This recent report by Motzer and colleagues further demonstrates the efficacy of this agent in treating advanced RCC. It is an open label, single-arm, multicenter trial evaluating 106 patients with metastatic disease who had failed cytokine therapy. Sunitinib was administered orally at 50 milligrams daily in a now established 6 week cycle consisting of 4 weeks of therapy followed by a two week rest period. The primary end point was clinical response and secondary end points were progression -free survival and safety. It is notable that the response evaluation was determined using the Response Evaluation Criteria in Solid Tumors [RECIST] guidelines by an independent third party core imaging lab, as well as by the investigators. In this analysis the longest diameter of each measurable lesion is summed and a partial response is defined as a 30% decrease in this aggregate measurement.

Objective responses were obtained in 36 patients of the 105 evaluable patients 34%; 95% CI (25%-44%). All were partial responses. A median progression free survival of 8.3 months; 95% CI (7.8-14.5) was noted. The most common side effects were fatigue [28%] and diarrhea [20%]. Laboratory abnormalities included neutropenia [42%], lipase elevation [28%], and anemia [26%].

It is important to remember that all of these patients had been pretreated with either interferon alpha, interleukin 2 or a combination of the two. Over 55% of patients had greater than 3 sites positive for tumor and the participants had an ECOG status of 0 or 1. The role of independent reviewers in determining treatment response was demonstrated in this study since the investigators estimated a response rate of 43% with one complete response, while the independent reviewers interpreted the data with greater stringency.

While the progression free survival was 8.3 months only 10 of 36 responders progressed, thus time to median progression was not reached. 53% of patients developed disease progression or died during the course of the study. The median overall survival had not been reached at 6 months, 79%; 95% CI (70-86). Patients completed 0-11 cycles of therapy. In addition to the side effects noted above, patients also developed hypertension, hand-foot syndrome, and stomatitis. 4.7% of patients demonstrated a 20% decrease in function on gated heart scans, although none of them demonstrated clinical symptoms of congestive heart failure.

A pooled analysis of this study and the prior phase II investigation of sunitinib as a second line therapy in RCC [Motzer et al, JCO24:16-24, 2006] provided 168 patients for review. In this analysis 42% of patients responded and the median progression free survival was 8.2 months; 95%CI (7.8-10.4). The median progression free survival in responders' was14.8 months 95%CI (10.9-24.2). An evaluation of preclinical factors that may have some effect on response status demonstrated a normal serum hemoglobin [78% vs. 43% p<0.02] and ECOG status 0 versus 1 [66% vs. 45%, p=0.008 as having an impact. In a multivariable analysis, low hemoglobin was an independent predictor of a shorter progression -free survival [HR 0.37; CI 0.25-056, p<0.001].

The data from this trial and the pooled analysis of this and the prior trial [JCO] demonstrate a response rate for a second line therapy which is twice that of cytokines in first line therapy. The role of sunitinab as a first line agent has been investigated in a 700 patient comparison of sunitinib vs. alpha interferon which has recently completed accrual. That study will further define the role of sunitinab as a first line agent in metastatic renal cell carcinoma, yet the available data clearly demonstrate a distinct impact of this agent on the treatment of a condition with very few previous therapeutic options.

JAMA 295:2516-24-24, 2006

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Renal Cancer Section

Written by S.Bruce Malkowicz, MD, a Contributing Editor with UroToday.

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