Brian Rini, MD
Findings from the phase III PROTECT trial showed that there was a 31% decrease in the risk of recurrence in patients with locally advanced renal cell carcinoma (RCC) who were treated with pazopanib (Votrient) at 800 mg versus placebo in the adjuvant setting. However, the study did not meet its disease-free survival (DFS) endpoint.
In the trial, 1538 patients with resected, high-grade clear cell RCC were randomized to receive pazopanib or placebo for 1 year. The starting dose of 800 mg, following treatment of 403 patients, was lowered to 600 mg to improve tolerability, and the primary endpoint was changed to DFS with pazopanib at 600 mg (N = 1135).
Results showed that the primary analysis results of the 600-mg dose in the intent-to-treat population were not significant (HR, 0.862; 95% CI, 0.699-1.063; P = 0.165). The secondary endpoint of DFS in the intent-to-treat 800 mg of pazopanib group and overall population demonstrated a 31% and 20% risk reduction, respectively.
These findings add to the questions researchers currently face with adjuvant treatment for patients with kidney cancer, a topic presented by Brian Rini, MD, during the 2017 OncLive®
State of the Science Summit on Genitourinary Cancers.
Rini, professor of medicine of Cleveland Clinic, discussed additional adjuvant trials that have perplexed the field, what potential immunotherapy could have in this setting, and other obstacles to tackle in the RCC landscape.
OncLive®: What does adjuvant treatment currently look like for patients with kidney cancer?
: There haven’t been any approved adjuvant therapies in kidney cancer; it’s been a barren field for decades, ever since I have been doing this. Recently, some of the targeted therapies that are approved in advanced disease have been tested in the adjuvant setting. There have been 5 or 6 large trials.
Two of them have shown conflicting results, so it has generated a lot of discussion in the field about which 1 is right or wrong, what is going to happen, or what the difference is. Therefore, I talked about those trials and where the field stands and how, possibly, it all could turn again.
What are the details of these 2 clinical trials with conflicting results?
The first trial to be reported was called ASSURE; it was an ECOG-led trial of a year of sunitinib (Sutent), sorafenib (Nexavar), or placebo in patients with resected high-risk kidney cancer. The results were fairly, flatly negative. It did not show a difference in disease-free or overall survival (OS). There was a fair amount of toxicity issues with getting that kind of therapy in that setting. After that trial came out, which was first reported about a year and a half ago, the whole field thought, “Well, every single trial is going to be negative. Too bad.”
Then, a trial called S-TRAC came out last fall at the 2016 ESMO Congress, and that was a Pfizer-sponsored trial of sunitinib versus placebo of 1 year in a higher-risk group of patients than ASSURE, with some dosing differences. There were definitely some differences in the trial; it was the same general concept, but not identical. That trial did show a benefit in DFS that was significant, although at a cost of some toxicity to the patients, as you might imagine.
It has generated a lot of discussion on why 1 trial was positive and 1 was negative. Even with the positive one, is it really worth it to give to patients? We are really sort of in this tumultuous time in RCC, with trying to figure out what we are supposed to do. The whole field is getting turned on its head.
What are your thoughts on immunotherapy in the adjuvant setting?
The next wave is these checkpoint inhibitors. There are 4 or 5 trials that I know of, and there is 1 with atezolizumab (Tecentriq) that is actually up and running. There are others with nivolumab (Opdivo) and durvalumab (Imfinzi); any drug you can imagine will be tested in that setting.
It probably makes a lot more sense. It is going to be better tolerated for patients. It probably has the potential to extend OS, which would be ideal and we haven’t done to date—even with S-TRAC. We will have those results in many years but, if we are sitting here in 5 to 10 years, we will be talking about those drugs as standard of care.
Would there be rationale to explore combination approaches as adjuvant therapy?
That is a more complicated question. Combinations are being tested in the frontline setting in metastatic disease, which will be a standard of care. In the adjuvant setting, you are treating a lot of people who don’t have cancer; they won’t have recurrent disease. Therefore, the tolerance for toxicity for you as a provider or they as a patient is different.