Treating Advanced Renal Cell Carcinoma - Episode 3
Transcript:Robert A. Figlin, MD: One of the strengths and also one of the challenges associated with the COMPARZ trial was they used the package insert 4 and 2 schedule for sunitinib at a time when around the world, many people using retrospective data and a little bit of prospective data were starting to see that maybe a different dosing schedule might have a therapeutic effect that is not modified and may be more tolerable, the 2 and 1 schedule. What are your thoughts about that data set? How have you incorporated that into your practice? How should people think about that? And where do you think the future of the 2 and 1 schedule is for Sutent going forward?
Martin H. Voss, MD: First off, going back to COMPARZ and the 4 and 2 schedule on that trial, so one of the criticisms that’s been brought up about the trial is that some of the quality of life endpoints and the adverse event assessment were done at the four-week mark. Now, pazopanib is given on a continuous schedule. And sunitinib, as a standard administration schedule, is four week, two week, like you said. So criticism has been that it’s unfair to sunitinib to assess toxicity at the four-week mark when toxicity is at its peak before patients then get a two-week break.
Now, in my own mind, I would say the patient feels crummy. At any point on the study they feel crummy, but that’s up to anyone’s interpretation. Now, the schedule change that you’re referring to is something that had sort of evolved over the years and there’s obviously a lot of different concepts that have been tested over time with the sunitinib schedule. There was the renal EFFECT trial a long time ago which looked at giving sunitinib continuously at a lower dose. That was a randomized phase II study that looked at 37.5 mg without a break compared to the four-week, two-week 50-mg dosing, and did not show a superior outcome from an anti-cancer effect. Now, the two-week, one-week schedule is something that you are bringing up and many of us have used that in practice outside of clinical trials.
For some time now, it seems intuitive that if you give the same dose, 50 mg, on a two-week on, one-week off schedule versus a four-week on, two-week off schedule, drug exposure should be the same. Patients get still get the same amount of medication over the course of six weeks but they get their break early. And, in my mind, it makes a lot of sense because we know that these toxicities build up over time. So we have patients for whom that schedule makes perfect sense because they recover quickly from their toxicities.
They tell me after they’ve been on it for the first six cycle or two, that the first week of their break, they’re still hurting, they still have some hand-foot syndrome, they might feel tired, they may still have diarrhea, but the second week is where they feel well. And then some patients take an unwanted break. Maybe they have a complication. Maybe they take a trip then take a break. And they realize if they take their break earlier, toxicities have not built up to that point where it takes them a whole week to recover from them. And, in my mind, that’s what makes sense about the two-week, one-week schedule.
And a lot of us have tried it several times and a number of groups who have reported on it, mostly in retrospective fashion, and it’s been shown by the limited data that we have that efficacy does not seem to be compromised. Now, there are limitations, obviously, to looking at this for only a few patients and not on a randomized trial. But at least to my knowledge, there’s no report that has ever been put out that shows there’s negative impact on outcome with sunitinib if it’s given on that schedule. So patients take the drug for two weeks, they take a one-week break and then they transfer over again.
My personal experience has been that it’s easy on the majority of patients and it’s easier to tolerate the medication, and I do not get the sense that patients do not do well in terms of their cancer-specific outcome. So I have fully incorporated that in my practice. I do still give a fair amount of sunitinib. For a patient with clear-cell RCC in the frontline setting, my preferred agent, like Nizar’s, is pazopanib based on COMPARZ. But I do have patients who are treated with sunitinib.
For instance, for patients with non-clear-cell RCC, as Sandy had mentioned before, we have more data with sunitinib than with any other TKI showing that this can be a very active agent. So it is my agent of choice outside of clinical trials for untreated patients with non-clear—RCC. And I do give it on a two-week, one-week schedule then.
Robert A. Figlin, MD: So, Sandy, before we turn our attention to kind of the non-clear-cell histology group, I think one of the things our audience would like to know is, do you start 4 and 2 and then switch to 2 and 1? Do you think there’s sufficient data to start 2 and 1? How do you incorporate that in your practice and taking this retrospective data and applying it?
Sandy Srinivas, MD: I think sunitinib has been around now for almost a decade, so people have built their own comfort in managing side effects. So I agree, I mean, in practice I do 2 and 1, but there are patients especially, as part of a trial, where we have sort of had to do 4 and 2 and then ultimately switch to 2 and 1. It’s definitely easier to tolerate. Patients love it, and I think it’s really allowed patients to stay on it for a longer period of time which we now know, that the longer you stay, the higher the benefit you’re likely to get.
I just wanted to add one more comment to both Nizar’s on the COMPARZ trial. Quality-of-life data is so challenging to read to a person who is not used to this kind of data. Nizar mentioned the timing at which the assessments were done. One other thing I think when you evaluate quality-of-life data is something that was statistically significant, is it clinically significant? So all of their domains were superior for pazopanib, but there is a whole body of literature about what is meaningful. And fatigue score, people have gone on to say, they call it the MID, minimally ineffective dose or a change. And for fatigue it’s about a factor of 5. So I think if you really have to read into this carefully, true pazopanib I think is a better tolerated drug and for many patients, I start them on pazopanib. But my advice to the physicians would be stick with what you are comfortable with and if you know how to manage side effects from a drug, that’s probably the best drug that you can use.
Transcript Edited for Clarity