At ASCO this year we presented results for the five year survival of a phase II randomised trial of dabrafenib and trametinib versus dabrafenib alone and there was also another dosing cohort. But the main results are those for the combination of dabrafenib and trametinib and we saw that the progression free survival of these patients, it’s a small study, was 13% at five years. Normally at five years 1-2% of patients are alive so this is 13% progression free at five years. We also saw the overall survival which was well over 20% at five years. But if we took the group that had a normal LDH at baseline and fewer than three metastatic organ sites involved they did particularly well, with a 25% progression free survival at five years and a 51% overall survival at five years. So there is a tail of the survival curve for patients treated with targeted therapies, with dabrafenib and trametinib, and it seems to be those who have a good prognostic disease, so normal LDH and few metastatic organs involved.
In that case we can move on to one of the other presentations about brain metastases.
Yes, there were some other interesting presentations at ASCO, one of which was the anti-PD-1 brain collaboration which was an investigator led study in Australia. In that we saw that patients with active growing melanoma brain metastases if they were treated with the combination of nivolumab and ipilimumab 42% had a response in the brain. If we only took the patients who were first line, so had not had previous BRAF and MEK inhibitors, 50% had a response in the brain. These patients usually survive only a few weeks so that’s pretty significant. The progression free survival in the patients who got nivolumab combined with ipilimumab was excellent with a six month progression free survival of 47% and the curve just flattens out. Furthermore, there were patients with a complete response, in fact 15% got a complete response, none of them have yet progressed and this is with a median follow-up of 16.8 months. If you had a partial response very few progressed so they’re still in response. If you had stable disease in the brain you had more progressions in that setting but a pretty significant game-changing result suggesting that you can give immunotherapy, particularly combined immunotherapy, up front in patients with active melanoma brain metastases.
There was another cohort in that trial who just got nivolumab alone and they didn’t do as well, they had a 20% response rate in the brain. So this trial really was very game changing in terms of how we approach brain metastases because usually we approach them with local therapy whereas this trial is saying in 50% you’ll get a good response in the brain without any local therapy before.
We’ve heard from other indications for nivolumab and ipilimumab together that the toxicity profile is something to overcome. Is that true for brain metastases as well?
Interestingly we didn’t see any new or unusual toxicities. We saw what we usually see in the big trials from the extracranial metastases so no new toxicities. It is a toxic regimen and we are exploring different dosing schedules of the ipilimumab to see if we can decrease the toxicity but keep that activity.
Were there any other benefits, say, this was just looking at brain metastases but any benefits to looking at their primary lesions, if they still had melanoma on the skin?
Most patients who have metastatic melanoma don’t have their primaries any more, they’ve been resected years ago. The common pattern of progression in melanoma is you have your primary and you develop stage 4 metastases later, sometimes 30-40 years later. So patients don’t have their primary lesions but what we did look at was the extracranial metastases in that brain study and they were very concordant with the brain response. So if you had a good response in the brain you tended to have a good response extracranially as well.
I think that covers that, are there any plans for expansion of that trial set?
Yes, that’s a very good question. We’re now looking at using ipilimumab and nivolumab in a trial setting and those that don’t get a response, so 50% get a response, the other 50% don’t, adding in radiotherapy after about six weeks to those who don’t get a response to see if we can get a nice response with an abscopal effect from the radiotherapy because we know radiotherapy is synergistic with immune therapy.
It sounds like the kind of therapy that will do you a lot of good if you survive it. It sounds pretty intense.
We had an abstract at this ASCO that we presented looking at the combination of anti-PD-1 plus radiotherapy and side effects and adverse events. It’s actually very well tolerated; you do see some radionecrosis, it seems to be manageable. We’ve actually published on it as well, there’s a general article, Liniker is the first author, and it reports on how well tolerated radiotherapy to the brain combined with anti-PD-1 is.