RTP On Demand — Head & Neck/Thyroid | Research To PracticePotential role of checkpoint inhibitors in head and neck cancer
7:21 minutes.
TRANSCRIPTION:
DR COHEN: We are, indeed, seeing promising activity for checkpoint inhibitors in squamous cell carcinoma of the head and neck. The 2 data sets that we have are with Merck’s drug, pembrolizumab, and with the AstraZeneca drug, MEDI4736. Interestingly, the data are fairly consistent, despite the fact that one is a PD-1 antibody and the other is a PD-L1 antibody. The data do appear to be consistent. With pembrolizumab, we have the much larger data set, now 2 cohorts that have been treated with the drug. The big difference between those 2 cohorts is that the first cohort required some expression of PD-L1, at least 1%. The second cohort did not, although many patients, of course, as you can imagine, that second cohort did express PD-L1. But the message is that the drug does have single-agent activity. It’s somewhere in the range of about 25% — 20%, 25%. It does appear that patients with higher PD-L1 expression do have a higher response rate. And it does appear that patients who have a response, those responses are durable — and incredibly durable. Really, durations of response that we do not normally see in refractory/recurrent metastatic squamous cell carcinoma of the head and neck, many months to even over a year. And the same is true of MEDI4736. The data set is smaller. There are fewer patients exposed to that drug, but the response rate seems to be in the range of about 20%. Both HPV-positive and HPV-negative. And the responses appear to be durable. So right now, this is an incredibly exciting area, incredibly promising, and, as you can imagine, these drugs are now all in Phase III studies. DR LOVE: So again, where have we heard this before? But thankfully, we are hearing stories like this all over oncology. One of the things that I was most interested in was to see what the relative benefits of these agents are, HPV or HPV-negative. You hear about, quote, mutational load, a lot of smoking relationships, but then you see Hodgkin lymphoma, where it has tremendous response rate — obviously not external mutations, maybe viral. What do we know right now about HPV status and response? DR COHEN: Yes. And it’s really such an interesting issue, because you do have these 2 sides of the argument that we know that HPV-negative disease carries a much higher mutational burden than HPV-positive disease. And yet HPV-positive disease, caused by a virus, you would think much more immunogenic. And, in fact, when we began to enter these clinical trials, many people’s hypothesis was that it would be the HPV-positive patients who responded dramatically, because here we have a virally induced entity that’s expressing completely different antigens that the immune system appears to be responding to. We know that HPV-positive patients tend to have a higher degree of infiltrate of CD8-positive T cells. And so we thought those would be the patients who really responded to the checkpoint inhibitors. It turns out that both groups of patients respond at about the same rate. So both HPV-positive and HPV-negative patients respond, and the response rates, as far as we can tell, appear to be very similar. And it may be that because the HPV-positive patients have such a high mutational burden, that’s what’s driving response in those patients, while the HPV-positives, as we hypothesize, being virally induced, that’s what’s driving the response rate in those patients. But what’s really beginning to emerge is that the response rates appear to be almost identical. DR LOVE: I’m curious what you think the algorithm is likely to be in a couple of years. And in particular, how you think, maybe, checkpoint inhibitors are going to be part of this. DR COHEN: Yes. I think in 2 years this will be dramatically different. I think we’ll have a checkpoint inhibitor approved in second line. Those Phase III trials are well underway. And we’ll have data — by 2 years we’ll certainly have data. So I think we’ll have approval in the second line. I also think that there’ll be a fair number of first-line patients who we will elect to treat with a checkpoint inhibitor. Because of the efficacy that we’re seeing in second-line, third-line and fourth-line patients, the response rate for those drugs appears to be somewhere in the range of about 20% to 25%. And they’re incredibly well tolerated. So I can imagine that there will be many patients in the first line, or a fair number of patients in the first line, where we would abjure using cytotoxic chemotherapy for a well-tolerated drug that is also effective, where the durations of response are prolonged. So I think in the second line it’s going to be the go-to agent. And I think there are some patients, a fair number of patients in the first line, where we’ll choose to use that. DR LOVE: And that discussion you just gave, I could close my eyes and I’ve heard that in a number of tumors or solid tumors. But 1 question, and I don’t know whether it might be different in each tumor that’s being thought about, and I’m curious about your thoughts about it, relates to, if you were going to talk about it in first line, okay, clinically, yes, you can start with it by itself, but does it make any sense to sequence it with other things, particularly chemotherapy? DR COHEN: It’s interesting, because there are some investigators who are using these agents that we’re getting the sense that the patients may actually do better with subsequent therapy if they’ve responded to a checkpoint inhibitor. That’s really just a sense now. There are very little data around that, but we’re accumulating that. So in terms of sequencing, first of all, let me step back a second and say we haven’t combined these yet. Those trials are being done right now or being planned right now, so combining a checkpoint inhibitor with other cytotoxics, with cetuximab, with standard of care. But there is a sense that sequencing these checkpoint inhibitors with standards of care actually does have a lot of merit. And, really, it may not matter which one you do first. It certainly appears that both the standard regimens and the checkpoint inhibitors have the same chance of working no matter which one goes first. |