Improving survival in uveal melanoma

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 with the advanced (metastatic) form of the disease. It is distinct from skin melanoma, insofar as it’s caused by different gene mutations, not linked to sun exposure, and responds differently to treatment.Unlike skin melanoma, the survival rate of patients with uveal 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.According to Dr Matteo Carlino, medical oncologist at the Melanoma Institute Australia (MIA), the drugs that are proving effective in treating skin melanoma only produce minimal activity in uveal melanoma.{{quote-A:R-W:450-I:2-Q: As has been the case with skin melanoma, more research and trials are desperately needed to elevate survival rates, -WHO:Dr Matteo Carlino, Medical Oncologist at the Melanoma Institute Australia (MIA)}}In skin melanoma, response rates to anti-PD1 treatment are greater than 40%. However, when these same immunotherapy treatments are given to people with uveal melanoma response rates are only 3–4%.“A lot of doctors use the same drugs to treat uveal melanoma that we have for advanced skin melanoma, but this is because of a lack of options rather than evidence of success,” 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.”A different diseaseIn addition to responding differently to treatment, uveal melanoma has different genetic mutations to skin melanoma. BRAF and NRAS gene mutations, which are commonly seen in skin melanoma, are not seen in uveal melanoma. The cancer, however, 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 melanomaEven with local treatment to the eye with surgery or radiotherapy, approximately half of all people with uveal melanoma will suffer a recurrence of the disease.There is also currently no standard treatment for advanced uveal melanoma, which results in variable care between doctors. Some oncologists treat patients with advanced uveal melanoma in the same way as a patient with advanced skin melanoma. Additionally, in selected patients, treatment directed at the liver – the most common site of recurrence – can be used.“90% of people with uveal melanoma will have liver metastases as their site of recurrence; often it is their only site of recurrence,” Carlino said.Uveal melanoma clinical trials“As has been the case with skin melanoma, more research and trials are desperately needed to elevate survival rates,” comments Carlino.MIA is conducting two new clinical trials to address this need by investigating novel treatments for patients with metastatic uveal melanoma.The Phase I study of a new targeted treatment for uveal melanoma, led by 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.“The Phase I 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 worldwide trend. Uveal melanoma has historically been underrepresented in clinical trials, but I think the tide is finally turning,” Carlino said.Aside from Carlino’s clinical trials, an MIA-affiliated research group from Macquarie University led by Professor Helen Rizos will conduct laboratory studies to understand the response to these and other novel treatments for uveal melanoma.There will also be a Phase III trial commencing at MIA in early 2017 to compare a new immunotherapy (called Immunocore) with chotherapy (dacarbazine) in patients who have not received any other treatments. This trial is being conducted under the guidance of Associate Professor Alex Guminski at MIA.