Merkel Cell Carcinoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Brian Gastman. Brian is the Medical and Surgical Director of The Melanoma and High Risk Skin Cancer Program here at Cleveland Clinic. He's talking to me today about the management of Merkel Cell Carcinoma. Welcome Brian.

Brian Gastman, MD: Thank you. Thank you for having me.

Dale Shepard, MD, PhD: Absolutely. Maybe just to start off, maybe you could briefly tell us about your role here at Cleveland Clinic.

Brian Gastman, MD: Sure. I happen to be a surgeon who has had a longstanding interest in tumor immune evasion and of course, immunotherapy revolutionizing cancer has been fortuitous for someone like myself and for the patients I treat. Over the years, I've helped as part of a larger team grow the melanoma and high risk skin cancer program. It's really become one of the national leaders, not just in standard of care clinical treatment, but also in clinical trials, as well as basic science research. And part of my role, it really is to help shepherd patients to the various options that we can now offer them. And this includes Merkel cell carcinoma for which we have about as many options for patients as anyone can find in the United States.

Dale Shepard, MD, PhD: I guess for a lot of the physicians listening and Merkel cell is not a very common tumor. Maybe you could just briefly kind of remind everyone, what is Merkel cell carcinoma? About how many cases are we looking at a year?

Brian Gastman, MD: First of all, like any cell in the body, it can transform into cancer. Within our skin, besides of course the epithelial cells and melanocytes, which forms for example, melanoma, are Merkel cells. Actually Merkel cells are part proprioception and believe it or not the majority of them in the body are probably in the hard palate in the mouth and yet we never seen Merkel cell carcinoma in the mouth. We mainly see it in the skin. Why nobody knows. It could be in part related to the fact of UV radiation. But interestingly, 80% of Merkel cell carcinomas are not necessarily UV radiation induced. In fact, 80% of them are induced by a polyomavirus and those who study viral oncology, they tend to like Merkel cells, one of their models for research. Interestingly though, the difference clinically between a polyomavirus driven Merkel cell and a UV induced Merkel cell has never been seen, not with therapy, not with surgery, regardless of treatment.

What's interesting about Merkel cells, number one, it tends to be in the elderly. It is not uncommon that we might see a 98 year old patient walk in the door with it. It tends to be obviously on the skin and in comparison to melanoma, it's usually more advanced for whatever reason, maybe because it's a faster growing tumor and as such, the death rate for Merkel cell is still near two to three times that of melanoma. Those numbers are constantly in flux with better dermatologic exams and use of immunotherapy. It's considered a rare cancer because of the numbers, but whereas a few years ago you would see numbers like 1,500 per year, the most recent estimates are that we have between 3,000 and 3,500 a year. And that's over the span of about six or seven years. Although it's technically still a rare cancer, its trajectory at this rate of increase, is that it won't be probably in the next 10 to 15 years based on rare cancer definitions.

Finally, most patients do come in with resectable disease. It's treated a lot like melanoma. For patients who come in with an isolated skin lesion, it would be a wide local excision with various ways of assessing margins and a sentinel lymph node biopsy. If you're sentinel node biopsy was not done, or it was done and it was negative, you'd be a stage one or stage two, depending on the primary characteristics. And if they were positive, you'd be upgraded to a stage 3A, a stage 3B disease is someone who has got gross local regional lymphadenopathy or in transit metastasis. And of course, stage 4 is disseminated, usually unresectable disease. After surgery, depending on characteristics unlike melanoma, radiation is commonly used and it's not been really shown to improve survival, but is a very powerful agent for local regional control. We use it sometimes for the primary or the nodal basin or both, but the probably biggest change in Merkel cell like melanoma is the use of immunotherapy, anti-PE1 immunotherapy specifically.

It's interesting if you look at all skin cancers, they have obviously a lot of them have UV signature. They have the highest tumor mutation burden in almost all of cancer and they all have very similar anti-PD1 overall response rates. Merkel cell melanoma and cutaneous squamous cell carcinoma have very similar overall response rates to the monotherapy if you're a naive treated patient, of around 40 to 50% and the survival rates are similar between melanoma and Merkel cell. It's a huge advancement, but unlike melanoma, some of the combinational therapies have not been as successful. For instance, ipilimumab and nivolumab does not seem to have the same power and because it's a rare cancer, many potential therapies have not yet been tested.

Dale Shepard, MD, PhD: What sort of trials are enthused about that we may be doing here at Cleveland Clinic?

Brian Gastman, MD: My goal was to have trials for the earliest disease, even prevention, quite frankly, all the way to refractory disease. Currently at the Cleveland Clinic, for example, for certain stage 1, all stage 2 and all stage 3 patients, we have what's called the STAMP trial, which is sponsored by the Eastern Cooperative Group, and it's co-sponsored by SWOG. I happen to be the national PI of that trial as I developed it and guided it through cTAP. And ultimately it in is now at over 420 hospitals. To date, I believe we have 75 or 76 patients accrued and that trial takes patients who again, in stages 1s, 2s and 3s who may or may not get radiation after surgery, it's sort of dealer's choice and they will get randomized one to one to postoperative pembrolizumab, an anti-PD1 from Merck, versus standard of care, which is essentially observation. And the primary endpoint there is recurrence free survival with a co-primary endpoint of overall survival, which is what the NCI and cTAP generally recommends for phase three trials. And it is a phase three trial.

Moving on up, for patients who have either naive, meaning they've never been treated but it's unresectable disease or they've had a one line of immunotherapy and failed, we have what we call the NIT trial. This is another trial that I happen to be the national primary investigator for. It's actually born out of research from my lab and was able to be partnered with a company who developed a interleukin-7 conjugant molecule with the receptor, making it more powerful, IL-7, in combination with atezolizumab, which is Roche Genentech's anti-PD-L1. That is accruing very well. It's at seven centers and I believe we'll have about 10 centers when all is said and done. And all of these centers are some of the usual suspects in terms of high accruing locations.

Moving on up beyond that, we have our NantKwest trial, which I'm shepherding at least locally here. And that's an interesting trial too, that is for further refractory patients. This trial is an interleukin-15 based conjugate, similar to the IL-7, it's connected to an IL-15 receptor. It's combined with avelumab, which is an anti-PD-L1, which happens to be proved in Merkel cell as well as an NK cell infusion. And these NK cells are specific for p16, which is highly unregulated neuroendocrine tumors and Merkel cell is a neuroendocrine tumor, which very interesting about NK cells is you do not need to do pre-conditioning like you would do with a bone marrow transplant, tumor infiltrating T-cells, CAR T cell type protocol. The morbidity of this trial is much lower. And because NK cells do not require autologous tumor antigen, these are actually allografts that are being given. And so it's all off the shelf products. We literally are opening this trial this week and we're very excited about it and we already have numerous patients are in line.

And I would add besides the standard of care approved agents like anti-PD1, anti-PD-L1 pembro, nivo, avelumab, we are also been a leader in the intratumoral injections and have published a small series of patients who had excellent outcomes combining TVEC, which is a engineered HSV oncolytic virus in combination with anti-PD1 agents. And we have been able to get insurance many times to approve this and we've been giving it to patients who both are in the naive stage, but have injectable unresectable disease, or even in the immunotherapy failed group with some really nice successes, including a few patients that are alive at least three years now. One of them had had three lines of immunotherapy, chemotherapy, multiple surgeries, multiple radiation and as we speak has had no evidence of disease using a combination of TVEC with pembrolizumab. And by the way, I do not endorse one drug over the other, it just happens to be the one that we use in that combination.

Dale Shepard, MD, PhD: Lots and lots of options out there. Lots of trials. When we think about other, you mention NK cells, are there any other cellular therapies that sort of have you excited at this point in terms of potential?

Brian Gastman, MD: Merkel cell has very few trials, as you can imagine. It tends to be baked into phase one trials or basket trials for skin cancer. There is a TIL therapy trial that's based out of Seattle and it's autologous TIL so in other words, it's tumor infiltrating lymphocytes. It's a trial that we are not opening, but it is a cellular based therapy. People are looking at genetic engineering T-cells, but I think ultimately Merkel cell is going to end up being folded into successes of larger volume cancers. A lot of offline, off label uses will eventually be found to be effective in these cancers sort of by happenstance because it's a rare cancer. There are other trials in the adjuvant setting that are being done in Europe. And there is some interesting data looking at actiatride because it's a neuroendocrine tumor, but those are pretty much the main areas. And again, to answer your question in terms of cellular therapy, I think it's going to be engineered T-cells or just expanded TILs for Merkel cell for now, at least.

Dale Shepard, MD, PhD: When we think about what's going on in other tumor types, certainly there's a move toward genomic based therapies, combinations of chemo, perhaps with immunotherapies. Is there any similar movement within Merkel cell?

Brian Gastman, MD: Chemo has been the stalwart for Merkel cell for years, but it essentially has zero curative effect. I think there's a little bit of apprehension to go backwards as opposed to trying multiple immunotherapy combinations. But I can tell you that what's interesting about Merkel cell similar to melanoma is that you can sort of hold onto patients for years with persistent disease and at some point, your back is against the wall clinically, so to speak. And there has been this sort of small brewing interest in doing exactly what you mentioned in melanoma. And I think of Merkel cell as like sort of the fish that swim at the big shark. Where the shark goes, the fish go. I think, as patients live longer and need some additional option, there'll be some renewed interest in that. But right now I think there's a strong objection to using chemo because we finally got past it if you will, at this point.

Dale Shepard, MD, PhD: And from a genomic standpoint, is there anything that has been even a little bit successful in terms of if we do next generation sequencing, anything that is a recurring hit?

Brian Gastman, MD: Not recurring. There's probably a one off here or there. Clearly having the polyomavirus in 80% of these, you would think that there would be some type of antiviral along those lines, but there's not been a good series other than case reports.

Dale Shepard, MD, PhD: Are most patients with Merkel cell, do they get referred in to see you and the team here at a place like Cleveland Clinic or are there a lot of community guys that kind of start the process? And are there particular patients you think really do need a second opinion and a multidisciplinary approach?

Brian Gastman, MD: Yeah. There's really a bimodal distribution of referrals. You got the larger referral, which comes from dermatology. And I think sometimes with moles, you might be suspicious it might be melanoma, but when it comes to Merkel cell, so many times it's catching the person who did the diagnosis sort of flat footed or in shock, like, "Oh wow, I wasn't expecting that. I haven't seen one of those in a few years." It could be a general surgeon taking on a quote unquote cyst, comes back Merkel cell, totally unexpected. And I think a lot of times they're really looking for someone who feels extremely comfortable to take this confusing, overwhelming situation so that they feel like something responsible is happening to those patients. And I think that's a large majority of where we get people from. We do see people come to us for second opinions and unlike melanoma, a lot of times we were surprised by sort of the haphazard nature of people who do this and rarely and how they sometimes will we'll treat these patients.

Now on the sort of unresectable side, I think, people are so enamored with anti-PD1 agents and they feel so comfortable with it, we do see more and more first line treated in the community because at some point it doesn't matter if it's Merkel cell or melanoma or what have you, it's a anti-PD1 responsive cancer and I can give anti-PD1 therapy. The problem then is good percentage of them do eventually have resistance or have primary resistance and then will show up and those are harder to treat. And obviously it makes the group that we see overall more difficult population.

But in the end, I think patients prefer having people who are not shocked by a Merkel cell diagnosis, feel comfortable with the diagnosis and are on the cutting edge of what the next treatment would be because they, like I said, we can keep people alive for a long, long time. And that means they will live long enough to see a new option that we haven't even discussed today. And they know being with us and sort of being locked in, they will get the first glimpses at those therapeutic options, working with us at the Cleveland Clinic.

Dale Shepard, MD, PhD: And of course, one of the concerns as well from a trial standpoint is if people have kind of meddled around in a treatment or two before coming to look at trial options, they may exclude themselves from some potential options.

Brian Gastman, MD: I would say yes and more because on one hand, yes, because a lot of times they are sicker, like you said, their ECOG status gets worse, they can't even get on, or the trial option, which might be better than standard of care, requires them to be immunotherapy naive. But I would tell you, it's really interesting when certain trials got started, which included cutaneous T-cell lymphoma, some lung cancer trials and Merkel cell, what people found at least with chemotherapy and I think it's probably true for most cancers, is that the more chemo you had, the worst year immunotherapy outcomes were. And Merkel cells is a classic example of that.

In the pembrolizumab CITN trial published in New England Journal of Medicine, those were all IO naive patients treated with pembrolizumab and their overall response rate was nearly double the avelumab trial, which was also led to an FDA approval, which I think was in Lancet or Lancet Oncology, not that far apart temporally, but those were allowed to be chemotherapy failures. And the overall response rate, obviously was then almost half. And so what's better at least now is that we're not seeing people in the community give them chemo and then sending them in when they failed. Now, at least they're trying immunotherapy, which maybe isn't as bad of a starting point.

Dale Shepard, MD, PhD: What would you be the key takeaways that you'd like physicians listening to know about Merkel cell and how to manage it?

Brian Gastman, MD:

Sure. Number one, it is a rare disease and ideally should be treated at a tertiary center that is very comfortable with this and that goes from everything to not just the surgeons and the oncologists, but even social workers and nurse practitioners who feel very comfortable communicating about it. Number two, although it's a rare disease, it's on the rise and it may not be so rare in the near future. Number three, it is an immunotherapy sensitive cancer and if you were in the unresectable setting and you want to treat this starting with an anti-PD1 and not chemotherapy, which is luckily becoming more the norm, is absolutely the way to go.

And then finally the use radiation, its uses are widespread in Merkel cell, but radiation has side effects, long term side effects and the uses of it for local regional control might be outweighed by a curative anti-PD1 one based therapy and so being more judicious potentially with radiation, despite the fact that you will see it really affect the cancer immediately need to be considered in their trials right now, like the Alliance trial and others that are trying to assess where radiation should stay or not stay within the Merkel cell field.

And then finally that Merkel cell, like all other cancers is being explored for new trial options and new treatment options and I would expect new FDA approved therapies probably in the next couple years and so it behooves us to want to try to keep our patients alive long enough to eventually experience those next level success.

Dale Shepard, MD, PhD: Thanks, Brian, appreciate your insights. That's very helpful. Do you have any additional comments?

Brian Gastman, MD: I think it's really helpful to get the word out because as well known as the Cleveland Clinic is, there's a lot of people out there, physicians especially, who may not know that we have a special and strong interest in Merkel cell carcinoma.

Dale Shepard, MD, PhD: That's great. Well, thanks a lot.

Brian Gastman, MD: Thank you.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.