Kidney Cancer Journal 137 dose of sunitinib was modified from 50 mg per day to 35 mg.2 The median DFS was 5.8 years in both the sorafenib and sunitinib arms and 6.0 years in the placebo arm. The 5-year DFS rate was 52.8% in the sorafenib arm, 53.8% in the sunitinib arm, and 55.8% in the placebo arm. In those with clear cell carcinoma, the DFS was 5.6 years with sunitinib, 5.1 years with sorafenib, and 5.7 years with placebo. The 5-year survival rate was 76.9% with sunitinib, 80.7% with sorafenib, and 78.7% with placebo. Earlier efforts to achieve favorable outcomes with other adjuvant therapies in this setting highlight the challenges involved and the disappointing results. They include the following reports: Chamie et al conducted a randomized trial of 864 patients, to determine if adjuvant weekly girentuximab could be effective following complete resection of localized, high-risk RCC.3 There was no difference in diseasefree survival between patients receiving girentuximab. Although the drug was well tolerated, results from the ARISER trial are discouraging for the use of this monoclonal antibody. The antibody binds carbonic anhydrase IX, a cell surface glycoprotein ubiquitously expressed in clear cell RCC. Earlier studies showing safety and activity led to the investigation into its use as adjuvant monotherapy. The ARISER study is one of the more recent attempts at validating an adjuvant approach. The challenge of doing so was apparent even 15 years ago when the Cy- Q.What were the results from S-TRAC on overall survival and progression-free survival? Dr Pantuck: In the S-TRAC trial patients were treated for one year and then followed for five years since last patient enrolled for disease recurrence. The study met its primary endpoint of improving disease-free survival (DFS) as determined by blinded independent central review in patients with renal cell carcinoma (RCC) who are at high risk for recurrence after surgery. The median duration of diseasefree survival was 6.8 years in the sunitinib group and 5.6 years with a hazard ratio of 0.76 that was statistically significant (P=0.03). At the time the S-TRAC paper was published, there was no difference in overall survival between sunitinib and placebo, however overall survival data were not mature at the time of data cutoff. Dr Drakaki: It is possible that clinicians and patients may wait until overall survival data matures before making a decision whether or not to recommend using sunitinib in the adjuvant setting. It is not clear that patients will be willing to take the drug for a year solely in order to delay going back on the same or a similar drug a year later. Because when the disease recurs, many patients will be put back on a VEGF TKI. So the question is, Q. So which patients are likely to be in the group that will benefit the most from administration of sunitinib according to S-TRAC? Dr Pantuck: The trial answers this question by breaking the patient population into subgroups. If you were in the highest risk subgroup—say, those with a T4 tumor or those with positive lymph nodes, there was a two-year rather than a one-year improvement in progression free survival in favor of the sunitinib arm compared to placebo. Thus, patients with the highest risk of recurrence also had the greatest benefit. So these highest risk patients may be the ideal group to utilize sunitinib in the adjuvant setting. They have the greatest risk of recurrence and the greatest benefit from adjuvant treatment after nephrectomy. Q.Where do we go from here? You are optimistic, but what remains to be elucidated? Dr Pantuck: The bottom line is that we have achieved a milestone, but it is not by any means the end of the story. We still need to find agents with better tolerability profiles and improved overall survival. We’re moving into a new era of adjuvant studies. We have spent the last 5-10 years testing the TKIs and now we’re preparing to look at additional agents, including the checkpoint inhibitors and other innovative therapies. Dr Drakaki: There are currently ongoing trials with PD-1 or PD-L1 inhibitors as well as combination of those with CTLA4 inhibitors in the adjuvant setting. The biggest challenge here will be, especially for the combination studies, the safety profile. From our experience using these drugs in advanced disease and other tumor types, immune checkpoint inhibitors could lead to serious immune mediated side effects that could even potentially be life threatening. We would need to see a significant and meaningful overall survival benefit before subjecting patients who may never have recurrence to a potentially toxic therapy. A lot will be learned from those studies and certainly will change the treatment arena for years to come. I envision that those adjuvant trials with immune checkpoint inhibitors will be positive if they are designed correctly. This will lead to the next question which is “what is going to be the best therapy, VEGF TKIs or immune checkpoint inhibitors in the adjuvant setting?” So I am also optimistic and hopeful that we will continue to make progress in this important field. KCJ (continued from page 135)
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