Immunotherapy Shows Potential in Rare Melanoma Subtype

Richard Joseph, MD

Few studies have investigated mucosal melanoma, a rare and aggressive subtype of melanoma. As a result, oncologists often base treatment choices on cutaneous melanoma data.

The use of nivolumab (Opdivo) was recently investigated in patients with mucosal melanoma based on a pooled analysis of 889 patients, 10% (86) of whom had mucosal melanoma.

At a median follow-up of 9.2 months (0.3-62.5), median progression-free survival (PFS) was 3.0 months (95% CI, 2.2-5.4) for patients with mucosal melanoma and 5.1 months (95% CI, 3.9-6.1) for all treated patients. The objective response rate (ORR) was 23.3% (95% CI, 14.8-33.6) for patients with mucosal melanoma and 35.9% (95% CI, 32.7-39.1) for all treated patients, with complete responses in 6% of patients in both cohorts.

Median duration of response was not reached for patients with mucosal melanoma and was 22.0 months (95% CI, 22.0-NR) for all treated patients.

This data marks the first analysis of nivolumab in this subtype and is significant for oncologists treating patients with the disease, says Richard Joseph, MD, a medical oncologist at Mayo Clinic.

OncLive: How common is mucosal melanoma?

In an interview with OncLive, Joseph discusses the challenges of treating mucosal melanoma and what oncologists need to know prior to using immunotherapies for the treatment of both mucosal and cutaneous melanomas.Joseph: Mucosal melanoma is a melanoma that does not arise from the skin itself, but instead from the mucosal surfaces of the body—the inside of the nose, mouth, vagina, rectum, and urethra.

It is a very rare form of melanoma, and only about 10% of patients present with it as their primary site. This type of melanoma is typically more aggressive compared with cutaneous melanoma, due to the biology and the late-stage that it often identified.

How should the treatment of mucosal melanoma differ from cutaneous melanoma?

What studies are looking to address this problem?

The rates of mutations are also different than cutaneous melanoma, with BRAF mutations less frequently seen and c-KIT mutations more commonly seen. They are clinically and genetically distinct diseases. Because they are so rare, it is difficult to conduct clinical trials or collect data with so few patients.Mucosal melanoma is genetically different than cutaneous melanoma. Despite this, we tend to treat them the same without a lot of great evidence to support that. This is an issue.Recently, there was an exciting study that investigated the efficacy of immunotherapy in mucosal melanoma, specifically with nivolumab.

In it, they looked at a database of patients who had previously been treated with immunotherapy in clinical trials. What they found was that the response rates tended to be slightly lower than what we typically see in cutaneous melanoma, but still a relatively good response rate.

If oncologists are utilizing immunotherapeutic agents for the treatment of mucosal or cutaneous melanoma, what challenges should they be aware of?

This gives us, for the time being, some quality data for when we are treating patients with mucosal melanoma. We can now give our patients some good numbers regarding if we should treat them with immunotherapy. Before, we were treating them with immunotherapy without really knowing the efficacy.The side effects of immunotherapy agents are very different than the typical chemotherapies and targeted agents that many oncologists are used to.

The first issue is that toxicities tend to occur longer after the time of administration. With chemotherapies, we see side effects within days and, with immunotherapy, it could be weeks. It doesn’t always quite register with the patients or the doctors that the side effects they might be feeling are related to the treatment they are receiving.

For example, a patient may develop diarrhea 2 or 3 weeks after a dose and attribute it to something they ate and not call their doctor. We really need to educate the patient that these side effects can happen and that we need to know about all of them, even weeks later.

The other challenge is that, while there are resolutions to these symptoms, treatment must be started soon. We can decrease the immune system through immune suppressants, such as steroids. That is very different than managing the toxicities associated with chemotherapy or targeted therapy. We have to get really good at figuring out what dose of steroids to use, when to start, and how quickly to taper. That is a bit of an art.

What do you see on the horizon for immunotherapy in melanoma?

Eventually, we could end up doing better at defining algorithms that are easier to follow than the ones that exist. At the end of the day, it takes a lot of experience to adequately treat these symptoms. There needs to be more education for the oncologists.We have had a rapid amount of success in the last couple of years with immunotherapy, and the bar is really high to improve upon that. Certainly, single-agent anti—PD-1 therapies have proven to give a dramatic benefit with very little toxicity. Now, the combination of PD-1 therapies and CTLA-4 agents has raised the bar even higher, but that does come with a higher toxicity.

One of the main ways that we could improve on immunotherapy is to focus on further developing the agents we have, rather than just focusing on new drugs. One of the ways we can do that is by determining how long to treat these patients. The duration of therapy is really unknown, especially for patients who are responding.

Biomarkers are also needed to determine which patients are most likely to respond. There are still a fair number of patients who do not benefit from these treatments, so we need to figure out how to preselect them. We need to also find a biomarker that can help determine when to stop treatment for patients who are already receiving therapy, so that we are not just treating indefinitely.

Larkin J, D’Angelo S, Sosman JA, et al. Efficacy and safety of nivolumab (NIVO) monotherapy in the treatment of advanced mucosal melanoma (MEL). Pigment Cell Melanoma Res. 2015;28(6):789.