PROSPER RCC study of perioperative nivolumab for renal cell carcinoma - future trial

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Published: 8 Feb 2018
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Dr Lauren Harshman - Dana-Farber Cancer Institute, Boston, USA

Dr Harshman speaks with ecancer at the 2018 ASCO Genitourinary Cancers Symposium about the recently started PROSPER RCC study, a phase III randomised study comparing perioperative nivolumab vs. observation in patients with localised renal cell carcinoma undergoing nephrectomy. It promises to be an interesting study to watch over the next few years. 

Dr Naomi Haas also spoke with ecancer about the PROSPER study and adjuvant therapy for renal cell carcinoma here.

For more on immunotherapy in kidney cancer, read about the impact of atezolizumab and bevacizumab on mRCC here.

I'm the overall study Chair for the PROSPER RCC study which is a global phase III study that's asking the question of whether we add PD-1 blockade in the form of nivolumab to surgery in patients with non-metastatic RCC, whether that will improve outcomes, hopefully cure but also delaying time to recurrence and improving overall survival compared to what is now the standard therapy which is nephrectomy, either partial or radical nephrectomy. So that's the basic study design. It is targeting patients with either clear cell or non-clear cell kidney cancers, they can't have evidence of metastatic disease. They have to have at least a stage 2 tumour, so 7cm or greater in size; they can have evidence of spread to the local nodes but not distant spread of the cancer. So the reason we're doing PROSPER is it is a little bit different, we are asking people to really disrupt their practice. Right now the standard practice is to go right to surgery and then if we do any form of systemic therapy we think about doing it afterwards in the adjuvant setting.

But all of the rage lately has been in immunotherapies and namely checkpoint inhibition and one of the most studied drug and established drug in kidney cancer is nivolumab which is an antibody against PD-1. How that works is it is against target and the target being PD-L1 on the tumour itself and then PD-1 on the immune cells. So nivolumab goes in, binds to PD-1 and disrupts that interaction which turns off the T-cells. So we think that you need the target around in order for those immune cells with the PD-1 to be around and to have some army to actually stimulate. So if we give at least two doses, as we plan in PROSPER, other studies are looking at three doses of neoadjuvant nivolumab in a phase II setting, but if we give these two doses ahead of time we have the highest chance of priming the immune cells, the T-cells against the target which is the tumour itself. So we don't delay surgery too much, do two doses of the nivolumab once every two weeks, and then within a week they can go to surgery. Then the patient recovers from surgery, within 4-10 weeks we hope that they will then start on their adjuvant nivolumab. We're giving the first six doses in the adjuvant setting every two weeks and then we stretch it out to monthly for the last six doses to improve their quality of life so they're not tied to coming to the cancer centre.

So we have started enrolment, we're really ramping up. As of February 2nd we had about 399 sites across, mostly in the US, Canada is coming on board but a couple of other global sites, that are just in the process and getting started. So we aim to enrol 766 patients and they'll be randomised one to one to either the neoadjuvant adjuvant therapy or to standard of care - surgery followed by observation. With that amount of patients contributing we will have significant power to detect a difference in recurrence free survival and, if that is found, also overall survival, specifically in the clear cell subset as well as the whole population.

When do you hope to report results?

If it takes ideally two to three years to enrol and then another couple of years to have enough, what we call, events which unfortunately means recurrences, for us to have enough power to detect a significant difference between the two arms. So that is the problem with adjuvant studies - these patients can be cured and can have long times to the disease coming back, on the order of five years 50% of the time. So these trials take a long time if we use the conventional endpoints of recurrence free survival or disease free survival or even longer if we use overall survival.
With things like PROSPER where we are going to have biopsies before you get the two doses of nivolumab and then we have the nephrectomy specimen, we have really this wealth of tissue and also doing blood tests that we have a wealth of samples from the patients to be able to really investigate biomarkers. Right now we have no good biomarker in kidney cancer to help say, OK, this person really has a high chance of recurring, even more than we know by just their higher stage alone. So we hope that not only will we improve cures and outcomes with this approach but we're also going to really provide quite a platform for discovery of hopefully biomarkers that can say, you know what, this patient actually does need the nivolumab on top of surgery or this patient doesn't, they're highly cured with just surgery alone and we don't have to subject them to the toxicities of therapy.