EADO Congress 2015

Anti-PD-1 or anti-CTLA-4 in first line therapy?

Prof Claus Garbe - University of Tübingen, Tübingen, Germany

We have some powerful immunotherapies and they’re being talked about right here at the conference. But there were recent results in the study that you very much participated in looking at a combination of anti-CTLA-4 therapies and anti-PD1. Tell me first of all about the basic findings of that study that were announced recently.

It’s already a large progress that we now have PD1 antibodies available and only with this type of immunotherapy we already reach response rates of 40-50% with objective tumour remissions just by an immunotherapy. Now this is even topped by the combination of PD1 and CTLA-4 antibodies. With the combination we reach around 60% of objective tumour remissions just by the immunotherapy. With this result the combination is clearly superior either to CTLA-4 antibodies alone or also to PD1 antibody alone but it is more toxic.

Now what, then, is the case for using single agent right now? Because great progress was made simply with single agents, wasn’t it?

I would say we have to define criteria. So, there are predictive markers like low tumour volume, lack of enlargement of tumour markers in the peripheral blood and a good immune system with high relative values of lymphocytes and eosinophils. If we have such patients it’s very likely that they will respond to PD1 antibodies alone with a relatively low toxicity. So probably we will be able in future to define and to select which patients should get the single substance and in patients with higher tumour volume and with more progressive disease, more advanced disease, we probably will start with the combination.

So is anti-PD1 therapy eclipsing the anti-CTLA-4 right now?

Yes. Anti-CTLA-4 will in future have only a role in the combination and not as a single agent and not in first line.

There is also, of course, a possibility of adding to all of this targeted therapies. How do you see those as coming in to the pattern of treatment?

We will develop a number of additional substances, TIM3, LAC3 antibodies, but presently we do not have much information. So we will learn what is their toxicity and what is their efficacy and then probably such substances will either be combined to the already existing ones or they will substitute, for instance, substances like ipilimumab.

What should doctors be doing for those patients who don’t respond well to the checkpoint inhibitors, whether single therapy or combinations?

For those who don’t respond well we assume that they do not have the anti-tumour response, the specific sensitisation against tumour antigens. On a long run we have to develop specific T-cell therapies for these patients. Presently we have to give chemotherapy, on those who have the BRAF mutation we give kinase inhibitors.

We’re getting big extensions of life; are we seeing the plateaus that were being talked about initially with checkpoint inhibition?

Yes. Let’s say that we know that the plateau for ipilimumab is around 20% long-term survivors. We presently do not know what will be the plateau for PD1 antibodies because the follow-up time is too short to already define a plateau. We hope that it will be 30, 40, 50% but we have no data.

So for the practical doctor in day to day clinical practice, what is your summary of what the approach ideally should be to individualise therapy for his or her patient?

I would say nearly all of our metastatic melanoma patients should receive a checkpoint blockade therapy. And for all those who carry the BRAF mutations an alternative remains the BRAF MEK inhibition targeted therapy.

Coming down the road do you see ways that this will be improved significantly? It seems it’s made such progress already it might be rather difficult to improve on that.

There’s still, let’s say, a majority of our patients dying from metastatic melanoma. So although some of those who initially respond to the immune therapy, they may progress later. Nevertheless I think we have to further improve our immunotherapies with specific T-cell targets.