EADO Congress 2015

Benefit and risk analysis from the phase III OPTiM trial

Dr Kevin Harrington - Institute of Cancer Research, London, UK

You’ve been looking at an oncolytic therapy, in fact an oncolytic virus. Tell me all about the study that you’ve just been reporting here.

The data that we’re presenting here today are related to the OPTiM study, that was a phase III clinical trial in which patients with melanoma between stage 3b and stage 4M1c disease were randomised between the oncolytic herpes simplex virus, talimogene laherparepvec, which is a genetically modified agent, or standard of care which was subcutaneous GM-CSF.

And known for short as T-VEC.

It’s called T-VEC and it has now, indeed, got a brand name and is called Imlygic is the other name for this.

And it has just been licensed in the US and could be soon in Europe.

It’s had a favourable opinion in Europe from the EMA for the CHMP and it got an approval yesterday by the FDA.

So tell me what you did, please, in these two groups of patients with different stages of melanoma.

Patients either received intratumoural injections of the T-VEC agent or subcutaneous injections of GM-CSF. The study involved 436 patients randomised on a two to one basis between the virus or the standard immunotherapy. We followed the patients with a primary endpoint of durable response rate which was defined as a patient having a response that lasted for a minimum of six months and that response could evolve at any time in the first twelve months.

And GM-CSF was a reasonable comparator because T-VEC works via GM-CSF, doesn’t it?

T-VEC has many mechanisms of action so one of the mechanisms is that it is able to replicate selectively in cancer cells and that’s because of some of the genetic modifications that have been made. But one of the things that has also been done is that by removing some genes from the HSV virus we’ve been able to reinsert other human genes, in fact in this case human GM-CSF, and GM-CSF is a potent immunogenic signal and so the virus not only kills directly but it also secretes GM-CSF and we hope in that way it has a dual mechanism of action – direct cytotoxicity and education of the immune system to attack systemic disease.

So could you run me through the data, so far as you have them, in round figures, then? What did you find?

For the overall study that actually has been published earlier this year in the JCO, that data showed that the study met its primary endpoint in durable response rate. The durable response rate in the T-VEC arm was a little over 16% and in the control arm was about 2%. In terms of the overall response rate the data were something like 26% overall response for T-VEC versus about 5% for GM-CSF. So the analysis that we present today is based on risk benefit analysis based upon those OPTiM data.

And what are your findings then?

The findings are that there is a significant benefit to patients and we define benefit in terms of durable response, overall response, overall survival and some other endpoints. We show that for T-VEC that this is a treatment that is beneficial to the patients. We show that in a number needed to treat analysis which gives us the NNT for benefit we show that on average for a benefit to a patient in durable response we need to treat a little over four patients to see a patient deriving benefit and in terms of the overall response analysis we need to treat a little over two patients in order to see a benefit from the T-VEC arm of the treatment. If we turn that analysis on its head and look at the harm done to patients we find that those numbers are reassuringly high and harm was defined either as an episode of cellulitis, an episode of oral herpes simplex or an autoimmune event, and those events were significantly higher showing that actually the treatment was being delivered with benefit but low risk of harm.

And the benefit is also related to the stage of melanoma that you have, isn’t it?

In this specific analysis that we have done we’ve looked both at the total population of patients included in OPTiM but we’ve also looked at a group of patients for whom we were able to define in subgroup analysis a more favourable outcome and that is the patients with stage 3b, 3c and stage 4M1a disease. We showed for those patients that in comparison to the total population the benefits to those were very significantly greater, and those are the data that I’ve just rehearsed with you earlier, and also the harm data, which again are the data that I’ve presented you earlier, were for that specific subset of patients.

So what are the clinical recommendations that can come out of this?

The recommendation that we can make is that T-VEC, Imlygic, is a sensible treatment for patients with locoregionally uncontrolled melanoma, for patients also with metastatic disease in whom they have a generally low burden of disease, probably a slow pace of progression of disease, T-VEC represents a new treatment that can now be included in the armamentarium, another immunotherapeutic that will give us benefit for patients with melanoma.

In the context of the increasing numbers of agents available to treat metastatic melanoma where would you place T-VEC?

I think T-VEC comes relatively early in the treatment course of patients and certainly for the European EMA application the group of patients in whom we’re going to be delivering treatment is going to be for patients with earlier stage disease, 3b, 3c, stage 4M1a disease. For the FDA, in fact, the license is broader and the license will include the later stages of disease. But certainly for patients with earlier stage disease some suggestions that earlier treatment phase, so for instance first line therapy, may be beneficial over later lines of therapy. So that group of patients will be well-served by T-VEC, potentially reserving the other immunotherapeutics for later stage disease. Of course there is huge excitement now about combination regimens in which we include T-VEC alongside some of those other monoclonal antibody based therapies.

In a few words what would you leave doctors with, as a message?

We now have a new immunotherapy that is available for the treatment of melanoma. It’s a first in class agent, an oncolytic immunotherapy and it’s an agent that will be very interesting to watch its evolution in combination with other immunotherapeutics in the future.