Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma

Background: Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to >= 6 yr. Objective: To analyze long-term safety with sunitinib in mRCC patients. Design, setting, and participants: Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g. cytokine refractory or treatment-naive). Outcome measurements and statistical analysis: Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (>= 2 yr) sunitinib treatment. Results and limitations: Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade >= 3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. Conclusions: Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. Patient summary: More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.