WIN Symposium 2013

Developments with PD1 and immunotherapy in melanoma

Prof Lex Eggermont – Institut Gustave Roussy, Villejuif, France

Melanoma, from an area where nothing happened for over forty years, has become the most dynamic field of drug development because of two reasons. Both in the drug mutation development, it has seen a spectacular development, but this year is really the year where the immunotherapy developments have been so convincing that it’s going to have an impact on many different other tumour systems as well.

So we know about ipilimumab, but now there are some other interesting things coming out in immunotherapy.

Yes, so the story about ipilimumab is one of fundamental scientific value that if you inhibit an inhibitor, so you put the brakes off the brakes of the immune system, you get reactivation of your T-cell system. Then you get tumour responses but not in a very high response rate percentage, 10-15%, but you get a patient population of around 20% that achieves long term tumour control for years, two, three, four, five years, something you don’t see with targeted agents. So the host immune system can create control with minor response rates but in a small subgroup, so not exceeding 20% of your patient population. Therefore people were not necessarily so convinced by the results of ipilimumab alone, also it’s a molecule that has quite a few side effects like colitis, dermatitis, hepatitis, hypophysitis, so it can knock out your pituitary gland in about 5% of patients, so unpleasant. And difficult to handle, complicated.

The new molecule is an anti-PD1 monoclonal antibody or anti-PD1 ligand monoclonal antibody and the difference is that now you have a monoclonal that works peripherally, so at the tumour site, and it neutralises the effect of PD1 ligand expression on tumours. PD1 ligand expression on tumours neutralises the effects of PD1 expressing T-cells, so T-cells express PD1. When they attack a tumour cell, when they engage with a tumour cell, and it’s a tumour cell that expresses PD1 ligand, that interaction will shut down the T-cell, it can even lead to the disappearance or the demise of the T-cell but at least it will neutralise its activity. So it’s the major way of escaping host immune control for many tumours, most likely. But like always, I would almost say in immunotherapy you hear now that melanoma has led the field so it has a very high percentage of PD1 ligand expressing tumour cells and if you prevent that interaction between PD1 ligand and PD1 the T-cells will remain active or will be reactivated by breaking up that neutralising influence. So melanomas are often quite well infiltrated by T-cells but then that T-cell population is silenced and so the tumour just progresses and will lead to the demise of the patient. Now you reactivate T-cells that are specific, that’s why they are there, they recognise the tumour cells but they have been neutralised. Now they are resuscitated and the very important thing is now we see response rates with these anti-PD1 monoclonal antibodies or anti-PD1 ligand monoclonal antibodies that are much higher than with ipilimumab, it’s around 30% to even 50%, 55% response rates. The responses come quicker than with ipilimumab alone whereas the response duration is phenomenal. So the long-term follow-up data presented at ASCO with nivolimumab, which is the BMS anti-PD1 molecule, demonstrated that the median response duration is two years whereas we used to talk about median survival for these patients of six months. So it’s completely now changing the field and it’s leading to mass conversion of medical oncologists to believe in these immunomodulatory approaches.

So it’s not only going to be true for melanoma but to some degree it’s also going to be true for renal cell, we already know that. We know that non-small cell lung cancer as well as small cell lung cancer responds to PD1 ligand monoclonal antibodies, even if it’s in third line so they already have failed two chemotherapeutic lines, still in 20-25% patients are responding to just breaking up this mechanism between PD1 ligand and PD1. So it’s a major event in oncology in general and it’s major major for melanoma because there was nothing there, as you know, only a few years ago. Four years ago there was nothing in melanoma and now we have drugs that have median duration responses of years. So I think the whole concept of a clinical cure is now actually emerging because as long as you have the tumour under control you may not be cured in an eradication type of sense but you may be cured in a controlled type of sense. So if you can transform melanoma into a chronically controlled type of disease, quite honestly nobody would have believed that four years ago so it’s major, major.

Are there any patients that are not eligible?

Right now, actually, that’s the other charm of manipulating the host immune responses, that it doesn’t care about mutational status of the melanoma. So it’s equally active, as far as we can see now, in BRAF mutated melanoma as in wild-type melanoma, as in NRAS mutated melanoma, as in we right now don’t have any indication that it’s not true, basically, across the board for all melanomas. This indirectly also opens up, therefore, for various other tumours to be explored. The PD1 and PD1 ligand programmes will be major across the board in all PD1 ligand expressing tumours, that’s what’s going to happen.

Just one more point is that the combination of anti-CTLA4, so ipilimumab, and an anti-PD1 monoclonal antibody, so for BMS it’s nivolimumab and for Merck it’s lambrolizumab, kind of new words we have to get used to, because of different mechanisms of action, one centrally, CTLA4, and one peripherally, anti-PD1, the combination of ipi and nivo has shown up to 80% response rates but, on top of that, the depth of the response is much greater than what we have seen thus far with either agent alone. So we see in the majority of patients that respond a near complete response type of regression. So we’re very hopeful that those patients will just be under control for years and years and basically have the profile then of a complete response.

So it’s high times for immunotherapy.

So someone coming to your institute, you would offer them combined therapy?

So right now it’s going to take some time before PD1 will be approved but I think it’s going to be superfast-tracked on phase II data, basically. So then they would just get up-front PD1; all metastatic melanoma patients, I think, are going to get up-front anti-PD1 as soon as it’s going to be available except for the BRAF mutated melanoma patients that are very rapidly progressive. Those patients, there you need to buy time so you need to induce a very rapid response with a BRAF inhibitor which you know will only be a transient phenomenon but you need to create that time to bring in your anti-PD1 monoclonal antibody. And we don’t know yet how the story of the combination of ipilimumab and nivolimumab will pan out, the initial report in the New England Journal of Medicine of June this year looks extremely promising but we’ll see. The report on just the anti-PD1 monoclonal antibody in the other article in the New England Journal of Medicine, it’s the Merck molecule, in the same issue of New England Journal of Medicine looks extremely promising as well with some 50% response rates, very good durability. So that remains to be seen. Right now I think we will primarily focus on immunomodulation combos and optimise the host immune response and thereafter explore combinations with targeted agents if we still need them. Because the immune story right now, for melanoma at least, is almost too good to be true.