As you will know, CheckMate 214 was a large phase III trial that recruited 1,096 patients with advanced clear cell renal cell carcinoma for first line therapy. Patients were randomised to receive nivolumab or ipilimumab or sunitinib. The primary analysis was focused on patients who had poor risk or intermediate risk by the IMDC criteria. The results, as you will know, were presented for the first time, the primary analysis, at ESMO 2017 and, again, at SITC in November 2017 and were published in The New England Journal of Medicine in March of 2018. Subsequently this regimen was approved by the FDA in April 2018 based on an important primary endpoint of the trial that was overall survival in patients who had either poor risk or intermediate risk by IMDC. Based on the overall survival benefit the FDA approved nivolumab and ipilimumab and subsequently, recently, it was also approved in Europe by the EMA.
So what I will be presenting on Saturday is the update of those results. The primary analysis that was the ESMO presentation and subsequent publication in The New England Journal of Medicine was a 17 month minimum follow-up and here we’re presenting the 30 month minimum follow-up. So this is an extended follow-up that basically confirmed the results that nivolumab ipilimumab produced a superior overall survival compared to sunitinib in patients with intermediate risk and poor risk RCC.
How did the follow up results compare to the preliminary results?
The median OS for nivolumab ipilimumab for patients with advanced poor risk or intermediate risk is still not reached at 30 months minimum follow-up and a 32 month median follow-up. So still the median OS for nivolumab ipilimumab is still not reached whereas it’s still 26 months with sunitinib. This is the median OS. Now, for the intent to treat, all patients regardless of the risk so that includes favourable risk as well as the intermediate and poor risk, the median OS was also superior in patients with nivolumab ipilimumab and the median OS is now 37 months with sunitinib, it’s still not reached with nivolumab ipilimumab in the intent to treat, all the patients.
Now, response rate was still in favour of nivolumab ipilimumab; overall response rate in intermediate risk or poor risk was 42% and was 29% in the updated analysis. So it’s still a significant improvement in objective response rate as well. CR rate is 11% with nivolumab ipilimumab in patients with intermediate risk or poor risk compared to 1% with sunitinib. So the updated analysis, the results confirm the initial analysis vis-à-vis OS improvement in intermediate risk or poor risk, higher objective response rate and when we look at the progression free survival, although the median of PFS was not significant compared to the PFS with sunitinib, however, if you look at the curves, the Kaplan-Meier curves, there is a plateauing, there is a shoulder, a tail end of the curve which is higher with nivolumab ipilimumab compared to sunitinib. So if you look at a snapshot median there is no significant difference but clearly as time goes by with further and further follow-up we’re seeing a plateauing for the nivolumab ipilimumab in patients with intermediate risk or poor risk compared to sunitinib vis-à-vis the progression free survival. But CR rate is 11% with nivolumab ipilimumab versus 1% with sunitinib in patients with intermediate risk and poor risk.
Interestingly now, in patients with favourable risk, which was an exploratory analysis in the primary data that was published in New England those were 249 patients, 125 of those were randomised to nivolumab ipilimumab, 124 were randomised to sunitinib. If you look at that patient initially, at that patient population, that cohort, which was an exploratory endpoint analysis, in the initial 17 month minimum follow-up the response rate was 52% with sunitinib, it was 29% with nivolumab ipilimumab. The updated analysis, as I will show on Saturday, the response rate, objective response rate, to sunitinib in favourable was 50% and was 39% with nivolumab ipilimumab. The median PFS was 25.1 months versus 13 months for the nivolumab ipilimumab; when you look at the updated it’s 19.9 versus 13.9. So really it went from the median PFS with sunitinib in favourable risk, 25 versus 15 with nivolumab ipilimumab, now it’s around 20 with sunitinib and around 14, rounding up 20 and 14, median PFS with sunitinib and nivolumab ipilimumab. CR rate, initially it is now for the favourable risk 8% CR rate with nivolumab ipilimumab versus 4%. Subgroup analysis is very small but obviously it’s important to show that of those patients who achieved a CR who had favourable risk it’s at 8% but if you look at those nine out of ten who had CR maintained those CRs, so continued complete remission. In the favourable risk treated with nivolumab ipilimumab, nine out of ten continued CRs versus only two out of five with sunitinib. So a doubling of the CR rate in favourable risk and, very importantly, although numbers are small nine of those ten patients who achieved CR with nivolumab ipilimumab are still in CR versus only two out of five.
What’s next for the study?
Obviously we want to build on this; nivolumab ipilimumab is a cornerstone for patients with intermediate risk and poor risk. I view this as the backbone for future trials to add on this so we are actually doing a trial with a triplet of nivolumab ipilimumab and another immune agent called NKTR-214 which is a CD122 agonist pegylated IL-2 that signals through the interleukin-2 pathway because in RCC and in melanoma there are three pathways that are relevant and validated in oncology and that’s the PD-1/PD-L1 pathway, CTLA4 pathway and the interleukin pathway. So a study that will be in the future after we finish this phase I where we are combining nivolumab ipilimumab and this new agent that is a novel pegylated IL-2. Moving forward we hope that the next iteration will be the triplet of nivolumab ipilimumab plus NKTR versus nivolumab ipilimumab. There are also efforts ongoing now to combine nivolumab ipilimumab plus a TKI, again to look at adding to the nivolumab ipilimumab.
The important findings of CheckMate 214 is that there is the opportunity for patients who have favourable risk, intermediate risk or poor risk to achieve a complete response that’s durable and there are patients on that study from CheckMate 214 who are now past three years and some are past four years who remain in remission. Some of them who had discontinued because of toxicity remain in complete response, have not required to receive further therapy other than the initial therapy they received with nivolumab ipilimumab.
Do you have any more information on the safety profile?
The study, the updated results with the 30 month minimum follow-up, 32 months median follow-up, of CheckMate 214 is that we did not see any new signals of concern regarding safety. Nivolumab ipilimumab overall yielded fewer grade 3/4 adverse events compared to sunitinib and the adverse events that you see with nivolumab ipilimumab are usually in the first two or three months whereas the adverse events with sunitinib are chronic and they continue for a long time. There were still only eight deaths on the nivolumab ipilimumab arm out of 547 and four deaths on the sunitinib arm. So really a 1.5% fatality rate with nivolumab ipilimumab that hasn’t changed.
So in my opinion this is an efficacious regimen, tolerable regimen that produces, so far, an unprecedented, in my opinion, CR rate that’s durable for many patients. I think we can speak of breaking the barrier of cure with this regimen. All, in my opinion, regardless of risk, whether it’s favourable, intermediate or poor risk, nivolumab ipilimumab now produces a higher CR rate than with sunitinib and now even that favourable 249 patient small cohort, there is no significant difference in response rate or PFS or survival between the two arms. I believe with longer follow-up I’m hopeful that we will see that the nivolumab ipilimumab arm will even break towards a superior outcome compared to the sunitinib arm when it comes to the OS with longer follow-up. But this is an exploratory cohort, it was not powered to really look at all those efficacy endpoints, it was just as an exploratory. A larger trial will probably have to look at favourable risk again to see if nivolumab ipilimumab will be superior to sunitinib. But, in my opinion, the CR rate is the key here with nivolumab ipilimumab producing 8% CR rate in favourable versus 4% with sunitinib and the fact that nine of ten, 90%, of those CRs achieved with nivolumab ipilimumab in favourable risk are maintained, have not relapsed, whereas three out of five have relapsed with sunitinib. So this is, at the end, what is going to drive towards cure is the CR and durability and I believe that’s achieved with nivolumab ipilimumab in all risk groups.