ASCO 2015

Nivolumab alone superior to ipilimumab alone in advanced melanoma

Dr Pier Francesco Ferrucci - European Institute of Oncology, Milan, Italy

Advanced melanoma is a big deal right here at ASCO and people are talking about checkpoint inhibition, various drugs, ipilimumab, of course, led the way. What were you doing in this new study?

I would say that melanoma and immunotherapy are a great deal in the past few years. For this study we just enrolled patients affected by advanced or metastatic melanoma and these patients were treated in a three arm trial with nivolumab or with the combination, with nivolumab and ipilimumab and compared versus the ipilimumab alone.

Of course ipilimumab is a CTLA-4 blocker, nivolumab a PD1 blocker, what’s the difference between the two drugs?

The two drugs just work on T-cells so the focus of the treatment is moved through the immunotherapy, through the immune system, and not to the tumour cells. So they just work making the T-cells be more active and reverse the block that usually happens, allowing the tumour to escape.

Why was it interesting to go for PD1 with nivolumab as compared with ipilimumab?

It’s very interesting because it allows us synergy between the two drugs. They help in different checkpoints and they are able to block this inhibition in the periphery and down at the tumour.

So theoretically with a combination of these two different agents you could have done even better. You’ve got a three arm study, can you describe that study to me?

Yes, the study was focussed on the combination because it was obviously possible to enhance efficacy. The patients who received both the drugs were compared with those who received just nivolumab and to those who received ipilimumab which could be considered the standard of care now.

And the results were quite interesting, weren’t they?

The results were very interesting. I have to say that we just presented the PFS data; we are still waiting for the overall survival one. This overall survival will be available in the next months, I would say the next twenty months.

And you had about a thousand patients or more, nearly a thousand patients, and there were quite big differences in progression free survival. Could you describe those differences to me?

Yes, the differences were mainly based on the results of the efficacy. I would say that with the combination there is almost 60% of responders while with the nivolumab arm, and nivolumab alone, they go down around to 43% and with ipilimumab they are just 19%, as previously reported. Then the medium PFS, progression free survival, is around 12 months for the combination versus around 9 and 6 months for the ipilimumab. This means that we need something to describe better the patients we are treating. One of the points is finding new biomarkers that will help to choose better the patients.

And you’ve got a new biomarker, haven’t you? One you’ve been trying out.

At least we are hoping that this PDL1 could serve as a biomarker. There’s still some work to do because the data are not completely interpreted and we have still the need for more information. Anyway, when the PDL1 is expressed on the tumour cells then the advantage for the combination is much higher, both from an overall response rate and for the progression free survival. When instead the PDL1 is not expressed, or at least is expressed less than 5%, then the difference is very reduced and both the combination and the nivolumab work similarly.

Now, you’ve got noticeable differences in progression free survival but what about additional toxicity, either from using nivolumab instead of ipilimumab or from using the combination?

Yes, nivolumab appears to be the best drug, let’s say, for what depends on toxicity. Instead, the combination of nivolumab and ipilimumab is much more toxic. We have 55% of patients who develop grade 3/4 toxicity and we have to say that the toxicity is the same we are used to managing for previous immunotherapy. So it’s the same that we are managing in other trials, nothing new in specific, but there are differences in the presentation of patients that develop them.

It seems that you have demonstrated what you refer to as a complementary activity of the two agents but it sounds to me as if nivolumab on its own is floating to the top. Have I got the right idea?

Nivolumab could be the right agent in selected patients, at least those who express the PDL1 molecule. In this case we can be able to discriminate and to offer the combination only in those cases in which we need a more rapid effect. In fact, one of the interesting data of the trial is that we have an enormous reduction on tumour burden when we use the combination in respect to the other. This means that we can have a more rapid action and sometimes this is really needed.

So there’s some way for the art of treating melanoma to go with these combinations but, from what we now know from your presentation here in ASCO, what are the clinical implications for the treatment of advanced melanoma?

There is still much work to do. Anyway, we think that this kind of combination could be able to make the level up of the responders and hopefully to maintain also this response over time. In fact, we demonstrated also that the response is maintained even after the interruption of the treatment. So I think that we have to work on the doses, on the lasting of the treatment, because we can even think to stop and maybe do a maintenance with lower doses.

And if you were to sum up in a few words what doctors should remember from this, what is that?

We learned a lot because we learned how to manage new drugs, we learned how to combine them and we learned how to manage toxicity.

And as far as PD1 targeting is concerned, what’s the take home message?

I think that PD1 is one of the most important targeting molecules and in this ASCO meeting we have wonderful information and data also now on other tumours, not only on melanoma. So this means that targeting the immune system would help not only melanoma but in controlling the whole disease.