Multidisciplinary Collaboration and Immunotherapy Help Overcome Treatment Challenges in MCC

Michael K. Wong, MD, PhD, FRCPC

Although Merkel cell carcinoma (MCC) remains an aggressive form of skin cancer associated with treatment challenges to treatment, the development of immunotherapy approaches and increased multidisciplinary collaboration have improved the management of this malignancy, according to Michael K. Wong, MD, PhD, FRCPC.

“MCC is an area that is ripe for research, and it’s one of opportunity for great outcomes for our patients,” Wong said in an interview with OncLive®. “When possible, it’s better to [consider] immunotherapy as a frontline therapy because in all the clinical trials of immunotherapy in MCC, the [overall] response rate [ORR] has been highest in the frontline. In the second- or third-line of therapy, it’s effective but the ORR is lessened. [However], there are a variety of [situations] where that may not be the case, and that’s why having a total assessment by [a multidisciplinary] team is important for our patients with MCC.”

Wong is a physician in chief and professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Retifanlimab-dlwr (Zynyz) became an approved immunotherapy option for patients with MCC when, in March 2023, the FDA granted accelerated approval to the agent for the treatment of adult patients with metastatic or recurrent locally advanced MCC. The regulatory decision was supported by data from the single-arm phase 2 PODIUM-201 study (NCT03599713), which demonstrated that patients with chemotherapy-naive metastatic or recurrent locally advanced MCC who received retifanlimab (n = 65) achieved an objective response rate of 52% (95% CI, 40%-65%), including a complete response rate of 18%. Notably, 76% of responders experienced a duration of response (DOR) of at least 6 months, and 62% had a DOR of at least 12 months.

In the interview, Wong discussed the historical challenges associated with treating patients with MCC, the importance of multidisciplinary management of the disease, and the impact of the emergence of immunotherapies such as retifanlimab in the space.

OncLive: What have been some of the treatment challenges for patients with MCC?

Wong: MCC is one of the most aggressive skin cancers we know of, and it has a very high mitotic rate. It has a reputation for extensive metastatic ability. In the past, this was a disease that was difficult to treat; it was treated with cytotoxic chemotherapy and radiation. [However], there have been tremendous changes in the management of MCC, to the point where we now have the routine expectation of response, and we see long-term survivors of this disease.

An important [aspect] of MCC is that it’s a lesion that can creep up on individuals. It’s not pigmented, so it’s not like a mole where one can see a change. In fact, if you survey patients with a diagnosis of MCC as to what they were told in the beginning, you get [responses about the disease looking like] a cyst or a bug bite, so it’s difficult to detect. However, the key is, as an adult, if you notice any changes in your body in a significant way that are persistent and unrelenting, then it’s time to seek medical attention. We know that MCC is a lesion that grows because of how mitotic it is. It grows, begins to change, and becomes symptomatic. If you start having symptoms, that’s a red flag to seek medical attention.

There are certain situations in which MCC can be more prominent. We know that it occurs in a population that, on average, is [approximately] 10 years older than the average melanoma population. We know there’s a propensity for it to occur in individuals with an immunologic issue, either from pre-existing disease or long-term immunosuppression.

What is important to know about identifying MCC and differentiating it from other forms of skin cancer?

MCC is considered a rare tumor, [but] we are finding that the incidence is going up in [the United States, which] reflects the fact that we are better at recognizing it. [This is] because we are learning more about it, and patients and physicians are paying attention to this rare cancer. Importantly, on the side of diagnosis, there are new tools and ways of interrogating tissue to make a diagnosis.

The incidence [rate] used to be [approximately] 1 per 1 million [individuals], but MCC is becoming more prevalent as we are [better] understanding the disease. Whenever there’s [a lesion] and there’s doubt as to what it is, the next step is to do a biopsy. MCC is distinctive under the microscope; it looks very different than melanoma, squamous cell carcinoma, or basal cell carcinoma. Once you have a [sample] under the microscope, the diagnosis comes to the forefront quickly.

How can a multidisciplinary care be used for the management of MCC?

The key to successful treatment of MCC is a multidisciplinary approach, which means that you want to engage the surgeon, radiation oncologist, and medical oncologist. The reason for that is that is this disease is best handled in a way that involves all 3 specialties. I tell patients that one of the most important individuals involved in their care is the pathologist, who is someone they never see.

Upon the discovery of the disease, the patient undergoes a thorough physical examination to ensure that we understand exactly what’s going on. We want to make sure that we know the location [of the disease] and that there isn’t any obvious clinical spread. Depending on the what the physician sees, they may order further imaging, such as a CT scan.

If the disease is localized, the treatment requires a surgeon to remove the tumor. We know that a biopsy and [tumor resection] is not good enough; [the patient] needs to have a proper excision. That’s important because MCC tumors have a reputation for being more than you see. Whenever we see MCC on the skin, it’s a bit like an iceberg, and you worry about the part you don’t see.

The analysis under the microscope tells you whether you need a complete resection. Oftentimes, patients will say, ‘Did the doctor get it all?’ Knowing that requires the pathologist to declare the margins are free. We [also] know that there are certain features under the microscope associated with spread beyond the primary site, which includes depth of invasion and involvement of other critical structures deep in the skin.

If [a patient] checks those boxes, then a surgeon may sample the lymph nodes associated with that site. Sometimes surgeons will map out [the surrounding] lymph nodes and take samples to ensure the disease hasn’t spread. We determine [when to do that] by looking at the [sample] under the microscope and the physical examination.

All of this comes back to the importance of a multidisciplinary approach. What we see from the resection and whether the lymph nodes are positive [determine] whether we need radiation. [Radiation is sometimes needed] to sterilize the area around the tumor so that we get rid of [the disease] once and for all. Luckily, MCC is one of those tumors which are particularly sensitive to radiation, so it’s a good modality to use.

I’m a medical oncologist, and, in the past, we didn’t get too involved because there weren’t a lot of [treatment] options, but there’s been tremendous change in the field, and that has to do with the recognition that this tumor is sensitive to immunotherapy. That has been a real breakthrough in this area. It turns out that MCC is a cancer that can evoke an immune response in the body. By using immunotherapy, you can unleash the patient’s immune system to attack the cancer. That has been a revolutionary change in the treatment of MCC.

How has the FDA approval of retifanlimab and the development of other immunotherapies affected the treatment paradigm of MCC?

Retifanlimabi s an immunotherapy, and it [adds to the] line of known immunotherapies that can attack the cancer. The current way we treat MCC—whether it’s locally advanced locally or metastatic—is to use medicines that will trigger the immune system to fight the cancer. These medicines target PD-L1.

There are now several [agents] that are used in MCC. Useful [agents include] avelumab [Bavencio], pembrolizumab [Keyrtuda], nivolumab [Opdivo], and retifanlimab. These are very effective immunotherapies. The use of immunotherapies in MCC comes with some of the highest response rates in oncology, approaching 50% to 60%. These responses can occur quickly, and within 1 to 3 infusions you can know whether you’ve triggered [a response].

The use of immunotherapy is global in a sense that it will attack the cancer anywhere in your body. Patients with extensive disease can respond to immunotherapy dramatically, and that has been the real key in in the change of how we treat this cancer. The advantage of immunotherapy is that it’s a bit like the gift that keeps on giving. It is intrinsic to the patient, and you’re triggering something within that patient. At some point, we can allow the patient’s immune system to take over, and we don’t need to treat them forever. With these robust responses, the door opens for a cure, and we are able to have long-term results in the absence of having to give [continuous] therapy. This has truly revolutionized [the treatment of] this disease.

Is there any other ongoing research in the field that could help move the needle for treatment?

The recognition that immunotherapy works in MCC has been a [key] breakthrough. It means that all the research in immunotherapy and all of those concepts we have in other cancers become applicable to MCC. We’re interested in using other checkpoint inhibitors, [such as] the addition of an antibody to an anti–CTLA-4 [agent] or an anti-LAG3 [agent]. Those are strategies have found use in other cancers, in particular melanoma. Their use is now being pioneered in MCC.

We [also] have recognized that vaccine therapies may be important. We now have intratumor oncolytic vaccines, where you can inject a vaccine directly into the tumor to induce an immune response. Something which is unique to MCC and not found in any other cancer is a recognition that there may be a viral link-up. The Merkel cell polyomavirus is found ubiquitously and for reasons we don’t understand it can integrate into the skin and cause MCC.

This is all new [research], but something that’s come as an offshoot of the recognition that we could use molecules that attack specific pathways within the Merkel polyomavirus to affect a response in the tumor. [This is] an exciting area which is growing. We don’t know where it’s going to go, but there’s a hint of efficacy. It’s something unique to MCC that is not found in any other cancer.

Finally, there’s a recognition that we have barely begun to scratch the surface of this disease. We are finding more ways to attack it, and it’s an area of prolific interest and research. I’m certain that there’s more to come in a short time.

Reference

FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. FDA. March 22, 2023. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel