Figure 1. Head: PET-CT showing the primary melanoma (uveal) in the left eye Image: Lisa Tarlinton, St Vincent’s Clinic Medical Imaging and Nuclear Medicine
Science Communications Specialist, Melanoma Institute Australia
With advances in melanoma research in recent years, for the first time survival rates are skyrocketing. However, these promises of hope are not being seen in a rare form of melanoma, known as uveal melanoma, and researchers are desperately trying to uncover new ways to treat this disease.
Uveal melanoma is the most common form of cancer originating from the eye in adults. While there are effective treatments for early uveal melanoma, options are limited for patients who develop advanced (metastatic) disease.
It is a very different disease from skin melanoma; it is caused by different gene mutations, is not linked to sun exposure and responds differently to treatment. Unlike skin melanoma, the survival rate of patients with uveal melanoma, which is a form of ocular melanoma, has not changed over the past 35 years. It is an understudied cancer and further research is essential if survival rates are going to change.
Dr Matteo Carlino, medical oncologist at Melanoma Institute Australia (MIA) says the drugs that are proving effective in skin melanoma have only minimal activity in uveal melanoma. In skin melanoma, response rates to anti-PD1 treatment are greater than 40 per cent but when these same immunotherapy treatments are given to people with uveal melanoma, response rates are only three to four per cent.
‘A lot of doctors treat uveal melanoma with drugs usually used for advanced skin melanoma, mainly because of a lack of other options rather than evidence of success,’ Dr Carlino said. ‘We don’t know why, but there is a very small percentage of people with uveal melanoma who do respond to those treatments, and we need to find out why.’
In addition to responding differently to treatment, uveal melanoma has different genetic mutations from those of skin melanoma. BRAF and NRAS gene mutations, which are commonly seen in skin melanoma, are not seen in uveal melanoma. However, uveal melanoma is commonly associated with mutations in two genes (GNAQ and GNA11), offering hope that specific drugs can be developed to target these mutations.
Treating uveal melanoma
Following local treatment to the eye with surgery or radiotherapy, about one half of all people with uveal melanoma will suffer a recurrence of the disease.
There is currently no standard treatment for advanced uveal melanoma and so there is variable care between doctors. Some oncologists treat patients with advanced uveal melanoma in the same way as a patient with advanced skin melanoma. In selected patients, treatment can be directed at the liver, the most common site of recurrence.
‘Ninety per cent of people with uveal melanoma will have liver metastases as their site of recurrence; often it is their only site of recurrence,’ Dr Carlino explained.
Figure 2. Liver: PET-CT showing liver metastases in a patient with uveal melanoma Image: Lisa Tarlinton, St Vincent’s Clinic Medical Imaging and Nuclear Medicine
Uveal melanoma clinical trials
‘More research and trials are desperately needed to elevate survival rates, as has been the case with skin melanoma,’ Dr Carlino said.
To address this need in patients with uveal melanoma, MIA is running two new clinical trials investigating novel treatments for patients with metastatic uveal melanoma.
The Phase 1 study of a new targeted treatment for uveal melanoma, led by Dr Carlino at Westmead Hospital in affiliation with MIA, is currently recruiting. The trial will test the safety, tolerability and efficacy of LXS196, an oral protein kinase C inhibitor, in patients with metastatic uveal melanoma. This drug has been specifically developed to target uveal melanoma mutations in the GNAQ and GNA11 genes.
There will also be a Phase 3 trial commencing at MIA this year to compare a new immunotherapy (called Immunocore) with chemotherapy (dacarbazine) in patients who have not received any other treatments. This is being investigated by Associate Professor Alex Guminski at MIA.
In addition to these clinical trials, laboratory studies to understand the response to these and other novel treatments for uveal melanoma will occur in Professor Helen Rizos’s MIA-affiliated research group at Macquarie University.
‘The Phase 1 study will be the first time MIA has run a clinical trial in uveal melanoma and I’m excited to be part of it. This is a world-wide trend; uveal melanoma has historically been under-represented in clinical trials but I think the tide is finally turning,’ Dr Carlino said.
Patients interested in participating in a clinical trial should have their oncologist contact Dr Carlino or Professor Guminski as strict eligibility criteria apply.
A patient’s view
Participating with Stage 4 melanoma in MIA’s Phase 1 trial
Being diagnosed with uveal melanoma at the age of 52 was not something Guy Winship could have imagined happening to him. Now facing a Stage 4 melanoma diagnosis, Guy’s only hope of spending more time with his family is to participate in a new clinical trial at Melanoma Institute Australia.
‘This whole experience has been somewhat surreal. I didn’t even know there was such a thing as eye cancer; I’d never heard of it,’ Guy said.
In September 2013, Guy presented to his GP with blurred vision in his left eye that had persisted, without pain, for a week. His GP thought his retina had detached and he was sent to the Sydney Eye Hospital. At the hospital, Guy was told that there was a mass behind his eye. He was referred to ophthalmologist Dr Michael Giblin and underwent enucleation under a local anaesthetic.
‘I regret having a local anaesthetic. Although my physical recovery time was minimal, I’ve been emotionally scarred from the experience,’ Guy said jokingly.
Living with one eye has been an adjustment but he’s learned to adapt to the changes well, and has a good sense of humour about it.
‘My car has scratches all over it,’ he said. ‘In the beginning, I found it really hard to pour water into a glass. It’s such a simple task but I’d end up with water everywhere. But you learn to adapt. I move my head more now to get more information in and I’ve learned to touch the top of the glass when pouring water.’
A year after his enucleation, Guy received from his oncologist, Professor Alex Guminski, the news that he had been dreading. The melanoma had metastasised. It presented in his liver, which is typical of uveal melanoma, and in his bones and joints.
‘I was told to get my affairs in order and he gave me 12 months to live,’ Guy recalled. ‘Going home and telling my kids, then 15 and 11 years old, was incredibly hard. It’s been hard on them and my wife too. Facing your own mortality is a very sobering experience. I’m a very positive person but you definitely have your dark periods.’
Guy has undergone a number of treatments to buy him time, including transarterial chemotherapy where a catheter delivers chemotherapy directly into the artery that feeds the liver. When this failed, his oncologist treated him with an immunotherapy, ipilimumab (Yervoy). After suffering severe side-effects, like losing the use of his pituitary and thyroid glands, he was put on another immunotherapy, pembrolizumab (Keytruda). Again, severe side-effects, this time pneumonitis, caused Guy to come off the treatment.
‘Tumours in my liver over the past year have been largely stable, thanks to the immunotherapies, although there has been a spread to the lungs and peritoneum but I can’t continue on the treatments because of the side-effects,’ Guy said.
Running out of options, Guy’s oncologist suggested that he participate in a new clinical trial being run at Melanoma Institute Australia. Guy has been on the Phase 1 trial testing the compound LXS196 since November. This is a new therapy that specifically targets gene mutations found in uveal melanoma.
It is still early days but Guy’s tumours have stabilised. He does have a number of side-effects again, most notably a rash all over his body, but it is being managed.
‘This research is a chance for me to live, to survive. It’s as simple and straightforward as that. This is the only realistic option I have of beating this cancer and surviving longer so I’ll do whatever it takes,’ Guy said.
‘It would be great if I could see my kids finish high-school. That would be really nice. I’ve got five years to go. If I can hang on, that’d be great.’