WCCS 2016

Checkpoint inhibitor therapy for treating melanoma

Dr Jeffrey Weber - Perlmutter Cancer Center, New York, USA

There has been an awful lot of activity in the field of immunotherapy for melanoma over the last decade and a number of new approvals in melanoma have been immunotherapeutic over the last five years so that’s, shall we say, a hot topic for this year’s meeting.

The most important updates at the AACR meeting, at the ASCO meeting several months ago and now, of course, at this EADO WCCS meeting relate to further data on combination therapies with checkpoint inhibition and targeted therapy, updates on survival from patients who got combination ipilimumab with nivolumab showing a 69% two year survival, which is pretty darn impressive, and updates on the progression free survival advantage which appears to plateau at a very high level in patients getting ipilimumab and nivolumab. Then discussions on some of the earlier phase trials where we have combined pembrolizumab or nivolumab with other drugs, for example there’s an IDO inhibitor called epacadostat which looks very promising when combined with pembrolizumab. T-VEC, which is the genetically engineered herpes virus combined with pembrolizumab looks impressive and then recent data from ASCO on the BRAF MEK inhibitors dabrafenib and trametinib when combined with pembrolizumab. All of them look very impressive in terms of their early results.

Then, finally, we have other agonistic molecules combined with checkpoint inhibitory molecules such as OX40 antibody or 41BB antibody which are activators, meaning the accelerators not the brakes like pembrolizumab or nivolumab. Those trials will, I am sure, be generating some very interesting data.

Could you discuss the “abscopal effect”?

Radiotherapy with checkpoint inhibition is a whole field of endeavour where there are literally dozens of trials, especially with ipi, looking for what’s called the abscopal effect. Again, the abscopal effect on a theoretical basis would consist of giving radiation to cause inflammation of a tumour, which would convert a cold tumour to a warm tumour, followed by checkpoint inhibition in a scenario where the patient with the warm T-cell infiltrated inflamed tumour would have a better chance of responding to the therapy. To be honest, this abscopal effect is much more honoured in the breach than in the observance, to tell you the truth. There have been only a few small trials so far that have shown its potential benefit and there are a variety of phase III trials of checkpoint inhibition versus checkpoint inhibition with radiation that will answer that question and none of them have quite matured. But the initial trials have not quite shown the promise that we would have expected from the preclinical and the phase I data.

In addition to radiation combinations there are also a couple of trials of adoptive cell therapy with checkpoint inhibition, for example at the National Institutes of Health they’re pursuing one, at my former institution at Moffat in Tampa, Florida, they’re pursuing one and we’ll hear about those data probably next year at ASCO, probably premature to be discussing them at this meeting. But lots of action in the combination checkpoint inhibition field.

Any final thoughts?

I was surprised and a little disappointed to hear that one of the nivolumab trials in front line non-small cell lung cancer had preliminarily been a negative study for progression free survival. While you can always argue that PFS is not the be all and end all, in melanoma certainly the PFS, the progression free survival, with checkpoint inhibition was clearly superior to that achieved with chemotherapy. So I was a bit surprised but, nonetheless, it would not deter me from or turn me away from the belief that checkpoint inhibition, both in melanoma, bladder, non-small cell lung cancer and a variety of other malignancies like Hodgkin’s disease, head and neck cancer, is a revolution because the tail on the curve will be superior for checkpoint inhibition in all of those histologies, meaning the long-term survivors without progression will be superior for those patients than with those who get chemotherapy.

I think over the next five years we’re going to be going to double and triple combination therapies. At NYU we’re pursuing the use of ipilimumab and nivolumab with HDAC inhibition which would be one of the first triple combination therapies. Again, the good news there is if we change the doses and schedules of the ipi/nivo combination we may get a good clinical result with less toxicity and thus the ability to add the third drug. The bad news is who is going to pay for all this if we end up having triple combinations. That’s a completely separate issue that will merit lots of attention in the coming years.