This was a randomised trial in over 900 patients in patients who had resected high risk melanoma, that is they had their tumour surgically removed, they had stage 3b, 3c or 4 melanoma which means locally advanced or metastatic melanoma, surgically removed, rendered free of disease but over five years they were all at at least a 50% risk of return of the tumour or relapse and over ten years at least a 50% risk of death. So that’s our definition of a high risk patient. These folks were randomly allocated one to one to receive either nivolumab, which is a PD-1 blocking antibody that has activity in metastatic melanoma and is approved around the world for that indication, or ipilimumab, which is a different type of checkpoint inhibitory antibody that blocks something called CTLA-4. That is approved in the US as adjuvant therapy and also for metastatic disease and has been approved for at least six years for metastatic disease and was approved almost two years ago in the US, but not in the EU or Canada or any other countries, as adjuvant therapy. So this was a one to one, head to head, randomised trial of nivolumab versus the standard ipilimumab.
The results of that study were that there was a clinically and very statistically significant benefit for the nivolumab group compared to the ipilimumab group. Relapse free survival was the primary endpoint and the study was stopped early at an interim analysis, which is always a good sign. So it had a planned interim analysis and it was stopped because the data safety monitoring committee reported the results and felt that it was inappropriate to continue. So the study was unblinded and clear benefit for the nivolumab group with a hazard ratio of 0.65, meaning a 35% reduction in the risk of relapse over time and a significant decrease in the risk of distant metastasis free survival which was not a primary endpoint it was a post-hoc analysis. And nivolumab was considerably less toxic than ipilimumab; the rate of grade 3/4 significant immune adverse events was only 9% in the nivolumab group and more than 40% in the group that got ipilimumab. If you look at the most important parameter to me, as the practitioner, which is how often did you have to stop because of toxicity in either group it was less than 5% in nivolumab and it was more than 30% with ipilimumab which is consistent with the experience of people in metastatic disease, suggesting that nivolumab was a much better tolerated drug.
So you can’t lose – nivolumab is a much more effective drug than in active control of ipilimumab and it’s less toxic. So we hope that it will get registered eventually in the United States, I assume that’s in progress, and I suspect eventually it will get registered around the world and it will become the standard adjuvant therapy for high risk resected melanoma.
Could this be taken as evidence for PD-1 targeted therapies offering more clinical utility than CTLA-4?
The death of CTLA-4 is premature or reports of its death are not accurate. There recently was reported a combination trial of ipi/nivo in renal cell cancer that’s quite positive. We’ll be hearing some of those data today. There is no question that in melanoma the survival of patients who get ipilimumab with nivolumab at year 2 and year 3, compared to nivolumab alone, seems to be higher especially in the PD-L1 negative group. In, for example, patients who get adjuvant nivolumab therapy in the future, what will you do if they relapse while on treatment or within six months of being treated with their adjuvant nivolumab? You’re probably going to want to give them adjuvant ipilimumab. And because of the results we heard at ASCO it looks like 3mg/kg of ipilimumab with respect to relapse free survival benefit looks as good as 10mg/kg. 3mg is less toxic, that’s more palatable for patients. So the reports of ipilimumab’s demise are premature and it goes the other way. Since everybody from now on who has stage 3 or 4 resected melanoma will be nivolumab experienced it will change the biology of the relapsing patients and many of them may not benefit from just more nivolumab in metastatic disease. I think it will open up new opportunities for the use of ipilimumab. Ipi plus nivo will have activity in lung cancer, now it’s got activity in kidney cancer, we know it has durable benefit in melanoma so if we can attenuate the toxicity somewhat by changing the dosing schedule there will be a significant place for ipilimumab in the cancer armamentarium going forward.
Would you describe yourself as an optimist in the case of ipilimumab?
It depends on your point of view. In the clinical oncology field you can be a glass half empty person or a glass half full person. I may be a cynic by reputation and by nature and a sceptic because I was raised and educated as a scientist but I would agree that ipilimumab can have benefit certainly in melanoma as a single agent and in combination with PD-1 blockade. Let’s say some of the new pembrolizumab epacadostat or pembrolizumab TVEC trials are positive and let’s say people aren’t using ipi plus nivo anymore, what do you do when you fail pembro epacadostat? Then you’re going to want to move quickly to an ipilimumab combination. So again it opens up new possibilities of changing the dosing schedule of ipi and adding another drug which may boost its activity or it may encourage the development of drugs that target ipilimumab to the tumour microenvironment or allow it to only act in the tumour microenvironment which would make it less toxic.
So there might be activity in priming the immune system?
There are, and I should give due disclosure - I work with a company that makes a masked CTLA-4 antibody, but that antibody has promise. There are other antibodies that people are trying to target to the tumour. I think that they would have considerable benefit if they’re developed properly.