Good morning. It’s my pleasure on behalf of my co-investigators to present these data. Very briefly, this was a large, randomised phase III trial in patients with resected stage 3b, 3c and 4 melanoma who we would consider to be at very high risk of relapse, which means people who have at least a 50% risk of relapse at five years and generally at least a 50% risk of death at ten years. This was a straight 1:1 randomisation; originally it was planned to have at least 800 patients, at the end of the day we randomised a little over 900 patients. They were randomised 1:1 to receive either ipilimumab which in the US at that time is and was a standard therapy, although not approved in the EU or elsewhere, given for one year at a standard dose of 10mg/kg every three weeks four times, followed by maintenance ipilimumab every twelve weeks, that’s the FDA approved regimen, versus nivolumab, which was the experimental arm, which was given at 3mg/kg every other week with appropriate placebo-matched controls so it was a double-blinded study. Duration for one year and then patients would be followed up for four years and the pre-planned stratifications were by stage, so 3 versus 4, and by PD-L1 staining.
The primary endpoint to the trial was relapse free survival. This study was stopped at a planned interim analysis, which is always a good thing. When you have a study that’s stopped usually that means the results are quite positive. Indeed, as you see here, the results were quite positive. There was a clear, clinically significant and statistically significant benefit for the nivolumab arm compared to the ipilimumab arm. The p-value was very favourable at 0.0001 and the hazard ratio was 0.65 which, as you all know, means there was a 35% reduction in the risk of relapse over time. Again, the follow-up for all patients was a minimum of 18 months. It was a relatively brief follow-up but, again, this was a study that was stopped early at an interim analysis.
If we look at the toxicity, again highly favourable in favour of the nivolumab arm compared to the ipilimumab arm. We’re looking at, in terms of all treatment related adverse events, 14% versus more than 40%. In terms of patients who had to stop because of adverse events, which to me, as a clinician, is really the most important practical issue when administering an adjuvant therapy, it was 5% or so for the nivolumab arm and it was more than 30% for the arm that received ipilimumab. So by any indication clearly there was superiority for nivolumab compared to the active ipilimumab arm and ipilimumab, of course, is an active regimen which prolongs both relapse free and overall survival compared to placebo in a prior EORTC study.
So when we think about the conclusions nivolumab clearly showed a very clinically and statistically significant improvement in relapse free survival versus high dose ipilimumab for patients with surgically resected stages 3b, 3c and 4 melanoma. I told you the hazard ratio was 0.65, the p-value was a very robust 0.0001. If you look at the 18 month relapse free survival rates we’re talking about 66% for nivolumab versus 53% for ipilimumab, a 13% difference. Interestingly, over time that difference opens up, at one year it was about 10% and then as we got to 18 months it was 13% so it was opening up that curve. The benefit for nivolumab was observed for virtually all of the pre-specified subgroups whether you look at stage, PD-L1 staining, BRAF mutational status, age, ulceration of the primary etc. Again, nivolumab had a superior safety profile in comparison to ipilimumab. There were fewer grade 3/4 adverse events and there were fewer adverse events of any kind that led to treatment discontinuation. In my opinion, nivolumab provides a very acceptable benefit-risk ratio as adjuvant therapy for high risk resected melanoma and has the potential to be an effective treatment option for patients with resected stage 3 and 4 disease, of which in the US we have quite a few, there are least twenty or so thousand that fit that category.
Again, our feeling is that if high risk patients receive nivolumab after resection those patients may have significant benefit and, interestingly, it may change the biology of melanoma because if most patients who ultimately relapse or who have high risk disease receive a PD-1 antibody, a number of interesting questions arise about have we impacted the biology of the disease. Then, of course, questions arise, many interesting questions, about how do you treat those patients once they relapse. Again, there will be longer follow-up needed to determine if there is an overall survival benefit although this will be complicated by the fact that there will be a de facto crossover because in all of the countries in which we did this study both ipilimumab and nivolumab were approved for metastatic therapy. So if someone who got the ipilimumab arm relapsed they would be able to receive nivolumab; if someone who got nivolumab relapsed they could get ipilimumab. So there would of course be this inherent or de facto crossover which will complicate survival. The other thing is, as you may know, the AGCC staging system changes and practice sometimes changes so that may complicate interpretation. But it’s very clear that we have a very nice and beneficial regimen in the nivolumab adjuvant therapy. Thank you.