Impact of concomitant acid suppressive therapy on pazopanib efficacy and dose reductions in patients with metastatic renal cell carcinoma

Abstract

Purpose

The aim of this study was to investigate the impact of acid suppressive therapy on clinical efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma (mRCC).

Methods

A single-center retrospective study was carried out. Charts of mRCC patients who received pazopanib as first-line treatment were reviewed and concomitant use of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was studied. Two groups of patients were identified, namely patients receiving PPI/H2RA and patients without acid suppressive therapy. Both groups were compared with regard to progression free survival (PFS), overall survival (OS), tumor response, and time to dose reduction of pazopanib.

Results

Ninety-one patients were included. Median PFS was 8 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (hazard ratio (HR) 0.76 (95% confidence interval (CI) 0.42–1.35)), p = 0.35. Median OS was 27 months in the PPI/H2RA group vs. 23 months in the no PPI/H2RA group (HR 0.87 (95% CI 0.46–1.66)), p = 0.68. Mean tumor response was 17% (95% CI 8–25%) in the PPI/H2RA group vs. 11% (95% CI 0–21%) in the no PPI/H2RA group, p = 0.52. Median time to first dose reduction was 9 months in both subgroups (HR 1.25 (95% CI 0.65–2.39)), p = 0.51. Median time to second dose (< 600 mg) reduction was 17 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (HR 0.26 (95% CI 0.07–0.89)), p = 0.03.

Conclusion

In this limited patient series, no evidence of a negative impact of PPI/H2RA on clinical outcome and time to first dose reduction was observed. These results suggest that PPI/H2RA might be considered, when there is a clinical need, in patients treated with pazopanib for mRCC. However, a prospective study is warranted to confirm these results.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter RN 3rd, Johnson JH, Knick VB, Laudeman CP, Luttrell DK, Mook RA, Nolte RT, Rudolph SK, Szewczyk JR, Truesdale AT, Veal JM, Wang L, Stafford JA (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 51(15):4632–4640. https://doi.org/10.1021/jm800566m

    Article  PubMed  Google Scholar 

  2. 2.

    Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068. https://doi.org/10.1200/jco.2009.23.9764

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schoffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet (London, England) 379(9829):1879–1886. https://doi.org/10.1016/s0140-6736(12)60651-5

    Article  Google Scholar 

  4. 4.

    Di Gion P, Kanefendt F, Lindauer A, Scheffler M, Doroshyenko O, Fuhr U, Wolf J, Jaehde U (2011) Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet 50(9):551–603. https://doi.org/10.2165/11593320-000000000-00000

    Article  PubMed  Google Scholar 

  5. 5.

    Sachs G, Shin JM, Hunt R (2010) Novel approaches to inhibition of gastric acid secretion. Curr Gastroenterol Rep 12(6):437–447. https://doi.org/10.1007/s11894-010-0149-5

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Shin JM, Sachs G (2008) Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 10(6):528–534. https://doi.org/10.1007/s11894-008-0098-4

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Miner P Jr, Katz PO, Chen Y, Sostek M (2003) Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 98(12):2616–2620. https://doi.org/10.1111/j.1572-0241.2003.08783.x

    Article  PubMed  Google Scholar 

  8. 8.

    Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson JJ (2013) Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 71(6):1635–1643. https://doi.org/10.1007/s00280-013-2164-3

    Article  PubMed  Google Scholar 

  9. 9.

    Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021. https://doi.org/10.1158/1535-7163.Mct-07-0193

    Article  PubMed  Google Scholar 

  10. 10.

    Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15(12):4220–4227. https://doi.org/10.1158/1078-0432.Ccr-08-2740

    Article  PubMed  Google Scholar 

  11. 11.

    Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, Lin Y, Swann S, Amado R, Pandite L (2014) Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer 111(10):1909–1916. https://doi.org/10.1038/bjc.2014.503

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Beuselinck B, Vano YA, Oudard S, Wolter P, De Smet R, Depoorter L, Teghom C, Karadimou A, Zucman-Rossi J, Debruyne PR, Van Poppel H, Joniau S, Lerut E, Strijbos M, Dumez H, Paridaens R, Van Calster B, Schoffski P (2014) Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib. BJU Int 114(1):81–89. https://doi.org/10.1111/bju.12494

    Article  PubMed  Google Scholar 

  13. 13.

    Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27(34):5794–5799. https://doi.org/10.1200/jco.2008.21.4809

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States. Natl Cancer Instit Can J Natl Cancer Inst 92(3):205–216. https://doi.org/10.1093/jnci/92.3.205

    Article  Google Scholar 

  15. 15.

    Verheijen RB, Swart LE, Beijnen JH, Schellens JHM, Huitema ADR, Steeghs N (2017) Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization. Cancer Chemother Pharmacol 80(6):1171–1178. https://doi.org/10.1007/s00280-017-3463-x

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lubberman F, Gelderblom H, Hamberg P, Vervenne W, Van Herpen CML, Erp N (2019) The impact of gastric acid suppressive agents on pazopanib exposure. J Clin Oncol 37:e16076. https://doi.org/10.1200/JCO.2019.37.15_suppl.e16076

    Article  Google Scholar 

  17. 17.

    van Leeuwen RWF, Jansman FGA, Hunfeld NG, Peric R, Reyners AKL, Imholz ALT, Brouwers J, Aerts JG, van Gelder T, Mathijssen RHJ (2017) Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet 56(7):683–688. https://doi.org/10.1007/s40262-016-0503-3

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    McAlister RK, Aston J, Pollack M, Du L, Koyama T, Chism DD (2018) Effect of concomitant pH-elevating medications with pazopanib on progression-free survival and overall survival in patients with metastatic renal cell carcinoma. Oncologist 23(6):686–692. https://doi.org/10.1634/theoncologist.2017-0578

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Mir O, Touati N, Lia M, Litiere S, Le Cesne A, Sleijfer S, Blay JY, Leahy M, Young R, Mathijssen RHJ, Van Erp NP, Gelderblom H, Van der Graaf WT, Gronchi A (2019) 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 25(5):1479–1485. https://doi.org/10.1158/1078-0432.Ccr-18-2748

    Article  PubMed  Google Scholar 

  20. 20.

    Beuselinck B, Verbiest A, Couchy G, Job S, de Reynies A, Meiller C, Albersen M, Verkarre V, Lerut E, Mejean A, Patard JJ, Laguerre B, Rioux-Leclercq N, Schoffski P, Oudard S, Zucman-Rossi J (2018) Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Acta Oncol 57(4):498–508. https://doi.org/10.1080/0284186x.2017.1388927

    Article  PubMed  Google Scholar 

  21. 21.

    Sternberg CN, Donskov F, Haas NB, Doehn C, Russo P, Elmeliegy M, Baneyx G, Banerjee H, Aimone P, Motzer RJ (2018) Pazopanib exposure relationship with clinical efficacy and safety in the adjuvant treatment of advanced renal cell carcinoma. Clin Cancer Res 24(13):3005–3013. https://doi.org/10.1158/1078-0432.Ccr-17-2652

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

Conceptualization and methodology: Van De Sijpe Greet, Van Nieuwenhuyse Tine, Beuselinck Benoit, and Spriet Isabel; Formal analysis and investigation: Van De Sijpe Greet, Poncelet Roxanne, and Beuselinck Benoit; Writing—original draft preparation: Van De Sijpe Greet; Writing—review and editing: all authors; Supervision: Beuselinck Benoit and Spriet Isabel.

Corresponding author

Correspondence to Greet Van De Sijpe.

Ethics declarations

Conflict of interest

Beuselinck Benoit received an unrestricted research grant from Bristol-Myers-Squibb for other research projects and honorarium from Merck, Pfizer, Bristol-Myers-Squibb, Ipsen, and Astra Zeneca. Tack Jan has given scientific advice to Sofar, Takeda, and Truvion, has received research support from Sofar, and has served on the Speaker bureau for Takeda and Truvion. The other authors report no conflict of interest.

Ethics approval

The hospital ethics committee approved this retrospective study.

Consent

Not applicable

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 407 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Van De Sijpe, G., Beuselinck, B., Van Nieuwenhuyse, T. et al. Impact of concomitant acid suppressive therapy on pazopanib efficacy and dose reductions in patients with metastatic renal cell carcinoma. Eur J Clin Pharmacol (2020). https://doi.org/10.1007/s00228-020-02902-3

Download citation

Keywords

  • Pazopanib
  • Proton pump inhibitors
  • PPI
  • Histamine 2 receptor antagonists
  • Renal cell carcinoma
  • mRCC
  • Drug-drug interaction