Rapisuwon Reviews Management Approaches for Advanced Noncutaneous Melanoma Subtypes

Partner | Cancer Centers | <b>Georgetown Lombardi Comprehensive Cancer Center</b>

Suthee Rapisuwon, MD, reviews management strategies under exploration for mucosal, acral, and uveal melanoma.

Although there is much room for improvement in the management of patients with advanced noncutaneous melanoma, novel strategies and combinations are showing encouraging activity in certain disease subtypes, according to Suthee Rapisuwon, MD.

“The efficacy of the noncutaneous melanoma therapies that are currently available are still suboptimal,” said Rapisuwon. “Enhancing the armamentarium will require teamwork from many institutions as well as other countries. We must work together enhance our knowledge and understanding of this uncommon space.”

Only 10% of patients with acral or mucosal melanoma have tumors that harbor a BRAF V600 mutation; for this subgroup, BRAF/MEK inhibitor combinations can be utilized, according to Rapisuwon. However, most patients with acral or mucosal melanoma do not harbor targetable mutations; as such, immunotherapy is often used. However, patients with mucosal melanoma appear to experience lower responses to immune checkpoint inhibitors compared with their cutaneous counterparts, said Rapisuwon.

The combination of axitinib (Inlyta) and toripalimab (JS001) has demonstrated promising activity in patients with mucosal melanoma, with an objective response rate of 48.3% (95% CI, 29.4%-67.5%) per RECIST v1.1 criteria and a median progression-free survival of 7.5 months (95% CI, 3.7–not reached).1 The combination was also found to be well tolerated.

For patients with metastatic uveal melanoma, combined immune checkpoint blockade has proven to be one of the most effective approaches available for this subgroup, based on data from a retrospective, multicenter study. Ipilimumab (Yervoy) in combination with a PD-1 inhibitor resulted in a best ORR rate of 15.6%, with a median duration of response of 25.5 months.2 The disease control rate was 37.5% with a median duration of clinical benefit of 28.0 months.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Melanoma, Rapisuwon, a medical oncologist at MedStar Health, reviewed management strategies under exploration for mucosal, acral, and uveal melanoma.

OncLive®: What notable biological and mutational variances have been discovered among the noncutaneous melanoma subtypes?

Rapisuwon: The mutations in mucosal melanoma are different from those in cutaneous melanoma. Oftentimes, we don't really see the BRAF mutation as the inciting event, or what we call the trunk or phylogenetic event, in mucosal melanoma as opposed to cutaneous disease.

In mucosal melanoma, sometimes we see a mutation or gene aberration spanning from chromosomes 5 to 12. About 20% to 30% have KIT mutations which can be used later on, but those are typically the originating event in the tumorgenesis.

As opposed to uveal melanoma, the tumor evolution process is much different. It usually starts off with a G-protein mutation, whether it be Gaq or Ga11. Notably, more than 80% demonstrate homology with each other, while the other 20% involve the mutation that bypasses those key protein mutations.

As the tumor grows or becomes more malignant, it accumulates the copy number variation; those patients will develop metastatic disease.

In your own practice, how do you approach the treatment of patients with acral and mucosal melanoma?

Since mucosal and acral melanoma often lack targetable mutations, we typically start off with immunotherapy. The data from the BMS 067 trial included the mucosal and acral subtypes and demonstrated activity with the combination of ipilimumaband nivolumab (Opdivo). However, the efficacy is generally less than what we have seen in cutaneous melanoma. That's the current standard of care that we typically use.

We’re always looking for new combinations. Chinese investigators are looking into the combination of anti–PD-1 and a VEGF inhibitor, which in this case is axitinib. This approach has been shown to have more than just an additive effect. The anti–PD-1 agent by itself seems to perform just as well as others. I believe this is a good starting point, although more data are needed before a consensus can be reached, and we move forward with other combinations.

Most patients don’t harbor mutations, but are you testing for those who might have targetable aberrations?

We start by looking for targetable mutations at the beginning. The choice is whether to use the mutations as a target for the inhibitor right away or [if you want to keep it in] the arsenal [for] later on. Typically, we tend to use immunotherapy first because there is potential for durable long-term response. The incidence of actionable mutations in mucosal melanoma is not very high. The incidence of KIT mutations ranges from 20% to 30%. A certain amount of mucosal melanoma can have BRAF mutations where BRAFor MEK inhibitors can be used.

What factors come into play when deciding to switch patients from immunotherapy to a more targeted approach?

We typically wait approximately 12 weeks before making the decision to switch the treatment approach. Unfortunately, in mucosal melanoma, the overall response rate with combination checkpoint inhibitors is not that great, only about 30%. As such, more patients will not respond versus those who will. However, that being said, I would generally refrain from doing an early switch.

It has been shown that patients with mucosal melanoma have lower responses to immune checkpoint inhibitors versus those with cutaneous disease. What are some of the approaches under investigation for the mucosal subgroup?

We’re now looking at different immunotherapy and targeted therapy combinations. We’re also looking into whether immune checkpoint inhibitors should be used as early adjuvant therapy to offset the chance of a patient developing stage IV disease. Other clinical trials are ongoing.

The limitation of performing clinical trials in the mucosal melanoma subgroup is that we don't have many patients to work with as opposed to other countries, where the majority of patients with melanoma have mucosal disease. We see this in Southeast Asia and in China, even though the distribution is generally the same. That’s the challenge we face with testing newer combinations in this subgroup in this country.

What is the role of the combination of axitinib (Inlyta) and toripalimab?

Toripalimab is an anti–PD-1 agent that was developed in China. The activity of this agent by itself is on par with the pembrolizumab and nivolumab in cutaneous melanoma, as shown in earlier reports. It's very modest when administered alone in acral melanoma and essentially doesn’t have any activity when it is used in mucosal melanoma.

Because investigators have seen more of the VEGF pathway aberration in their melanoma cases, that served as the basis of their study to use the oral VEGF inhibitor axitinib in combination with toripalimab. Results appear to be pretty impressive with a response rate around 40%.

Shifting to uveal melanoma, how are you currently navigating the options available in practice? What is the role of dual immunotherapy in this subgroup?

Treatment for patients with uveal melanoma, especially metastatic disease, still leaves a lot to be desired. Even with a combination checkpoint inhibitor approach, efficacy is still not very good. The response rates [that we see with this approach] is quite low. We need to do a better job in identifying those who may be responsive to the treatment. By using combination immune checkpoint inhibitors, we saw that these patients tend to require ipilimumab.

Results from a multicenter, retrospective analysis published by investigatorsfrom the University of California San Francisco showed that the activity of the single-agent anti–PD-1 agent was pretty minimal. Ipilimumab [does seem] to have an essential role in uveal melanoma. Also, another group at the University of Texas MD Anderson Cancer Center examined the role of ipilimumab in this disease and they have published in a paper examining its use in the adjuvant [setting]. The relapse-free survival [is] higher than what we would expect in patients with higher-risk uveal melanoma.

That's also why we tried to shift the immune checkpoint inhibitor from the metastatic setting into the adjuvant setting. In those settings, the efficacy of combination immune checkpoint inhibitors might help salvage some patients who would otherwise progress into metastatic disease.

In terms of other standard treatments that we offer patients, outside of the clinical trial setting, we would still offer combination immune checkpoint inhibitors first, as targeted therapy or MEK inhibitor activity is not very good and hasn't been very good. Richard D. Carvajal, MD, of NewYork-Presbyterian Hospital, and colleagues examined the efficacy of selumetinib plus dacarbazine or placebo plus dacarbazine; this approach didn’t perform as well as we thought it would.

Other than that, in patients who progress on frontline combination immunotherapy, a tumor-infiltrating lymphocyte (TIL) therapy is also still a viable option for them. After seeing an almost 30% response rate in a study that came out of the University of Pittsburgh, we thought maybe the way the TIL are being grown or are being selected for adoptive cell therapy could also modify the disease process, as well.

Are there any specific clinical trials that you’re excited about?

Given the activity [that was have seen] in patients who are treated with TIL therapy, [that approach] can be further explored in combination with an immune checkpoint inhibitor or a targeted therapy. The bispecific targeted biologic IMCgp100 [is under exploration in malignant melanoma] and we have seen some promising results from the phase 1 trial.


  1. Sheng X, Yan X, Chi Z, et al. Axitinib in combination with toripalimab, a humanized immunoglobulin G 4 monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: an open-label phase 1B trial.J Clin Oncol. 2019;37(32):2987-2999. doi:10.1200/JCO.19.00210
  2. Heppt MV, Amaral T, Kähler KC, et al. Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. J Immunother Cancer. 2019;7(1):299. doi:10.1186/s40425-019-0800-0