Novel Targets Set to Add to Checkpoint Blockade Success in Merkel Cell Carcinoma

James A. DeCaprio, MD

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer for which treatment options are limited. Moreover, mortality and morbidity remain high, said James A. DeCaprio, MD, who added that the high response rates observed with checkpoint inhibitors in MCC have raised awareness of the disease and could pave the way for research efforts of novel targeted options, such as MDM2 and LSD1 inhibitors.

“Within the medical community there has been awareness raised for MCC because of the success [seen] with checkpoint blockade therapy,” said DeCaprio. “Now, more people know about MCC, and even people who are not involved in skin cancer [treatment] are aware of it. We’re never going to see an ad on TV for MCC treatment because it is rare, but there are certainly opportunities to build on the really spectacular responses to checkpoint blockade [we’ve seen].”

For example, the novel, oral, MDM2 small molecule inhibitor KRT-232 is being evaluated in a phase 2 study (NCT03787602) for patients with p53 wild-type MCC who have failed treatment with a PD-1/PD-L1 inhibitor.¹ Initial results of the study demonstrated early efficacy signals and good tolerability with KRT-232 monotherapy in this patient population.²

In an interview with OncLive, DeCaprio, a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, discussed the incidence of MCC, risk factors for the disease, established treatment options, and investigational regimens on the horizon.

OncLive: How does MCC typically present?

DeCaprio: MCC is a very interesting cancer. It is among the rarer skin cancers; it is 40 times less common compared with melanoma and many times less common compared with squamous cell carcinoma and basal cell carcinoma. MCC is highly aggressive, so we can’t fool around with [diagnosing] it. It shows up as an innocuous little skin bump but can grow very quickly. Usually, just the speed of growth has a patient coming to their doctor.

Many patients with MCC already have a dermatologist because they have a history of skin cancer, such as squamous cell carcinoma or basal cell carcinoma. A few patients with melanoma have also gone on to develop MCC.

What is the incidence of MCC?

[The incidence of MCC] is about 1 per 100,000 in the United States. The incidence is going up, however. Part of that increase in incidence is because MCC is a rare cancer. It was only first described in 1972 by [the late] Cyril Toker, [MBBCh, FRCS, MS, JD, of the University of Maryland]. MCC is rarely suspected when a patient shows up with a skin bump. Most pathology specimens do not have [the ability to] rule out MCC on the clinical diagnosis. In fact, I’ve only seen one pathology report even suggest that [a patient] could have MCC. Usually, MCC is thought to be a benign cyst that [can be resected]. Then, the pathologist will call back and let [the patient] know it is MCC.

Sunlight exposure, as well as age, are contributing to the rising incidence of MCC. MCC can show up in younger people in their 20s with tanning bed exposure, as well as in people in their 30s and 40s. The incidence starts taking off in [individuals between the ages of] 60 years to 90 years.

What are some of the risk factors for MCC?

One risk factor for MCC is sunlight exposure or intense ultraviolet (UV) exposure. Often sun-exposed areas, such as the face, neck, arms, and legs, are where many MCC [nodules] show up.

Maybe as much as 10% of all patients with MCC are immunocompromised in some way. Solid organ transplantation is another risk factor, as well as the treatments of some autoimmune diseases, such as rheumatoid arthritis, and psoriatic arthritis. Therefore, there is an immune component to this disease, both in its risk factors and treatment. We have had a few patients have some genetic predisposition to immunosuppression as well.

MCC is rare even under all of those circumstances. Most people with psoriatic arthritis do not develop MCC, but it is definitely a risk factor.

How do you categorize some of the unique challenges in MCC?

There are 2 unique challenges with MCC: one is on the biologic side and the other is on the clinical side.

On the biologic side, MCC can be caused by excessive UV damage to the tumor genome [that causes] lots of mutations. The other form of MCC is caused by the Merkel cell polyomavirus. This virus is very common; everyone has it living on the skin. On the wrong day, the virus can get into the wrong place and become integrated into a normal cell to transform it into MCC.

The tumors of [both forms] of MCC look and act identically. They are almost indistinguishable in where they show up on a patient, who is at risk, and how they respond to treatment; it’s quite striking. The similar phenotypes, presentations, histologies, and biologies, but completely unique etiologies are why I study MCC. How does this [polyomavirus] trick a normal cell into becoming this highly aggressive cancer? [The UV-exposure form] helps us to decipher thousands, if not millions, of mutations that UV light [can] introduce into the tumor genome. What driver mutations are really causing the cancer?

On the clinical side, MCC is a solid tumor with the highest response rate to checkpoint inhibitor therapy. PD-1/PD-L1 antibodies have dramatic activity in [patients with] MCC [inducing response rates of] 50% to 60%, often for quite a long time.

It’s great news that MCC responds, but why does it do that? Conversely, why do some patients with MCC not respond to checkpoint blockade? There are a lot of very important questions [being asked] related to that. Of course, we use the biology of this virus to understand this phenotype as well as why [a patient’s disease] would be sensitive [to checkpoint inhibitors] or not.

The other unique thing about MCC is that it shows up commonly on the head and neck area [where] a lot of important and complicated structures [are], but it can also show up in the hands. Because MCC is a rare cancer, there is not much experience in treatment. However, it is very clear that we need skilled teams of physicians that can take care of these patients. These tumors are very sensitive to radiation therapy; radiation can cure MCC without the need for disfiguring surgery to remove the entire tumor. How much of the tumor do we need to remove? How much do we need to radiate? Is there need for additional therapy, such as checkpoint blockade? Often, a lot of morbidity related to surgery or chemotherapy could be spared if the team has experience and knows how to best take care of these patients [with a good] treatment plan.

How have checkpoint inhibitors improved upon historical treatment, such as chemotherapy? How can the field improve upon responses with checkpoint inhibitors?

The world is completely different since 2016 with the first report of checkpoint blockade response in MCC. Up until 2016, we were commonly giving chemotherapy with cisplatin or carboplatin plus etoposide for advanced cases of MCC. This is very toxic chemotherapy but very effective in MCC. Most patients would respond rapidly to that form of therapy.

Chemotherapy itself is immunosuppressive so we were inhibiting the body’s own immune system in trying to protect against MCC by using a cytotoxic therapy. It was also recognized that the responses to chemotherapy did not last that long—maybe 2 to 3 months on average.

When checkpoint inhibitors became available and showed efficacy in MCC, it changed practice dramatically. Pembrolizumab [Keytruda] and avelumab [Bavencio] were both FDA approved rapidly with very small case numbers because responses were so dramatic and there wasn’t an FDA-approved alternative. [The treatment landscape] is completely different now since 2016.

In melanoma, we know that checkpoint inhibitors are also very effective, but [they don’t elicit] response rates as high as 50%. Often in melanoma, the response duration is quite long, [meaning] up to several years. I think of [former president] Jimmy Carter [who has melanoma with brain metastases] and how well he has responded to checkpoint inhibitors for years now.

In MCC, the responses to checkpoint inhibitors may not last as long [as they do in melanoma], so physicians are forced to adapt their checkpoint blockade by changing the dosing schedule, drug, or combining drugs. Because the response durations are not as long, there are significant challenges and opportunities to improve what is already a success story.

Can we extend the responses for patients who do respond? Can we improve the response? Can we find something to help patients who don’t respond at all, either up front or later on? A lot of key challenges [exist].

We study the biology of the virus, which has definitely given us clues about how to go after virus-positive MCC. One of the opportunities [to improve upon responses] is [to use] p53 and MDM2 inhibitors. As it turns out, the polyomavirus goes after p53 in a way that leaves p53 susceptible to MDM2 inhibition; it is a unique virus in that sense. It gives us the perfect opportunity to activate p53 by inhibiting MDM2. Papillomavirus, for example, goes after p53 very well, but it eliminates our opportunity to activate it. We haven’t been able to get in the middle of papillomavirus and p53. In MCC, polyomavirus leaves itself exposed to p53 activation. There is a phase 2 clinical trial [NCT03787602] from Kartos using KRT-232, a small molecule inhibitor for MDM2, that is showing very promising activity. We are excited about that and hopefully we will hear more about it in the coming months.

Are there other research efforts ongoing that you would like to highlight?

There is a great [clinical] opportunity with MDM2 [inhibitors] but related to that are MDM4 [inhibitors]. MDM2 and MDM4 work collaboratively with each other to get rid of p53. Our lab has found that we can independently inhibit MDM2 and MDM4, and that combination will synergistically activate p53. There is a golden opportunity to target MDM2 and MDM4 together, so with some luck, we will have an [FDA] approval for MDM2 inhibitors [, and potentially MDM4 inhibitors, in the future]. This can also be expanded for drugs that inhibit both [MDM2 and MDM4].

Another pathway we’ve uncovered is LSD1. There is an opportunity for LSD1 inhibitors in MCC and we have talked to a few companies [about trials to that end]. Because MCC is rare, it makes it challenging to put together a study. The MCC that we have studied has been very sensitive to LSD1 inhibitors.

Because the virus is driving a normal cell [to turn into a cancer cell], we’ve found several other targets that could be opportunities for therapy. We are just getting started and there is certainly a really interesting possibility that one of the drug targets could synergize with checkpoint inhibitors. We could have a rational strategy to inhibit checkpoint blockade but then work with the virus to activate the immune response. We will look at some inhibitors in that regard too. Hopefully, we will all be reading about that soon.

How can the community raise awareness for MCC?

In Australia, MCC is a household word and is well understood because of [Australians’] increased risk for all skin cancers. MCC is of a higher incidence [in Australia]—though it is still rare—so it is well understood.

Although melanoma, for example, is a terrible disease, patients can often live a long time with it, particularly when it is caught early before metastasizing. Now, because of certain therapies, even patients with metastatic disease live long to tell their story. MCC is so aggressive that patients don’t often live to tell their story. Patients with stage I or II disease with just a lump and no lymph node [involvement] can mostly be cured.

[Advanced-stage disease] is highly aggressive. Those are the patients we are trying to learn from so that some of them will be able to tell their stories. We are getting some success in this disease. Encouraging patients to tell their stories is one way to get the word out.

References

1. This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with (p53WT) Merkel cell carcinoma who have failed anti-PD-1/PD-L1 immunotherapy. ClinicalTrials.gov. Updated December 20, 2019. Accessed June 1, 2021. https://clinicaltrials.gov/ct2/show/NCT03787602.
2. Wong MKK, Kelly CM, Burgess MA, et al. KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy. J Clin Oncol. 2020;38(suppl 15):10072. doi:10.1200/JCO.2020.38.15_suppl.10072