Dr Pantuck: The fact that we now have an effective strategy as determined by S-TRAC is a landmark in kidney cancer. There have been three large adjuvant studies published just in the last year. One was the ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) study, one was the ARISER study (Adjuvant RENCAREX® Immunotherapy trial to Study Efficacy in non-metastasized Renal cell carcinoma), and most recently the S-TRAC trial. There is also a fourth, ongoing trial having a similar design in which pazopanib is being used in the adjuvant setting, however the results of this study are still pending. To date, the S-TRAC study represents the only adjuvant study in RCC to have a positive result. Q. How would you distinguish between the results, particularly with regard to ASSURE and S-TRAC? Dr Pantuck: There are a number of important distinctions. First, the S-TRAC study was positive and the ASSURE trial was negative. The ASSURE study was similar to S-TRAC in its enrolling patients at high risk for recurrence and placing them on a year of sunitinib (Sutent®). The ASSURE study, however, had three arms—sunitinib, placebo, and sorafenib. Two important differences in these studies were the eligibility criteria and dosing. For example, the S-TRAC study mandated that all subjects have clear cell preponderant histology, while the ASSURE study accepted all RCC subytpes except collecting “We do not know yet for certain whether the FDA will approve the adjuvant labeling for sunitinib. By granting approval for the drug for this indication, the FDA would be broadening the use of sunitinib to high-risk, non-metastatic, post-nephrectomy patients—basically adjuvant usage. And it would be the first drug approved for the prevention of recurrence in this context.” — Dr Drakaki duct and medullary carcinomas. The ASSURE study also allowed for a greater number of lower risk patients—those who had a lower risk of locoregional recurrence after nephrectomy. These were patients with high grade T1b and any grade T2 tumors. In the S-TRAC trial the population tended to include patients at higher risk for recurrence, which included only high grade T2, T3, T4 and node positive patients. Secondly, there were differences in the dosing regimens between the two studies. The ASSURE study began at a lower dose of Sunitinib, and allowed dose reductions down to 25 mg./day, while S-TRAC mandated treatment initiation at 50 mg/day and allowed dose reductions only down to 37.5 mg/day, which clearly resulted in differences in exposure to sunitinib between the two studies. These represented several possible reasons why one study would be positive while the other was negative. Q. How then, would you assess the implications of S-TRAC in terms of its effect, if any, on clinical practice? 136 Kidney Cancer Journal Dr Drakaki: This is the most important question. We do not know yet for certain whether the FDA will approve the adjuvant labeling for sunitinib. By granting approval for the drug for this indication, the FDA would be broadening the use of sunitinib to high-risk, non-metastatic, post-nephrectomy patients—basically adjuvant usage. And it would be the first drug approved for the prevention of recurrence in this context. The question is whether clinicians will adopt the use of sunitinib in this setting even if given the labelling approval by the FDA since, in the metastatic setting, the first line-drug of choice for many clinicians is pazopanib over sunitinib due to its better side effect profile Q. On what basis would clinicians be hesitant to use it as adjuvant therapy? Dr Pantuck: There are reasons why they may, at least at first glance, be hesitant to do so. When you look at the data from the ASSURE study and the S-TRAC trial, there were a significant number of patients who discontinued the treatment because of toxicity. Although it should be stated that the safety profile of adjuvant sunitinib in both S-TRAC and ASSURE was acceptable and consistent with the experience in metastatic RCC, we are dealing with a different patient population in the adjuvant setting. These patients have undergone and have recovered from their surgery, and are now presumably feeling fine and have no evidence of disease but merely the risk of cancer recurrence. Understandably, someone with metastatic disease would be willing to accept a high degree of inconvenience and adverse toxicity and side effects. Metastatic disease makes for a clear and compelling argument to accept the adverse effects. But, on the other hand, if you have no evidence of metastatic disease but only a risk for recurrence disease, your propensity for accepting and being compliant to a toxic regimen may be less. The ideal adjuvant agent would have minimal side effects and have the ability to completely eradicate micrometastatic disease., However sunitinib does have significant side effects, and instead of being cytotoxic, it is a cytostatic anti-angiogenic agent that exerts a treatment effect through preventing growth of new blood vessels. If it only prevents the growth of new blood vessels, what happens after you discontinue the drug after a year? Will tumors grow at that point? If so, will they then be resistant to the effects of sunitinib and other anti-VEGF TKIs? These questions remain unanswered.
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