Brian Rini, MD, discusses additional adjuvant trials that have perplexed the field, what potential immunotherapy could have in this setting, and other obstacles to tackle in the renal cell carcinoma landscape.
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.
OncLive®: What does adjuvant treatment currently look like for patients with kidney cancer?
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.Rini: 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.
What are the details of these 2 clinical trials with conflicting results?
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. 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.
What are your thoughts on immunotherapy in the adjuvant setting?
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. 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.
Would there be rationale to explore combination approaches as adjuvant therapy?
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. 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.
How do you find that patients handle additional treatment after surgery?
Combinations make sense to me in the metastatic setting. I am not sure that they make sense in the adjuvant setting. Will somebody do it? Probably. That is kind of what we do. However, immunotherapy monotherapy makes more sense. If somebody has metastatic disease, they have no choice; they have to get treated. The other option is progressive cancer and death. They are willing to put up with a lot more side effects, at least, with initial therapy. If you have your tumor resected, you’re motivated at first because it is high risk and then, 3 months later, you’re less motivated and, 6 months later, you have kind of forgotten about it and you have a couple scans that are normal. You are feeling a little better about your odds and patient motivation goes down. That is 1 issue.
Taking a look at the overall field of kidney cancer, what would you like to see tackled in the near future?
You were the chair of this State of the Science SummitTM. What is the value in holding this type of event?
The other is physiologic. The drugs are just tolerated differently with the tumor in place or not. It is something we don’t understand. It is sort of a mental component and a physical component. We still don’t have reliable curative therapy for patients. We can control disease; we have 11 FDA-approved drugs and we are starting with combinations. That is all exciting. When a patient walks into my office, I can’t say, “I am going to give you these drugs and get rid of this problem” like we can with germ cell tumors and lymphoma. Until we get there reliably, we have a long way to go. These smaller events are nice. The ASCO meetings are kind of crazy and other events can get sort of overwhelming. Therefore, it is nice to get a little more in-depth looking at data sometimes than you can do in a big forum like ASCO. Here, you get to interact with faculty, which we hope has value to sort of pick our brains.
Frankly, when I do these things, it is nice for me to see how community physicians approach how they choose drugs and how they think about patients. I think about it differently because I am thinking about trials. Patients who make their way to see me are generally of a better fitness level by the time they get here. Therefore, it is really complementary in terms of taking care of patients.