A Monumental First Step in Uveal Melanoma

Guest blog post by Keith T. Flaherty, MD, Associate Professor of Medicine at Harvard Medical School, Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center and Co-Chair of the MRF’s CURE OM Scientific Steering Committee:

Twenty years ago, we had no therapies that could reliably improve outcomes for patients with any type of melanoma that was beyond the reach of surgery. Uveal melanoma, skin melanoma, all types of melanoma had the same, ominous prognosis once there was evidence of disease spread beyond lymph nodes in the case of other forms of melanoma, or the eye in the case of uveal melanoma. Enrollment in a clinical trial investigating any approach was considered better than pursuing what constituted the available therapies.

Ten years ago, gene expression testing of primary uveal melanomas was validated and introduced as a standard diagnostic test. This method provided phenomenal prediction of who was at very high risk and who was at very low risk of microscopic spread to sites distant from the eye when all other tests showed no evidence of the problem. But, there was nothing that we could offer patients to treat those invisible sites of disease.

In the past ten years, the treatment of skin melanoma that has spread (metastatic) has been revolutionized. Year after year, the percentage of patients with metastatic skin melanoma who were surviving for 5 years and longer climbed by 10% increments. It was an exhilarating time to be in melanoma research. Individual drugs were supplanted by two-drug combinations based on rapidly developing knowledge regarding the basis of success and failure with the first therapies. From 2011, when the first single-drug approaches received FDA approval, combination therapies demonstrated further improvements in outcome, leading to FDA approval of two-drug combinations starting in 2014.

Throughout this decade in which metastatic skin melanoma jumped from being one of the least treatable cancers to the one of the most successfully treated, uveal melanoma outcomes didn’t budge. More than a decade ago, we learned that what makes uveal melanoma tick is fundamentally different than skin melanoma: the genetic mutations that occur in melanocytes in the eye are completely different from those that occur in melanocytes on the skin. And, the ability of the immune system to “see” uveal melanoma was almost non-existent compared to skin melanoma. As a consequence, the drugs that targeted mutations commonly found in skin melanoma were irrelevant for uveal melanoma. And, the drugs that unleashed the immune system to attack skin melanoma rarely produced a similar effect in patients with uveal melanoma.

All of that is changing.

We now have a drug that leads the immune system directly to uveal melanoma cells regardless of where they may have travelled. In a large trial, this drug (tebentafusp, IMCgp100) reduced the risk of dying of uveal melanoma by half compared to any other therapy offered to patients in the other arm of the trial. A notable limitation of this approach is that patients must have a certain “type” of immune system (similar to blood type).

Now our task is clear: use the same approach that allowed us to rapidly move from first generation to second generation drugs; from single-drug approach to combination approaches in skin melanoma. This requires continued research and partnership between patients, melanoma researchers, and companies who have treatments that might build on this monumental first step.

2022 in uveal melanoma feels like 2011 in cutaneous melanoma. Two drugs were FDA approved in that same year; portending the beginning of a revolution that played out over the subsequent years.

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