Meet The Professors: Myelodysplastic Syndromes Edition, 2016Checkpoint inhibitors in MDS
4:36 minutes.
TRANSCRIPTION:
DR GARCIA-MANERO: We know from the solid tumor experience that hypomethylating agents actually activate the expression of PD-1 and PD-L1. So the group at Hopkins published very beautiful data that actually was based on our clinical observation. So I heard one, Stephen Baylin at MD Anderson around 4 or 5 years ago talking about some trial of lung cancer where patients came to Hopkins for a trial of decitabine or azacitidine, some type of methylating agent. And the patients did not respond. And then somehow this small, 2 or 3 patients — I think this was anecdotal — went to Memorial or something like this. And then they got into a trial of PD-1 and the disease apparently disappeared. And then Steve came back and they saw actually that you could, in a way, prime these cells with the hypomethylating agent. So I was listening to this talk, and that afternoon we decided to check the expression of PD-1/PD-L1. And this paper was published in Leukemia in 2014. We saw exactly the some thing. So if you look at the cellular stem cell of this disease, the CD34-positive cell, they actually express PD-1 and PD-L1 at the mRNA level. And if you treat them with hypomethylating agents, you actually enhance that response. So now I can tell you that, thanks to this data, there may be in the country probably over 10 clinical trials looking at different PD-1 — from pembro to nivo to — they’re like 4 of these drugs. DR LOVE: Anti-PD-1 and PD-L1. DR GARCIA-MANERO: One. And then there are trials where people are looking at monotherapy with PD-1 or combinations with these PD-1s and PD-L1 and, importantly, with hypomethylating agents. So we completed a multicenter study of what we used to call MK3475 for low-risk MDS, and we’re trying to put that data together. And there are a number of studies looking at aza plus PD-1 and PD-L1. DR LOVE: Could I just clarify one thing though, because this comes up, as you know, in every single cancer nowadays. And one of the issues is, have you yourself or anybody, let’s say at your place, in your trials, observed patients who seem to be having an extraordinary response either to a checkpoint inhibitor alone or more than you would expect from a hypomethylating agent? DR GARCIA-MANERO: Okay. So this I have to be careful because none of this data has been really presented at any meeting. But I can tell you, we have treated over 100 MDS patients with PD-1/PD-L1 inhibitors, and there are people in the first wave of trials, what we call HMA failure, and the perception is that, similar to what you see in the solid tumors, it appears that there’s a fraction of these patients who stabilize and that they are now alive well longer than what they should be. But this was not tested yet in a randomized trial or in a really solid prospective study. These companies are so busy with the solid tumor trials and the lymphoma studies that they are doing the smaller trials in MDS just to pick what type of signal there is. But from our studies, there are people alive. I just saw yesterday before coming here, she’s on her 55th dose of pembro. This is given every 2 weeks with HMA failure MDS. DR LOVE: Wow. Interesting. Harry? DR ERBA: So just to follow up on that. For the last year, year and a half, I’ve been the chair of a working group of investigators from the Cooperative Groups in North America and Canada, and we’ve designed a randomized Phase II/Phase III study in cooperation with C-TEP that is now going through the activation process, first steps. Interestingly, based on the MD Anderson data and some of these reports, our control arm in older AML patients is going to be azacitidine for less fit patients. So it’s AML, but often these patients have evolved from MDS, same kind of biology. And one of the several treatment arms is going to be nivolumab with azacitidine. DR LOVE: This is just AML or also MDS? DR ERBA: It’s just AML at this point. DR LOVE: Anything like that being talked about for MDS? DR ERBA: There’s a separate working group in the Cooperative Groups for MDS. And so that’s one of the ideas that’s been proposed there as well. DR GARCIA-MANERO: I know 5 clinical trials looking at this in MDS. DR LOVE: So it’d seem like that may be attractive as a lot of checkpoint inhibitor trials are nowadays. |