We had the honour at the ASCO 2021 plenary session to present the first results from KEYNOTE-564. This was an adjuvant study of immunotherapy with the immune checkpoint inhibitor pembrolizumab versus placebo in patients with risk of recurrence after a curative intent nephrectomy. The study is based on the fact that immune checkpoint inhibitors do have activity and are standard in metastatic disease so we were trying to take that concept to the earlier stage disease to see if recurrences could be prevented or delayed.
What was the methodology of this study?
Overall we enrolled over 900, closer actually to 1,000, patients with intermediate-high, high or M1 NED clear cell RCC or sarcomatoid histology. They were randomised 1-to-1 to receive pembrolizumab or placebo for the duration of one year. The primary endpoint of the study was disease free survival by investigator assessment; safety and overall survival were secondary endpoints. The analysis for the primary endpoint was overall event driven and at that time we had enough events to look at the primary endpoint. Overall survival remained immature with less than 30% overall of events that happened.
What were your findings?
Key findings were the fact that the study met its primary endpoint in reducing overall the risk of recurrence or death by 32%. The hazard ratio was 0.68. When we look at different risks and at different categories and when we look at several subgroups the benefit was in all subgroups with the hazard ratio being less than 1.0. We looked also at safety and overall survival. As I said, with overall survival there were a few events overall but nevertheless the overall survival hazard ratio was quite promising. It didn’t meet statistical significance but hopefully we’re going in the right direction which is quite encouraging.
The safety results also were presented and overall, despite the toxicities, the low grade and the high grade toxicities were higher in the pembrolizumab arm, there were no new signals of toxicities with pembrolizumab. So overall we concluded that pembrolizumab delays progression and recurrence of disease and could be soon becoming standard of care in high risk renal cell cancer.
How can these results impact the future treatment of renal cell carcinoma?
This is an important question because we struggled with adjuvant therapy for a long time. The first adjuvant trials were even in the ‘70s and used radiation, chemotherapies, vaccines, cytokine, all were negative. Even in the targeted therapy era with VEGF targeted agents the results were largely inconclusive. There is one FDA approved drug, sunitinib, from an S-TRAC trial where disease free survival was met but actually there was no overall survival and quality of life was inferior during the one year of therapy. When using this drug, sunitinib, or other VEGF targeted agents, in other trials there was no disease free survival advantage. So while the drug is approved by the FDA it’s not approved by the EMA and it’s use in current practice is quite limited. So this remains an unmet need and hopefully with pembrolizumab this unmet need is filled, at least in part.
Is there anything you would like to add?
The study will continue to look at events for overall survival. This will be also an important key secondary endpoint. Quality of life – hopefully we’re going to see in the next couple of meetings quality of life data which was collected. Of course the maturity of the data is important. This is a large study over, as I said, almost a thousand patients so we need to see how the results mature because the primary data cut is with a median follow-up of 24 months.
