AACR 2016

Pembrolizumab yielded durable responses in patients with advanced Merkel cell carcinoma

Dr Paul Nghiem - University of Washington, Seattle, USA

We’re very pleased to talk about the findings from this trial in which we used pembrolizumab to treat patients who had not previously received any systemic therapy for their Merkel cell carcinoma. The bottom line is there’s a very robust and nice response rate and, given that there are no approved therapies for this cancer at this point, we and the patient  community are very pleased about this progress.

Merkel cell carcinoma is an unusual cancer in that it’s typically caused by a virus and a virus, indeed, that is extremely common on our normal appearing skin. It infects children with no known problems at all on normal skin and yet five decades later it will, in about one in 3,000 people, turn into a cancer that is more likely to kill them than melanoma by several-fold.

What causes advanced Merkel cell carcinoma to become active?

The fact that most people don’t get Merkel cell carcinoma until the average age of about 69 or 70 we believe relates to immune senescence and the immune system having less diversity and strength in its capacity to recognise pathogens like this virus. So we also know, though, that multiple unusual genetic events have to happen to lead to this cancer and neither the cell nor the virus wants those events to happen so fortunately they are very rare.

What effect does pembrolizumab have?

It seems that the immune system has the tools to fight this cancer but that they are on holiday. Therefore when we give pembrolizumab to reverse some of the T-cell exhaustion we are seeing sometimes no response at all but when we do see responses, which is quite common, they’re very rapid, suggesting that the immune system was truly poised and had been shut off via this PD-L1 pathway and it’s quite readily reversible, at least in a good fraction of patients.

So the tumour is blocking the immune system?

That is what we think, that those tumours have used this pathway to inhibit the T-cells that are specific for it and when they’re unshackled they can really do their job.

What kind of response rates have you seen?

The response rate in a formal objective RECIST manner was 56% meaning that people had to have a response and that response had to be verified on a subsequent scan several months later. So it was a high rate for a solid cancer, over 50%, and the good news in particular is that of those people who had confirmed responses 86% of them are remaining in response now on average more than six months after starting. So that’s a very different number than cytotoxic chemotherapy which is a very small minority of patients and by the time you’re at 9-12 months you’re at fewer than 10% who have not progressed on chemotherapy. So we’re very encouraged by the evidence, early evidence, of durability for these responses.

What method did you use in the pembrolizumab study?

The pembrolizumab study was done absolutely by itself as first line therapy and it was not randomised to chemotherapy. So while we talked about doing that it was going to be more expensive and more difficult. So we are talking about making a comparison just based on historical controls which is fraught with problems. However, when we see only 5% of patients not progressing at one year on chemotherapy and many times higher rates, it appears to be, for this, we think that there may be some ability to make a comparison.

Is there anything that you’d like to put out [?? 4:30] awareness for any clinicians watching this about the potential or the threat of Merkel cell carcinoma because it does seem to have eluded a lot of attention due to its low incidence rate but also to attract any attention towards pembrolizumab as it seems to be the wonder drug, or this PD-L1 or PD-1 activity is getting a lot of attention across a whole range of different tumours. How would you like to put out a statement of intent to that?

What do you expect to see in the future for this kind of treatment?

Talking about the broad efficacy of pembrolizumab across a number of cancers and what this means for pembrolizumab in terms of the Merkel cell carcinoma data, I would say that this is a high response rate compared to most other cancers and the other interesting thing is it’s pretty likely that it’s actually recognising the virus in terms of the immune system. That has not really been shown up to now; in a lot of other cancers I think that studies just haven’t been done. But it does suggest that virus driven cancers, which are up to 20% or more of all cancers, are potentially targetable with this approach.

Are we likely to see vaccinations in the future?

We and others have thought about whether it would make sense to vaccinate against the Merkel cell polyomavirus but I think it’s a non-starter in terms of the public health facts there. We have a virus that’s incredibly common, typically causes no problems at all and only in one in 3,000 people five decades after they’re exposed they will get the cancer. So I don’t think we could justify a vaccination programme based on the risk of the cancer. Now, if you talk about active vaccination in patients who have developed the cancer, and we try to broaden or deepen the immune response against the virus, that may make sense.

What is your take home message?

This couldn’t have been done without a broad coalition of support from the National Cancer Institute, from Merck and from the investigators at eight individual sites because no-one really thought that the response was going to be this strong, number one, but everybody realised this is a rare cancer which has really never had a successful trial before and it wasn’t clear how easy it would be to enrol or how beneficial the results would be. So it was a risk and it was a shared risk and it happened because people came together across a number of different organisations.