I was asked to comment on what do we know about adjuvant therapy in renal cell carcinoma and what is being tested? So I have divided my conversation into two parts, one is a review of what we know about adjuvant therapy regarding the three clinical trials that have recently presented, that includes the ASSURE trial and the ProtecT trial which I was one of the study Chairs or was involved in the design, and the third is the S-TRAC trial. These study the use of adjuvant pazopanib or adjuvant Sutent or adjuvant sorafenib with regard to placebo in patients with high risk kidney cancer.
So what I'd like to say about those three trials is that you have three very large datasets that have somewhat different results. The ASSURE trial included patients who had both non-clear cell and clear cell histology although the study was powered towards clear cell histology. It randomised patients to one year of adjuvant sorafenib or sunitinib or placebo and disease free survival was the primary endpoint. That study was the first to report and did not show a benefit in either disease free or overall survival. The S-TRAC trial, however, which was an industry trial, a smaller trial, was limited to a slightly higher risk population of patients with clear cell histology only and treated patients with either Sutent or sunitinib for a year or placebo for a year. That trial did show an improvement in disease free survival although not overall survival by their primary endpoint which was a central radiology review. The ProtecT trial used one year of adjuvant pazopanib versus one year of placebo and that trial, and ASSURE also, made some dose adjustment during the trial in which patients, because of a high degree of dropout, were allowed to start at a slightly lower dose and dose escalate. So the ProtecT trial also did not show an improvement in disease free survival or overall survival.
So we wonder why one study is positive and the other two did not show a benefit. So in going back and analysing these populations to see can we dissect a difference, we went back in ASSURE and looked at the same patient population, presumably, that was enrolled in S-TRAC and limited by clear cell histology and also by the higher stage and we still didn't see a difference. We did a dose analysis, this was post-hoc, and there was really no difference, at least in the acceptable dosing quartiles as far as outcomes. So that also in our trial did not explain why our trial results were different from S-TRAC.
ProtecT had some very interesting data in that they measured patient pharmacokinetic pazopanib levels and in a separate publication which will be in Clinical Cancer Research this study showed that patients who were able to achieve a higher clearance early on, a higher dose of pazopanib in their AUC, that there was an improvement in disease free survival. However, interestingly, when you look at the patients, these were primarily patients who were receiving 600mg dosing which is the majority of patients and they started at the lower dose range and there was quite a variability in patients achieving that high AUC who all started at the same dose. So that really implies that a lot of the benefit might have to do with something regarding the metabolism of the pazopanib and to try to figure out then which patients might benefit from these higher doses. Unfortunately AUC PKs were not measured in S-TRAC. We do have some PK analysis in ASSURE but that analysis is ongoing. So that's one unanswered question.
There were three important trials that are about to report, one of them is the axitinib trial which is axitinib given up to three years versus placebo. So the range of patients is anywhere from one to three years. There's a large Asian population of patients enrolled in this trial so that will give us some very interesting results about the duration of therapy as well as different patient populations. The SOURCE trial is another trial that looks at duration of therapy and that's either one year or three years of sorafenib versus placebo in patients. That one has the same enrolment as ASSURE, both clear cell and non-clear cell, and encompasses those stages.
So I think it's very important to see what those show and then there was also a metastasectomy trial that has completed which is patients with clear cell who have had metastasectomy and get one year of adjuvant pazopanib versus placebo. That will also give us some important information about people that have early metastatic disease.
The second part of my talk is basically highlighting three of the immune checkpoint inhibitor trials which are now open and enrolling. The first of those is the PROSPER trial which is answering a very important question about whether having the kidney tumour present at the time that you start immune checkpoint inhibition is important in T-cell priming. So patients that are enrolled in that trial can have any histology of RCC, they have to have a biopsy ahead of time, and half of them will get two doses of nivolumab prior to resection of their primary and then an additional nine months of adjuvant nivolumab. The other group, and this was very much supported by the patient advocates, have standard therapy, so they have a needle biopsy but then they go on to have resection of their primary and then they go with the usual surveillance.
The other two trials are industry trials, they are both purely adjuvant and they are powered or enrol only clear cell histology or clear cell with sarcomatoid features. They also will allow patients who have metastasectomy to enrol, primarily synchronous metastasectomies, so metastasectomy done at the time of their initial surgery. Those are looking at either adjuvant atezolizumab or adjuvant pembrolizumab. Then there's a fourth trial which is planned which is ipilimumab and nivolumab in the adjuvant setting for patients with clear cell histology. That one is, I believe, going to be enrolling later this year.
So the main thing that I guess I'd like to convey about what I think or where we think we are with adjuvant therapy now is that there is one drug now that has been recently FDA approved for the use in adjuvant therapy, that's Sutent, and that was based solely on the S-TRAC data. There was about a 60% toxicity experienced in all three of the reporting trials that was grade 3 or higher so these drugs do cause a lot of side effects in patients.
So if you see a patient who either presents with a large kidney tumour or is considered post-op to have adverse features for risk of recurrence you can certainly discuss that sunitinib is an option. Its NCCN rating is level 2b so it's not the highest level of evidence but it's important to choose the patient population as far as if a patient is a very good study candidate I would really encourage them to enrol in the immune checkpoint inhibitor trials because there's a lot we don't know about really who benefits from adjuvant therapy and who doesn't. The immune checkpoint inhibitors are exciting because in addition in the advanced disease we see patients who have very durable responses and sometimes complete responses and you don't usually see those with VEGF tyrosine kinase inhibitors. So it's really important to basically tease out who are the patients who did respond to sunitinib therapy, wait for these other very important trials that use drugs that might also be a little bit better tolerated, like axitinib and possibly sorafenib and really see are those trials positive, are they negative. If they're negative do we want to just look at this one trial in a sea of other trials that were negative? If they're positive then perhaps there's more evidence that we should be considering using these as a comparator arm. But I will mention that the immune checkpoint inhibitors do not include Sutent as a comparator arm even with this new approval.