ASCO 2015

Initial nivolumab-based treatment halts melanoma progression

Dr Jedd Wolchok - Memorial Sloan-Kettering Cancer Center, New York, USA

CheckMate 067 we investigated two different immunotherapy medicines individually, ipilimumab or nivolumab, as well as the combination of the two. We were looking in this study at progression free and overall survival. These were untreated metastatic melanoma patients, 945 in total, blindedly randomised to one of those three treatment groups.

So a big study and there were clear differences emerging, weren’t there?

There were differences between the three groups. The study was statistically powered to compare nivolumab alone or the combination versus ipilimumab. Both nivolumab and the combination of nivolumab and ipilimumab were statistically significantly better than ipilimumab alone in terms of progression free survival as well as response rate. Now, in an exploratory analysis, just looking at the numbers descriptively, the combination had both a longer progression free survival as well as a higher response rate than nivolumab alone.

It seems from a quick look at the figures that you’re getting quite good results as long as you have nivolumab as part of the treatment, although ipilimumab is also still obviously very significant. How is this looking to you, the clinical application of all of this?

I think this regimen is very clinically applicable. The other important consideration here is safety, the combination has more side effects than either of the monotherapies. 55% of patients will have grade 3 or 4 adverse events. Importantly in this global study we saw no treatment related deaths at 137 centres worldwide which is important because it means that our treatment safety guidelines are working and that we can apply this therapy in a variety of venues.

Have you got any markers that tell you whether you’re going to do well on nivolumab rather than ipilimumab?

We don’t have a marker that tells us whether a patient will do better on nivolumab compared with ipilimumab per se but we do have a marker that we’re studying in the study which is tumour cell expression of PDL1, one of the ligands for PD1. We actually prospectively stratified the three treatment groups for PDL1 expression at a 5% level. What we saw is that in the primary endpoint of progression free survival if a patient’s tumour had at least 5% expression of PDL1 then they actually had the same progression free survival with nivolumab or the combination, 14 months, compared to about 3 months for the ipilimumab. Now, if the patient’s tumour had less than 5% expression of PDL1 they actually had a significant increase in the progression free survival when they expressed the biomarker at this lower level. So this really provides an opportunity for us to use the biomarker in discussions with patients about what is the correct treatment option for them, balancing risk and benefit.

So how do you see this panning out in the near future about which patients should get which drugs and which drugs are likely to be the more popular in the future?

I think that the PD1 blocking drugs, because of their better efficacy and safety profile, are going to be considered a potential first choice for patients with metastatic melanoma. Now, whether to offer patients the combination or a PD1 blocking medicine alone is still uncertain. We have the availability to offer the combination as part of an expanded access programme that is not yet available everywhere. Of course we await regulatory discussions about the availability of the combination. If a patient is interested in simply the likelihood of response, the response rate, then for the combination, regardless of what the PDL1 expression status is, the combination yields the highest response rate.

What should busy cancer doctors be thinking about these data right now, do you think?

I think busy cancer doctors need to first of all recognise that there are expanding treatment options for this previously difficult to treat cancer, that they can actually now have several different options in terms of standard therapies but that we believe that this combination is a very, very important consideration if it becomes available commercially.

And what does this imply, briefly, for the future of advanced melanoma?

I think this implies that we have a therapy that in an unselected group of patients provides 11 months of progression free survival which is a very significant accomplishment, as pointed out by Dr Atkins yesterday. Because this was a disease that had an overall survival of 7 months not just five years ago, so we have introduced a significant amount of hope into discussions with our patients because of the availability of treatments like this. That is something that most oncologists should be aware of.

Is there a hint of extended survival plateauing?

For each of the monotherapies we know that there is a population of patients that has durable survival. So for ipilimumab there’s about 20% of patients that live three years or longer; for nivolumab we don’t have this and for pembrolizumab, the other PD1 blocking medicine, we don’t have as many patients out that long, they’re simply newer drugs, but it does appear to be a plateau around 30-40%. For the combination the best data we have long term is from the phase I study where we actually had 88% alive at two years, that’s a smaller group of patients. We will not have the overall survival data for this for quite a while.

So a quick take home for doctors coming out of this is what?

The quick take is that the combination seems to yield the highest likelihood of clinical benefit. It does have more side effects than either nivolumab or ipilimumab. Nivolumab has better efficacy and a better safety profile compared with ipilimumab and that we await the safety results.