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Expert Reflects on Recent Pivotal Data in RCC

Angelica Welch
Published: Monday, Dec 17, 2018

Daniel J. George, MD
Daniel J. George, MD
Renal cell carcinoma (RCC) is a field that is shifting dramatically in the metastatic setting, but progress has been slower for patients with high-risk stage III disease, said Daniel J. George, MD.

The future of treatment for patients with stage III disease should be individualized, he said, and with the newly available data, physicians should have an open line of communication with their patients about treatment options.

In an interview with OncLive® during the 2018 State of the Science SummitTM on Genitourinary Cancers, George, professor of Medicine and Surgery, member, Duke Cancer Institute, discussed the status of treatment for patients with high-risk stage III RCC, as well as the role of sunitinib (Sutent) and checkpoint inhibitors in the RCC paradigm.

OncLive®: What are the recent data seen with TKIs in the landscape?

George: RCC is a field that is dramatically changing—we are making progress in advanced metastatic disease. However, for patients with stage III disease who are high risk for disease recurrence after surgery, there really have not been any breakthroughs until recently. For the most part, that has been an unmet need. We have done some clinical trials looking at TKIs in that setting. 

One study was positive. That was the S-TRAC study, which looked at the use of sunitinib (Sutent) for 1 year versus placebo in patients with high-risk disease. In that patient population, we demonstrated a 24% reduction in risk of disease recurrence for the entire population. At 5 years, there was an absolute improvement in recurrence-free survival of 8%, roughly 1 out of 12. Overall, there was an approximate 50% disease recurrence for that population at 5 years, so this was indeed a high-risk patient population.

This was a positive study that led to an FDA approval. It is interesting to us that in this context, there has not been a lot of use of sunitinib in this setting, and there has been some pushback regarding the results because of some other studies that were contemporary and did not meet their primary endpoints. 

The ASSURE study was one of those studies. This looked at sunitinib, sorafenib (Nexavar), and placebo, demonstrating no difference in disease-free survival (DFS). But, there were a lot of dose reductions all the way down to 25 mg of sunitinib. About two-thirds of the way through, they changed the dosing from 50 mg down to 37.5 mg. That relative decrease probably explains a lot of why we did not see the efficacy. 

In the PROTECT study of pazopanib (Votrient), a similar drug to sunitinib, they changed the initial dose from 800 mg to 600 mg halfway through due to tolerance. What we found was that in the patients who started at 800 mg, there was indeed a statically significant improvement in DFS similar to what was seen in S-TRAC. However, in the patients who had the dose reduction from the beginning, there was a reduction of that effect that was no longer statistically significant. 

Therefore, dose matters when it comes to the adjuvant setting. The struggle is that dose also results in toxicity. How to balance that is key. Identifying patients who have fully recovered with [an ECOG performance status of] 0 following surgery is important, and counseling patients around the tolerance and being proactive with dose interruptions, rather that dose reductions, is very important. However, if you do that, there is definitely a patient population out there that can benefit and tolerate these drugs in this setting.

Could you expand on the evolution of sunitinib’s role over the last few years?

Sunitinib has been in the field for over 10 years. It was approved by the FDA in 2006 based on some robust progression-free survival (PFS) data versus interferon in frontline metastatic RCC. It has been the mainstay of our treatment for metastatic RCC since then. However, in the last couple of years, we have begun to see trials reporting out comparing other agents with sunitinib, particularly in patients with intermediate- and poor-risk disease. In those settings, nivolumab (Opdivo) and ipilimumab (Yervoy) showed a statistically significant improvement in overall survival in those patients treated with immunotherapy versus sunitinib. 

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