Abstract
Purpose
The objective of the study was to describe the occurrence of stomatitis and noninfectious lung disease in patients with metastatic renal cell carcinoma (mRCC) treated with second-line everolimus in a real-world setting.
Methods
This multicenter, prospective, observational study was conducted in France by physicians with experience of treatment of patients with mRCC. Patients aged ≥18 years who received everolimus after first-line antivascular endothelial growth factor (VEGF) therapy were included in the study. The primary safety assessments were occurrence of stomatitis (in terms of severity, event dates, and therapeutic management) and noninfectious pneumonitis (in terms of detection methodology, severity, event dates, and therapeutic management).
Results
Between September 2010 and August 2012, 284 patients were enrolled at 77 centers, of whom, 274 received everolimus therapy. Most patients had mRCC of clear cell histology (88%), and most of them (84%) received first-line sunitinib. In total, 40% of patients experienced treatment-related stomatitis, and 15% of patients experienced noninfectious lung disease. Most of them had a single episode. The incidence of grade 3 stomatitis and noninfectious lung disease were 8 and 3%, respectively. Mean time to the first episode was 27 days for stomatitis and 72 days for noninfectious lung disease from treatment initiation. Stomatitis and noninfectious lung disease resulted in treatment discontinuations in 2 and 7% of patients, respectively. The primary first-episode treatment was mouthwash (86%) for stomatitis and corticosteroids (65%) for noninfectious lung disease.
Conclusions
This study confirms that stomatitis and noninfectious lung disease are commonly associated with everolimus use. Both adverse events were rarely severe and were managed easily and efficiently.
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References
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484
Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the MTOR signaling network for cancer therapy. J Clin Oncol 27:2278–2287
Duvel K, Yecies JL, Menon S et al (2010) Activation of a metabolic gene regulatory network downstream of MTOR complex 1. Mol Cell 39:171–183
Motzer RJ, Escudier B, Oudard S et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256–4265
Grunwald V, Karakiewicz PI, Bavbek SE et al (2012) An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. Eur J Cancer 48:324–332
Bergmann L, Goebell PJ, Herrmann E, et al. (2013) Final results of a non-interventional study of everolimus in mRCC after exactly one previous VEGFR-TKI. Poster presented at: European Society of Medical Oncology; Sep 27-Oct 01, 2013, Amsterdam, Netherlands
European Medicines Agency (2013) European public assessment report (EPAR). Afinitor® 16.03.2013. European Medicines Agency (EMA), London, pp 1–3
Sonis S, Treister N, Chawla S et al (2010) Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 116:210–215
Shameem R, Lacouture M, Wu S (2015) Incidence and risk of high-grade stomatitis with MTOR inhibitors in cancer patients. Cancer Investig 33:70–77
White DA, Schwartz LH, Dimitrijevic S et al (2009) Characterization of pneumonitis in patients with advanced non-small cell lung cancer treated with everolimus (RAD001). J Thorac Oncol 4:1357–1363
White DA, Camus P, Endo M et al (2010) Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 182:396–403
Atkinson BJ, Cauley DH, Ng C et al (2014) Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes. BJU Int 113:376–382
Duran I, Goebell PJ, Papazisis K et al (2014) Drug-induced pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms. Expert Opin Drug Saf 13:361–372
Rugo HS, Geberth M, et al. (2013) Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: 13th St. Gallen International Breast Cancer Conference; Mar 13–16, 2013, St. Gallen, Switzerland
Chawla SP, Staddon AP, Baker LH et al (2012) Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 30:78–84
Dancey JE, Monzon J (2011) Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies. Future Oncol 7:827–839
Afinitor (everolimus tablets for oral administration) (2014) Afinitor disperz (everolimus tablets for oral suspension) [prescribing information]. Novartis Pharmaceuticals Corporation, East Hanover, NJ
Boers-Doets CB, Raber-Durlacher JE, Treister NS et al (2013) Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol 9:1883–1892
Albiges L, Chamming's F, Duclos B et al (2012) Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann Oncol 23:1943–1953
Acknowledgments
Medical editorial assistance for the manuscript was provided by Sai Krishna Arepalli, Ph.D. (Novartis Healthcare Pvt. Ltd.) and Cathy R. Winter, Ph.D. (ApotheCom, Yardley, PA). This study was funded by Novartis Pharmaceuticals Corporation.
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Jean-Christophe Eymard, Thierry Lebret, Frederic Rolland, Thierry Nguyen, and Aline Guillot report no potential conflicts of interest. Florence Joly reports consulting or advisory fees from Novartis. Dominique Spaeth reports personal fees and consulting or advisory fees from Novartis. Alain Ravaud reports consulting or advisory fees from Pfizer, Novartis, Roche, BMS, and MSD as well as institutional grant support from Pfizer and Novartis. Laurence Albiges reports consulting or advisory fees from Pfizer, Novartis, Sanofi, BMS, and Bayer. Nadia Kelkouli and Khemaies Slimane are employees of Novartis Pharmaceuticals Corporation. Brigitte Laguerre reports personal fees from Novartis. The authors have had access to full data and analyses presented in this manuscript and will allow the journal to review the data if requested.
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Nadia Kelkouli was an employee of Novartis Pharmaceuticals Corporation until August 2016
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Joly, F., Eymard, JC., Albiges, L. et al. A prospective observational study on the evaluation of everolimus-related adverse events in metastatic renal cell carcinoma after first-line anti-vascular endothelial growth factor therapy: the AFINITE study in France. Support Care Cancer 25, 2055–2062 (2017). https://doi.org/10.1007/s00520-017-3594-y
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DOI: https://doi.org/10.1007/s00520-017-3594-y