Challenges Remain in Melanoma Treatment, Expert Says

Merrick I. Ross, MD

Merrick I. Ross, M.D.

Merrick I. Ross, M.D., discussed key issues in melanoma as the treatment paradigm continues to change.

Can you discuss your presentation on liver metastases in melanoma?

In an interview with CURE at the 7th European Post-Chicago Melanoma/Skin Cancer Meeting Ross, Charles M. McBride Distinguished Professor, Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, shared his thoughts on ongoing challenges in melanoma, including treating liver metastases, the diminished yet important role of surgery, and the need for better biomarkers.We have a very active multidisciplinary program at MD Anderson. I was invited to [Post-Chicago Melanoma] to talk about a couple different topics—one of them has to do with how to treat liver metastases for melanoma. It is a very difficult problem for a variety of reasons, one being that it is possible that the liver is somewhat of a sanctuary, and the very active immunotherapeutic agents may not be as effective in the liver. Although we certainly see responses with the PD-1 therapies and the combination with Yervoy (ipilimumab), generally speaking, it doesn’t seem like that disease responds as well as some other sites.

There are two different types of melanoma that will produce metastases in the liver. The more common melanoma arises in the skin, cutaneous melanoma. But there is another entity which a relatively rare form of melanoma, an ocular melanoma that starts in the uveal region of the eye. Interestingly enough, the most common site for that melanoma is in the liver. As a matter of fact, of the patients who have metastatic disease, 95 percent of them will have some component of liver involvement. Many of them have liver-only.

Unlike the cutaneous melanoma, we do not have a lot of good systemic therapies for the metastatic uveal melanomas. That has led to identifying different ways to treat the liver, as it is the predominant source of metastasis for the uveal sites. One of the more interesting approaches is to target chemotherapy to the liver, give high-dose chemotherapy to the liver, then have it filter out from the liver and back into the bloodstream. The problem with the study so far is that the filters that have been used haven’t been efficient enough to get rid of the chemotherapy, so there has been a lot of toxicity. But the response rates in the liver were actually tremendous and there was a prospective randomized phase 3 trial that showed a huge difference in progression-free survival and response within the liver compared with standard-of-care systemic therapy. The FDA did not approve it because of the toxicity, so we are doing another trial with an improved filter that will remove most of the chemotherapy.

The other disease in the liver is cutaneous. While there are still a lot of patients with melanoma who have metastases disease in the liver, they generally also have disease elsewhere. Liver-directed therapy is not as useful and not as effective for those patients. But there is a group of patients who may have predominant disease within the liver or in the liver only. They’ve had disease elsewhere and responded but the liver didn't respond, so it is useful to consider liver-directed therapies for those patients. Some of them can have surgery if they have minimal disease and it’s safe to do the resection—and that has probably been the most useful for identifying those select patients. You could also use hepatic profusion as well for those patients, though the frequency is going to be lower because they will rarely have liver-predominant disease.

Where do you see the future of this treatment landscape progressing?

Your other presentation was about surgery and other systemic treatment. Could you provide an overview of what you discussed?

The talk summarized the different regional approaches that are available for metastatic melanoma in the liver when that is the predominant site of disease. And also to go over the different studies that have been published on survival outcomes for resection of liver metastases. Interestingly enough, the outcomes appear to be similar if you can resect the cutaneous melanoma in the liver or the uveal. There was some historical suggestion that the cutaneous melanoma patients did not do as well with liver resection, but the data that’s available suggests that it doesn't really make a difference. If you can resect the disease in the liver, whether the primary is uveal or cutaneous, that is a useful approach if that is the only site of disease.The treatment landscape moving forward is going to be a variety of things—one would be a neoadjuvant approach. If the disease was resectable, let’s say it was cutaneous, you may want to give systemic therapy upfront to maximize response in the hope of destroying whatever microscopic disease might be present elsewhere, then remove what is left of the liver. If it is not resectable, then you can consider doing the percutaneous hepatic profusion approach for cutaneous melanoma that we have been using for uveal. Until we get an active systemic therapy for uveal melanoma, the mainstay approach for patients with liver-dominant disease would be the hepatic profusion. That approach seems to have the most promise. The landscape of metastatic melanoma treatment has changed significantly in the last five to 10 years. We have about 10 new approvals of different agents in both the BRAF-mutated as well as BRAF-wild type melanoma. And the role for surgery, at least for frontline therapy, is pretty much diminishing—I would say that it is gone. But in the past, prior to those these therapies, surgery was the best option for patients who had resectable disease, because you could identify groups of patients who would achieve long-term survival after resection of limited number metastatic deposits.

What are some remaining questions in this space that you'd like to see answered?

What would you like to emphasize about this talk?

But, generally speaking, patients are getting systemic therapy first, so the role of surgery is changing. I would say the role is in the second-line setting for patients who do not get a good response to therapy and still have resectable disease. Also, for patients who have symptomatic metastases, receiving systemic therapy is difficult, so for removing a relatively large, bleeding or painful or metastatic focus which makes it difficult for them to start novel therapies, surgery would be a good option to make these patients better candidates. What I'd like to see is at least the recognition that there may be some patients who could benefit from surgery. And we are hopeful that, moving forward, our medical oncology colleagues will not make decisions about treatment in isolation. That, again, a multidisciplinary approach is always useful. I sometimes find the exact opposite—that we are in a multidisciplinary setting and the surgeon wants the patient to get systemic therapy, and the medical oncologist wants to operate. I think, ultimately, some combination of effective systemic therapy and then surgery to be the consolidating modality, is going to emerge as the future standard of care.We have learned something in treating the advanced stage 3 patients with a novel approach using neoadjuvant therapy that I think will be a very useful approach for patients who have resectable stage 4 disease: You can optimize the treatment of a disease and hopefully systemic therapy will destroy any or all of the micrometastatic tumors which are the source for relapse or new sites for developing distant metastatic disease. I think that is a very important evolving paradigm that I am hoping will be studied in a more vigorous way moving forward.

The most important thing is probably the need for better biomarkers. Imagine how good these survival curves would be for the immunotherapeutic agents if we had very good markers to say who is inherently resistant to immunotherapy, or who is likely to acquire resistance to therapy. We could develop alternative therapies instead of going into something that we know they probably won't respond to. If there are patients who are BRAF wild type, who have markers to suggest no response to immunotherapy, and have disease that is resectable, maybe those patients should have surgery. There may be markers, or gene expression profiles within the primary tumor, even for patients that have metastatic disease. If we go back and look at their primary, we may find a signature that may be useful to predict favorable outcome from a surgical approach. I think the future challenge is to establish really good biomarkers.