Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Treat Uveal Melanoma that Recurs in the Liver?

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A Q&A with Emma Shtivelman, PhD, Chief Scientist at Cancer Commons; emma@cancercommons.org

Q: Malignant melanoma may arise from multiple sites, including the eye.

What would you recommend be done for a 50-year-old man in the San Francisco Bay Area who was entirely well for nine years after undergoing enucleation surgery for a large uveal melanoma, but has now been informed by his physician that he may have a mass in his liver?

A: Uveal melanoma (UM), sometimes called ocular melanoma, is a rare type of cancer, and there are no definitive guidelines for its treatment once it spreads to other organs. Because of the location of the tumor and interference with vision, most patients are diagnosed when there are no metastases. However, many patients (up to 50%) who have successful surgery and/or radiation for the primary tumor will develop metastases, which occur most often (in almost 90% of cases) in the liver.

The mutational landscape of UM is well described, but this has not translated into effective targeted treatments, in spite of clinical research efforts that have tested potentially relevant drugs. The treatment options for metastatic UM (mUM) are not many, and none are endorsed by clinical guidelines nor approved by the U.S. Food and Drug Administration (FDA), underscoring the lack of progress in treatment of mUM.

For the patient with late recurrence of UM described in your question, my first recommendation would be to seek a clinical trial. The main reasons for this are:

  1. No chemotherapy regimen is effective in mUM.
  2. While the treatment landscape of cutaneous melanoma was transformed by the introduction of BRAF/MEK-targeting drugs and by immune checkpoint blockade (ICB), this transformation has not extended to UM. BRAF mutations are practically non-existent in UM, and so far, responses to ICB have been less than spectacular. Only a low percentage of patients respond to monotherapy with anti-PD-1 or anti-CTLA4 drugs.
  3. The combination of nivolumab and ipilimumab reported an overall response rate of 16% and disease stabilization in 47%. There is an obvious need to improve the response rate, not to mention the fact that this combination is not FDA-approved for mUM, and may not be available to some mUM patients.

Liver-directed treatments present a currently available option for liver-dominant disease, and are available in a number of larger cancer clinics. They usually involve liver embolization (chemo, radio, immune) or percutaneous hepatic infusion. Precision radiation—and, less frequently, radiofrequency or cryoablation—and surgery can be used as well. Liver-directed treatments translate most often into prolongation of progression-free survival (PFS), sometimes offering a significant survival benefit. Systemic treatment (for now, most likely dual ICB) should be considered alongside or after liver-directed interventions. Recent reports based on treatment of a small number of patients indicate better PFS and overall survival (OS) in patients who received liver radioembolization with Yittrium-90 and ICB, or chemoembolization and ICB.

So, my advice to the 50-year-old patient with mUM would be, first, to biopsy the liver tumor to confirm the diagnosis and to perform mutational testing. Mutational testing can test for possible predictors of the patient’s response to combined ICB and for the slim possibility that a targetable mutation is present.

For liver-dominant disease, liver embolization should be considered as the first line of treatment, and/or enrollment in one of several ongoing clinical trials.

The current clinical trial landscape includes:

  1. ICB combined with liver embolization (Y90 SIR-Spheres or immunoembolization)
  2. Tebentafusp(IMCgp100), a bispecific antibody bridging CD3 on T cells and gp100 on melanoma cells. Tebentafusp has received the FDA fact-track designation for uveal melanoma, based on the results of a small clinical trial in which OS at 1 year was 74%. It is available in one trial only, and that trial is unfortunately randomized to investigator’s choice of dacarbazine or a single immune checkpoint drug. Moreover, it is only relevant to patients who have a certain HLA type: HLA-A*0201 (found in 44% of the population in general).
  3. A virus-based drug: oncolytic VSV-IFNbetaTYRP1 (vesicular stomatitis virus expressing IFNbeta and tyrosinase), which is designed to replicate in and induce cytolysis of cancer cells specifically, and instigate an immune response.
  4. If a BAP1 mutation is present (and most often it is in mUM), it is possible that treatment with a PARP inhibitor will have a desired effect.
  5. Cell-based treatments. These include a CAR T-cell approach with T cells modified to target the protein SLC45A2, which is often present on uveal melanoma, and tumor-infiltrating lymphocytes (TILs).

The last three trial options are new, and have not reported even preliminary results. Liver embolization (if not offered in the trial) could be considered first to reduce the tumor burden and thus hopefully increase the possible efficacy of investigational approaches.

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