Elsevier

Urology

Volume 81, Issue 1, January 2013, Pages 143-149
Urology

Medical Oncology
Safety of Everolimus by Treatment Duration in Patients With Advanced Renal Cell Cancer in an Expanded Access Program

https://doi.org/10.1016/j.urology.2012.09.019Get rights and content

Objective

To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program.

Methods

Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors.

Results

The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates.

Conclusion

Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations ≥1 year and not associated with cumulative toxicity.

Section snippets

Study Design

The study design of REACT has been previously reported.9 Evaluation of everolimus safety in a large population of patients with mRCC who progressed on previous VEGFr-TKI therapy was the primary objective of REACT. Adult patients with mRCC who progressed on, or were intolerant of, previous VEGFr-TKI therapy were enrolled from 34 participating countries (Clinicaltrials.gov: NCT00655252). Enrollment commenced in July 2008 and was completed by June 2010. Protocol approval was sought and obtained

Patient Characteristics and Disposition

A total of 1367 patients from 34 countries enrolled in REACT were divided into 4 treatment duration strata: 626 to <3 months; 395 to ≥3 months and <6 months; 294 to ≥6 months and <1 year; and 52 to ≥1 year. Analysis of baseline characteristics (Table 1) revealed that a greater proportion of patients who received treatment for ≥6 months were aged <65 years compared with those who received treatment for <6 months. All patients who received everolimus for ≥1 year had tumors with clear cell

Discussion

Sequential administration of targeted therapies has now become the recommended standard of care for most patients with mRCC,2, 3, 4, 5 and patients will increasingly receive treatment with VEGFr-TKIs and mTOR inhibitors over longer time periods. Long-term administration of a targeted agent might lead to a high incidence of toxicities associated with treatment-related AEs. For example, in the phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) trial of sorafenib,

Conclusions

Overall, everolimus is well tolerated in patients with mRCC for treatment durations of up to 1 year and longer. Certain mTOR inhibitor class-effect toxicities were more prevalent in patients receiving everolimus for >1 year, such as pneumonia, noninfectious pneumonitis, and hyperglycemia, but they do not appear to lead to treatment discontinuation. The first occurrence of AEs presented early in the course of treatment for most of the patients, suggesting that cumulative toxicity does not arise

Acknowledgments

The authors thank Tapas Chakraborty for analytical support.

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Financial Disclosure: S. Bavbek has received consulting fees and honoraria from Novartis, Pfizer, GlaxoSmithKline, Sanofi-Aventis, and Bayer. S. Bracarda has received consulting fees from Pfizer, Sanofi-Aventis, Jannsen, Boehringer-Ingelheim, GlaxoSmithKline, and Novartis and has held nonremunerative positions of influence for Bayer Schering Pharma. A. Bahl has received research grants from Sanofi and served as advisor to Sanofi, Amgen, Roche, and Novartis. D. Kim and O. Anak own stock in and are employees of Novartis. A. Panneerselvam is an employee of Novartis. V. Grünwald has received consulting fees and served as speaker for Pfizer. Other authors have no disclosures.

Funding Support: Editorial assistance in the preparation of this manuscript was provided by Karen Miller-Moslin, Ph.D., and Clare Lee, Ph.D., of ApotheCom (Yardley, PA), and was funded by Novartis Pharmaceuticals Corporation.

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