I’m really happy to show you this slide because this is the disclaimer because about ten days ago we were pleasantly surprised that the FDA has, in fact, approved avelumab, or the trade name of Bavencio, for the treatment of metastatic Merkel cell carcinoma. So I’ll show you some of the data that they were excited about. These are some of my disclosures and I have served on advisory boards for EMD Serono who is the study sponsor.

So if you don’t know about Merkel cell carcinoma it’s a fairly rare but very aggressive form of skin cancer and has been associated with very poor survival, particularly in patients with metastatic disease. The risk factors for Merkel cell carcinoma include advanced stage exposure to ultraviolet radiation and immune suppression. This is a unique tumour in that it is associated with a virus that’s been called the Merkel cell polyomavirus and somewhere between 50-80% of patients will have detectable virus. Merkel cell is fairly sensitive to chemotherapy and radiation, however long-term survival really beyond six months has not been reported with chemotherapy and until recently there were really no approved agents for this disease.
Avelumab is a humanised anti-PD-L1 antibody and so the rationale for using this in Merkel cell carcinoma really began with a collaboration with Isaac Brownell and James Gulley at the National Cancer Institute and Paul Nghiem at the University of Washington. In our lab, and later confirmed, actually, by the Johns Hopkins group that many Brownell and James Gulley at the National Cancer Institute and Paul Nghiem at the University of Washington. In our lab, and later confirmed, actually, by the Johns Hopkins group that many Merkel cell carcinomas were associated with the expression of PD-L1 either on the tumour cell or other cells within the tumour microenvironment. The presence of PD-L1 is important in cancer because it binds to the PD-1 on the T-cells and will then cause deletion of those T-cells or at least the energy of those T-cells and really prevent clearance of the tumour. So T-cells and will then cause deletion of those T-cells or at least the energy of those T-cells and really prevent clearance of the tumour. So avelumab is a monoclonal that binds to the PD-L1 and really interferes with this interaction, allowing the T-cells to stay active and, we believe, mediate anti-tumour activity.T-cells to stay active and, we believe, mediate anti-tumour activity.

The PD-L1 antibody does not interact with the PD-L2/PD-1 interaction; the antibody has a half-life of about four days and we give this at a dose of 10mg/kg. It’s an IV infusion, we do it every two weeks. Because it’s an IgG1 isotype we also think that there is evidence, at least in vitro, that the antibody can induce ADCC, antibody directed cytotoxicity activity, and that may also contribute to the anti-tumour effects. The drug is actually being studied in a large number of different cancers and now that it has been approved in PD-L2/PD-1 interaction; the antibody has a half-life of about four days and we give this at a dose of 10mg/kg. It’s an IV infusion, we do it every two weeks. Because it’s an IgG1 isotype we also think that there is evidence, at least in vitro, that the antibody can induce ADCC, antibody directed cytotoxicity activity, and that may also contribute to the anti-tumour effects. The drug is actually being studied in a large number of different cancers and now that it has been approved in Merkel cell it’s really the first drug to ever be approved for the treatment of this disease.
The confirmation of this actually comes from the JAVELIN Merkel 200 study. This was a phase II prospective open label study and 88 patients were enrolled in this study which actually makes it the largest Merkel cell carcinoma study ever done. There are probably around 2,000-2,500 cases of Merkel cell each year in the United States and the incidence is increasing. The eligibility for entering into the study were patients had to have histologically confirmed metastatic Merkel cell carcinoma and they had to have failed at least one prior round of approved chemotherapy. Patients also had to be immune competent. We looked at PD-L1 expression as part of the study but we did not require PD-L1 expression for entry into the trial and patients had to have relatively good performance status. Again, the treatment, as I mentioned, was the 10mg/kg dose IV every two weeks and they continued until they either had a confirmed progressive disease or unacceptable toxicity.10mg/kg dose IV every two weeks and they continued until they either had a confirmed progressive disease or unacceptable toxicity.

The primary endpoint of the study was the best objective response and this was determined by RECIST 1.1 criteria and was independently reviewed by a committee. We also looked at secondary endpoints, at response duration, progression free and overall survival and, of course, safety and tolerability.
We initially reported our results in The Lancet Oncology at the six month time point and the purpose of our presentation at AACR this year was to really report this now with longer term one year follow-up data.
So these are the characteristics of the 88 patients treated. You can see 25% of the patients were under 65, the vast majority of patients were over the age of 65, consistent with the clinical course of Merkel cell carcinoma. 74% of the patients were men, most had good ECOG performance status. Not surprisingly, 76% of the patients presented with a primary cutaneous Merkel cell carcinoma but some patients their initial presentation was in the lymph node or other sites. Although 59% of the patients had one prior therapy it’s important to note that 35% of this population had actually failed two or more lines of prior therapy so this is a fairly advanced group. 53% of the patients had evidence of visceral metastases at the study entry and 21% had only lymph node disease at the time they entered.

We also looked at the tumour burden to see if that might be an independent predictor of response, so that data is shown there. We basically measured the sum of the longest diameters of all the index lesions and took the median. Those that were above we considered to have a high tumour burden and those below that were a low tumour burden. Then, as you can see, we looked at the PD-L1 expression and 65% of the patients were PD-L1 positive and then 52% of the patients tested positive for the Merkel cell polyomavirus.

The median follow-up that we have now is 16.4 months with a range of 12 to 25.4. At this point 19 of the 88 patients are still undergoing treatment actively and you can see the disposition of the other patients. So about 50% of the patients had disease progression, 8% discontinued treatment for an adverse event and there were a number of deaths, largely attributed to disease progression. 16 of the patients are off treatment but are still actively being followed with a response and then you can see of those who did discontinue the study about half the patients have now died and a few others have been lost to follow-up or withdrew consent.

Here are the clinical responses, so I just wanted to point out this is actually showing the data at six months and this is now showing the updated data with one year follow-up. Essentially what’s happened is we’ve had a slight increase in our objective response rate as two additional patients went into complete response. So in our initial report we had a 31.8% response rate, that’s now 33% and so our CR rate went up by two patients; our PR rate is relatively stable. I would also point out that about 10% of the patients had stable disease. In terms of the median duration of response this has not been reached yet for this population. The other important point is that while 92% of the patients were in response of six months or more, 74% of this population who responded remained in response at one year after treatment.

This is the swimmers plot, I just want to point out a few things here. The triangles are partial responses and the squares are complete responses. The median time to response was six weeks so the responses here occurred very rapidly. Despite that there were two patients here that went into complete response a little bit later. The arrows show patients in continued response.

These are three contemporary studies looking at progression free survival at one year. These are largely chemotherapy based studies and you can see that there’s essentially no long-term responders at twelve months. This is now our updated progression free survival where 30% of the population has progression free survival at one year, again looking at the tail of the curve which we like to see with immunotherapies. This is our overall survival data, just to show it to you, and our one year overall survival is now at 52% which is quite remarkable for this disease. Looking at the forest plot for objective response in selected subgroups we didn’t really see any statistically significant difference among the subgroups but there are some trends here that are worth pointing out. So patients who had only one prior therapy actually did a little bit better – you can see a 40% response rate versus 22% if they had two or more lines of therapy. We do have a study now looking at avelumab in first line Merkel cell. Also disease burden did seem to make a difference so the lower disease burden seemed to do better and PD-L1 expression, those patients who were positive actually did do a little bit better. Interestingly, the presence of the Merkel cell polyomavirus did not have any impact on responses.

Again, 74% of the patients are in response at one year and looking at the progression free survival across the various endpoints there didn’t seem to be any things that stood out to us so it seems that patients with PD-L1 positive or negative, polyomavirus positive or negative or other disease characteristics were all likely to respond. This is just the PD-L1 expression and virus data.

The last thing is just the adverse events. This is a drug that has been fairly well tolerated; the most common side effect we saw was fatigue and infusion related reactions. This is just a listing of some of the non-immune mediated adverse events that were seen throughout the study. You can see a lot of these are fairly common or constitutional type symptoms. There were immune mediated adverse events that occurred, those are listed here except for the infusion related reactions which seemed to be blunted with premedication. Most of these were relatively of low grade and there were only three grade 3 or greater events and many of these were isolated lab increases.

So, just to conclude, avelumab monotherapy showed durable anti-tumour activity and a fairly good safety profile in patients with metastatic Merkel cell carcinoma in the second line setting. Our confirmed objective response rate with one year of follow-up is 33% and the proportion of patients in response at one year is 74%. We have maturing progression free and overall survival data that does suggest that we’re going to see long-term benefit similar to other diseases where T-cell checkpoint inhibitors have been used. Avelumab is now approved by the FDA as a therapeutic option for these patients and actually the approval includes patients in both second line and first line and for patients who are twelve years of age or older. Avelumab is currently being tested now in a number of other different types of cancer. Thank you.
Thank you. So you have now heard about the very first drug of any kind approved by the FDA for the treatment of advanced Merkel cell cancer. Merkel cell cancer is an orphan disease meaning that it’s very uncommon in the United States and for that reason sometimes pharma development is slow in orphan diseases. In this case it made sense to look at checkpoint inhibitors because evidence from laboratory work showed that the checkpoints were actually present in the Merkel cell cancers.

Now, as Dr Kaufman mentioned, this is a disease of older people on average and the average patient age in this study was 73 years. Most of these patients had had several prior therapies. In that setting, a difficult to treat patient population, this treatment was relatively well tolerated and you saw the clinical results with a third of the patients responding to the treatment and most of them having durable responses.
Now, we think that as people age their immune systems are not as able to cope with what needs to be done. Nevertheless, you saw a nice response rate and survival in this study. Did you look at the drug activity in the older patients versus the younger patients on this trial and was there any difference?
I don’t think we specifically divided them that way but I don’t think we saw any differences in the elderly versus the younger patients. This actually has been a trend that has been reported before so we’ve actually published work with high dose IL-2 which actually historically we haven’t used it in elderly patients and we found that our older patients actually were just as likely to respond and interestingly had a statistically significant lower rate of side effects. I actually am beginning to think that maybe because the immune response isn’t as robust that we’re also not seeing as much toxicity which may allow us to keep treating these patients and they’re clearly able to respond. So age in and of itself should no longer really be considered a contra-indication to these agents.

We’ll open it up for questions. Any questions from the floor?

[Audience member] I’ll just say congratulations.

Thanks. This is really good news for these patients so I know Suzanne probably knows some of these patients but this is a terrible disease. We’ve seen doubling times of 24 hours and just see this tumour just take over these patients very quickly. So to have something that can just turn it around like this has really been amazing and it’s been really great to watch some of these patients doing so well for so long now.

[Audience member] What gives you the sense that it might be effective in some of the other cancers that you mention?

Well in general we know that the checkpoint inhibitors have been helpful in some of these other cancers and I have the advantage of knowing that we have about a 1,600 patient phase I study that’s been done with this drug in a number of different cohorts and it does look like there’s some good activity in a number of these different cancers. So we’re actually very hopeful that there may be some real advances in a number of these coming up shortly.

[Audience member] What cancers?

So we’re studying it in non-small cell lung cancer, in bladder cancer, renal cell carcinoma, ovarian cancer. I think anywhere where PD-1 or PD-L1 has shown an effect this is a drug that might be worth studying there.

[Audience member] Charles Bankhead, MedPage Today. At this meeting last year I believe there was a study of either nivo or pembro in Merkel cell. Do you know if those investigations are still going on and how do these results compare with what’s been seen?

There was a study reported last year, this was a study of pembrolizumab and the difference is that study was looking at first line treatment and they did report, at least in the first 25 patients, about a 56% response rate. So I think that looks very good and based on that the avelumab is now being studied in first line and the pembrolizumab study the plan was to increase the number of patients and that study is ongoing and hopefully will be completed very soon.

[Audience member] You say it was approved first line and second line and it’s the only drug approved now. So what would you say to clinicians who have a newly diagnosed patient? Should they move directly to a PD-L1 inhibitor?

I think so and I think even before this approval we were trying to get one of these drugs for these patients because this is the first time we’ve actually seen a real benefit in Merkel cell carcinoma. So the avelumab is available for order now and, again, this is a tumour that many oncologists don’t see a lot. So when they get that diagnosis a lot of times these patients are moved around the system quite a bit but we now actually have a drug that can be done in most oncology centres, even in private offices. It’s really important that patients get access to these drugs as soon as possible.