This was the first combination of two immune checkpoint inhibitors, ipilimumab and nivolumab;they act in distinct places in T-cell activation and function. They’re both very active in melanoma individually and this, obviously, was the first attempt to combine the two together. It was a phase I trial, the initial results actually were presented last year at ASCO and were already published in the New England Journal of Medicine so what we were trying to do today is present updated data on safety activity and survival for those first 53 patients that were published and then report preliminary activity on another 41 patients that we treated with this combination.
What was the category of patients that you were looking at?
These were patients with advanced metastatic melanoma.
So conventionally what sort of approach would they have had therapeutically?
In today’s world there are two standard treatments. If you have a BRAF mutation you receive targeted agents, usually dabrafenib in combination with trametinib or vemurafenib and if you don’t have a mutation, or even if you have a mutation, the other alternative is ipilimumab by itself.
Now, so far, great strides forward have been made with ipilimumab, haven’t they? So what were you hoping for here?
Well, ipilimumab is a great drug, it produces an improvement in overall survival and it produces a tail on the curve approximately, we think, somewhere between 10-12% of patients might have long-term durable responses with this agent. But we were looking to improve that activity; nivolumab by itself has an objective response rate of 31% and, based on the preliminary data that actually was presented last year and again this year, the survival, at least in the initial cohort, looks very good, it’s in phase III trials now. But the intent was to make a combination that would improve the activity over both of those agents individually and, in fact, that’s what we believe we saw in this small trial. It’s only 53 patients that we were reporting on overall survival and another 41 patients in a confirmatory cohort for activity but, even given the small numbers, a phase II trial that produces a 79% two year survival rate and a 40 month median overall survival is remarkable.
So the headline figures are of a considerable improvement in survival?
In a phase IB trial of 53 patients which needs to be confirmed in a.... in a phase III trial which has already been complete.
Absolutely. Do you think there’s a case for fast-tracking this at the moment because it looks quite interesting, doesn’t it?
We should wait for the randomised data. Nivolumab by itself, anti-PD1 by itself, is a wonderful drug and we need to know for sure that the combination is better than nivolumab alone.
What are the potential, then, clinical implications coming out of this study for cancer doctors?
There are two major implications. One is if this activity is correct, and we believe it is, ipilimumab and nivolumab would probably become the standard of care for many patients with metastatic melanoma and that includes patients who have BRAF mutations. From there on what we need to do is improve the activity of this regimen, we need to find ways to make it more active and also approaches that might reduce the rate of adverse events.
Of course toxicity is an issue, isn’t it?
It’s an issue but a manageable issue. Like everything else in medicine there’s a risk/benefit ratio and in this case, although there were... the rate of grade 3 adverse events was 62%, many of those were laboratory abnormalities. We have algorithms in place that allow us to manage patients safely. We had one treatment-related death. But, nevertheless, we feel that these are manageable toxicities, that they’re reversible and that the activity justifies the rate of adverse events that we saw in this trial.
And this is in advanced melanoma, regardless of BRAF mutation status.
What does that imply?
There hasn’t been a head to head comparison of targeted therapy versus immunotherapy in patients who have BRAF mutation so there’s no question that targeted therapy, dabrafenib, for example, in combination with trametinib or vemurafenib produce remarkable results in patients who have BRAF mutations. We don’t believe that those agents produce durable unmaintained remissions, in other words patients have to continue on the drugs in order to receive the activity. It is possible that combination immunotherapy might be superior to targeted therapy and, as a practising physician and being familiar with these drugs, I’d much rather offer a patient immune therapy first and if they don’t respond to that then offer them the targeted therapy. But at the end of the day we don’t know what sequence is going to result in the best outcomes so a randomised trial is probably necessary.
How has the scene changed for doctors because there’s talk of a plateauing of survival? Is this tantamount to a cure using some of these checkpoint inhibitors?
I don’t know where that plateau is going to be. I think it’s going to be higher than where it is now. We already have an idea of where that plateau is, based on the ipilimumab alone data that was presented recently in a very large cohort of patients. But that plateau could be 30-35% which is amazing and it could even be higher. Obviously our goal is to cure everybody. I do believe that some of those patients are cured of their cancer but it’s hard for us to say that until we have follow-up after ten or fifteen years. But I do believe that a good number of these patients might never need any additional therapy.
What’s the take-home message, then, for doctors coming out of this ASCO presentation?
Look out for the approval of nivolumab which is the next improvement in treatment for patients with metastatic melanoma; when we have the results of the combination trial that may be the next therapy. They need to learn how to administer these drugs, they have unique toxicities. Nivolumab by itself is very well tolerated but the combination will have these ipilimumab-like toxicities and they’ll just need to learn to manage the toxicities.
Do you think there could be other drugs added in to this mix?
I just want to point out that this is not just melanoma, these drugs are active in other diseases, in small cell, bladder, renal cancer. So I think physicians will become very familiar with this. We’ve made all of these advances with just attacking two targets, PD1 or PD ligand 1 and CTLA-4 but there’s a huge number of other targets in the immune system that could improve the outcome here, a huge number.