Melphalan for Liver-Directed Treatment of Uveal Melanoma With Richard Carvajal, MD

Oncology Data Advisor: Welcome to Oncology Data Advisor, a digital resource for the multidisciplinary cancer team. Today, I am joined by Dr. Richard Carvajal, a leader in rare melanoma research from Northwell Health Cancer Institute in New York, to discuss the recent FDA approval of melphalan as a liver-directed treatment for uveal melanoma.

Richard Carvajal, MD: My name's Rich Carvajal. I'm a Medical Oncologist at Northwell Health Cancer Institute. I'm the Deputy Physician-in-Chief overseeing hematology and oncology at the Northwell system.

Oncology Data Advisor: Thank you, Dr. Carvajal, for meeting today to talk about this FDA approval. It's very exciting. Just for a brief background, I wanted to ask you, how does uveal melanoma affect the liver, and how does liver-directed treatment work for treating the disease?

Dr. Carvajal: Uveal melanoma is a really uncommon subtype of melanoma. We'll see maybe about 3,000 cases a year. The biology of this disease, the way it responds to therapy, is very different from the more common cutaneous disease. It's characteristically very hepatotropic. About 40% to 50% of patients who are diagnosed with a primary uveal melanoma will ultimately develop metastasis, with the vast majority having involvement in the liver, either liver only or liver predominant. Because of that, when we think about how we manage patients with metastatic disease, we can think about doing systemic therapies certainly. We have tebentafusp approved for a subset of those patients who are HLA-A*02:01­–positive. But we can also think about what we call regional or liver-directed therapies, again, because it's so liver predominant. When we think of those liver-directed therapies, historically we've thought about doing things like infusion of chemotherapy, so hepatic arterial infusion of chemotherapy, or kind of embolic-type procedures addressing the tumor vasculature, so things like radioembolization and chemoembolization have been common.

Oncology Data Advisor: To talk a bit more on the clinical trial aspect of it, could you give us a brief overview of the FOCUS trial that led to the FDA approval of melphalan for treatment of uveal melanoma?

Dr. Carvajal: Yes, so now we have, with this FDA approval, the first liver-directed therapy with regulatory approval for metastatic uveal melanoma. That's based off of this FOCUS trial, which started out actually as a randomized trial of the percutaneous hepatic perfusion of melphalan versus investigator choice. But because of accrual issues, it really became a single-arm trial.

In the end, this is a phase 3 single-arm trial of 91 patients who were treated with this Delcath Systems treatment. The primary end point of this trial was response rate, with importance certainly played to duration of response. The procedure itself, a little bit intensive, requires general anesthesia. The liver itself is kind of taken out of systemic circulation. So, the melphalan is infused in really high concentrations to the liver, and this is a procedure. Again, it requires general anesthesia. It's done in the interventional radiology (IR) or surgical suite. It's percutaneous. It's not an open surgery, but it's a procedure that can be repeated at six- to eight-week intervals, and on the trial, patients who receive up to six therapies.

The trial had impressive results in terms of response rate and durability of response. The response rate was 36%, which frankly, I've been managing and treating patients with this disease for a long time, and when we saw a response rate of 10%, we were really excited; so, to see a 36% response rate I think is meaningful. But more important than that, the durability response was really good at about 14 months. The clinical efficacy was good.

The procedure comes with associated toxicities both from the procedure as well as from the melphalan. If you look at the FDA approval, there is a black box warning. I'm talking about the periprocedural complications of things like thrombosis or bleeding, as well as we'll commonly see myelosuppression due to the melphalan. The approval comes with a risk evaluation and mitigation strategy (REMS) process to mitigate those risks.

Oncology Data Advisor: Fantastic. Thank you for sharing all that with us. You started talking about how this is the first regular approval for metastatic uveal melanoma. What does this approval mean for the future of this rare disease?

Dr. Carvajal: I think it's amazing because just over the past few years, we have approval of tebentafusp as the first systemic therapy approved for this disease, and now we have this as the first liver-directed therapy for this disease. I mean, it's really amazing that it took this long to make this degree of progress. I think to have therapies with proven efficacy now, this really serves as a springboard to build upon even better therapies.

Now we have an approved liver-directed therapy, and questions may be, how can we deliver this more safely or more easily? Is this something that we might consider combining with systemic therapy, whether it's perhaps checkpoint blockade or targeted therapies? Certainly there are additional questions now that I think hopefully will be investigated and answered with this approval.

Oncology Data Advisor: Going through the clinical trial and research, are there any limitations on the study that you would like to see addressed in future studies to potentially broaden the treatment options for this disease?

Dr. Carvajal: I think one of the questions will be—I mean, the efficacy in this single arm trial, it's good. We see the high response rate, it's durable, but it comes with a cost of some toxicity. I guess one question will be what is the uptake of this procedure going to be? It is complicated. It will have to be done at specialty centers. It is resource-intensive, and there are other regional therapies like radioembolization, chemoembolization, maybe other things, immunoembolization, as well as other investigational therapies. It's not entirely clear that this really going to be superior to these other procedures which are more commonly done, and in terms of procedural feasibility, it may be a little bit easier to do. So, I think that's something that's going to be important to figure out. Certainly, if we knew the efficacy was superior despite that toxicity, if we knew it was better than radioembolization, then I think institutions and investigators would be pushing more to increase availability of this to our patients.

Oncology Data Advisor: Fantastic. Final question I have for you today is, are there any current or future studies you're aware of that you'd like to bring awareness to?

Dr. Carvajal: Thankfully, in this field, there is an ever-increasing number of therapies and agents being studied. There's really promising emerging data about darovasertib, which is being developed by IDEAYA. Darovasertib is a protein kinase C inhibitor, which when combined with crizotinib is showing really nice response rates that tend to be durable with promising long-term clinical efficacy. So that's data that's been released.

The phase 3 trial has just started where darovasertib plus crizotinib is being compared with investigator choice, and that drug is also being tested in the neoadjuvant setting prior to a nucleation or plaque brachytherapy. So, I think that's one to look out for. Another company is studying the intrahepatic delivery of a drug called SD-101, which is a Toll-like receptor 9 agonist, that is being infused into the liver. It's another regional liver-directed therapy aimed at kind of modulating the immune microenvironment to the liver. That's being administered concurrently with checkpoint blockade, and in data that's also been released, it is showing really promising progression-free survival. I think that's another one where I'm really excited to see where that data goes.

Oncology Data Advisor: Thank you so much for all your research and insight on this topic, and congratulations on this approval. Thank you so much, Dr. Carvajal.

Dr. Carvajal: Thanks, Lyn.

About Dr. Carvajal

Richard D. Carvajal, MD, is Deputy Physician-in-Chief and Director of Medical Oncology at Northwell Health Cancer Institute in New York, where he is also the R.J. Zuckerberg Chair in Medical Oncology. Dr. Carvajal's research is focused on the development of novel therapies for patients with melanoma and other cancers, including uncommon clinical and molecular subsets such as those arising from the eye (uveal melanomas), mucosal surfaces of the body (mucosal melanomas), and palms of the hands, soles of the feet, or under the fingernails (acral melanomas). He has been the principal or co-investigator of over 500 clinical trials and has authored or coauthored over 200 peer-reviewed manuscripts, books, and book chapters. In addition, Dr. Carvajal serves as Co-Chair of the International Rare Cancer Initiative Uveal Melanoma working group, a joint initiative between the National Cancer Institute, the European Organization for Research and Treatment of Cancer, and the Cancer Research UK to enhance international collaboration in clinical trials for uveal melanoma.

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Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.