First I’ll give a little background about uveal melanoma because it’s a pretty rare cancer. It’s a rare melanoma subtype but it is the most common primary tumour in adults. Patients present in a couple of different ways, normally to the eye doctor, and then the tumour is normally treated with either plaque radiation or nucleation. Then after primary treatment, primary treatment for the eye is very effective but unfortunately up to half of the patients can recur with metastatic disease and, once metastatic, prognosis is normally pretty poor and historically there have not been a whole lot of treatment options.
Uveal melanoma is pretty different from skin melanoma so skin melanoma responds very well to immune checkpoint inhibitors and can have a BRAF mutation that we can target. Uveal melanoma that’s not the case. Historically the immune checkpoints haven’t worked as well and it’s very unique in that it has a specific mutation called GNAQ and GNA11that previously we’ve not been able to target. So the trial is really looking at a drug called a PKC inhibitor, darovasertib, which targets just downstream from this hallmark driver mutation of GNAQ and GNA11. Then we combine this PKC inhibitor, darovasertib, with a MET inhibitor crizotinib. There have been shown in preclinical models and some of the early phase I that this combination could have synergy and could work well for patients with metastatic uveal melanoma.
Could you outline the methodology?
Currently there is an FDA approved systemic therapy for patients with metastatic uveal melanoma who are HLA-A2 positive because the other drug that is approved is a type of immunotherapy that requires that HLA testing. So in this trial specifically patients who were HLA-A2 negative and treatment naïve. There were two major portions of the trial, the IIa portion that was the dose finding, dose optimisation, and then we took a dose from the IIa and moved that into the IIb which is the data that is presented here at ASCO looking at the primary endpoint of progression free survival.
What did you find?
In the IIb portion that’s being presented here what we found was that patients who were randomised to the darovasertib and crizotinib, that’s the PKC and MET inhibitor, versus investigator control which was really the option of ipilimumab and nivolumab, pembrolizumab or dacarbazine, there was a near doubling of progression free survival, so 6.9 months in the darovasertib and crizotinib arm and 3.1 months in the investigator choice arm. Also then when looking at other secondary endpoints such as overall response rate, duration of response, disease control rate, the darovasertib and crizotinib combination did better than investigator choice.
We also looked at safety. Both of these drug approaches have been tested before so we knew what the side effects would be. There were no new side effects in either arm but you did see in the darovasertib/crizotinib arm side effects such as nausea, vomiting, diarrhoea, swelling, low blood pressure. In the predominantly what was an immune checkpoint inhibitor arm with ipilimumab, nivolumab or pembrolizumab, you saw the immune-related side effects of things like colitis, hepatitis and endocrinopathies.
What impact could these findings have?
Prior to this we had no effective systemic therapy, especially for HLA-A2 negative patients for metastatic uveal melanoma. So this is really the first targeted therapy, again, in this unique patient population to show an improvement in progression free survival. So the hope is this may be potentially a new therapeutic for a disease with a very poor prognosis and a high unmet need.
