), with patients taking pazopanib and GAS therapy achieving a median of 8.0 months versus 12.6 months for nonusers. This equated to a significant adjusted HR of 1.81. 

And the detrimental effect of GAS therapy on PFS and OS was greater with longer periods of co-administration of pazopanib and GAS agents, report Olivier Mir, from Gustave Roussy Cancer Campus in Villejuif, France, and collaborators. 

Of note, no such association between GAS therapy and outcomes was observed among 110 placebo-treated participants of the EORTC 62072 trial, “which confirmed that the detected impact on clinical outcomes was most likely caused by the drug–drug interaction between GAS therapy and pazopanib”, write the researchers. 

They believe that “the effects of GAS therapy on the pharmacokinetics of pazopanib could account for this observation.” 

The team explains that the absorption of pazopanib is pH dependent, and that the drug is rendered practically insoluble at pH values over 4. 

“As a consequence, the increase in gastric pH caused by GAS therapy could decrease pazopanib solubility and absorption, leading to suboptimal plasma concentrations.” 

For patients who are unable to discontinue GAS therapy for medical reasons, Olivier Mir et al suggest that “that the dose of pazopanib should be taken without food, once daily in the evening, concomitantly with the GAS agent.” 

Looking to the future, they recommend that alternative schedules for combining tyrosine kinase inhibitors and acid suppressants be investigated to prevent suboptimal exposure of the anticancer agents.

 

Reference 

Mir O, Touati N, Lia M, et al. 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 . Clin Cancer Res; Advance online publication 14 February 2019. doi: 10.1158/1078-0432.CCR-18-2748

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