ASCO 2015

Randomised trial of pembrolizumab versus standard treatment in patients with recurrent or metastatic head and neck cancer

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

The KEYNOTE-012 study had clinically meaningful findings using pembrolizumab and that was in recurrent or metastatic head and neck cancer, what is it, what is the challenge that you are looking at right now?

Last year we heard for the first time results from the KEYNOTE-012 study showing that there was activity of pembrolizumab in both HPV negative and HPV positive cancer. This year we’ve heard data from an expanded cohort of patients in that study, more than a hundred patients treated. What we’re seeing is we’re seeing response rates of about 20% in the HPV positive population, 27% in the HPV negative population. This, for the first time, is showing us that we can use immune therapies against relapsed metastatic head and neck cancer.

Now that is putting it in focus for your new study which is going to do what?

Having seen that signal, it’s now important to test whether or not pembrolizumab is able to achieve results that are going to be better than standard of care. So in the KEYNOTE-040 study the randomisation is between pembrolizumab or standard of care physician choice chemotherapy, which represents one of three drugs which would either be single agent cetuximab, single agent methotrexate or single agent taxane-based chemotherapy.

Now what about the HPV signal, is that being taken into consideration as well?

Yes, it’s a very interesting piece of information. So we know that the mutational burden of tumours is important in determining how well they respond to immune therapies. We know that the HPV negative tumours are probably highly mutated as a result of exposure to tobacco and alcohol. We also are seeing, now, that the HPV positive tumours are showing responses to pembrolizumab as well and that’s probably due to both mutational burden but also the presence of viral antigens.

What is it that pembrolizumab is doing or that you’re hoping to do with it within the molecular structure of what’s happening in these patients?

We’re beginning to understand that, as with many other types of solid cancers, the tumour cells often will express on their surface the PDL1 ligand, the programmed death ligand 1, that is capable of turning off the immune response that comes into attack or to address the tumour. By blocking the ability of that ligand on the tumour cell to engage with the receptor on the T-cells, what we are hoping to see is that we are able to wake up the immune response against the tumours.

And the earlier results did show something like half of the patients responding. Do you think that could happen here?

The initial study showed about a fifth of the patients were responding to treatment. We would hope that we’ll see results that will be as good as that, hopefully better in the phase III study, but hopefully we think that a significant proportion of patients with relapsed metastatic head and neck cancer can derive benefit from these therapies.

Because the 50% I was referring to is called disease control.

Well, disease control, of course, is another issue. I was talking about objective responses of the tumour which is what most oncologists would recognise as activity of the drug. But, of course, if you include the presence of stable disease where the disease doesn’t get bigger then you can improve outcomes for a larger proportion of patients.

So where could this leave clinicians? Does it represent, do you think, a potential new weapon for patients who don’t have too many choices?

We know that there is no treatment currently approved in second line treatment of head and neck cancer as being the gold standard. What we are hoping for with this particular protocol is that we’ll derive evidence of a gold standard therapy whereby pembrolizumab will beat physicians choice second line chemotherapy and potentially if it’s a positive result, and of course we’re a long way from that, establish a new standard of care in these patients.

Of course the harnessing of checkpoint inhibition is a new departure in head and neck cancer do you see this going a long way, perhaps even with other agents?

I think that’s certainly the case. We know already that a number of the other pharmaceutical companies that have a range of different assets, including both PD1 and PDL1 blockade, are already in this space and are already assessing head and neck cancer patients. So I think we’ll see a lot of activity in the coming years.

So what should practising cancer doctors take away from this now here at ASCO?

I think they should take away the message that head and neck cancer, as with a number of other solid cancers, is now a disease that is very reasonably targeted with immune therapies including checkpoint blockade and they should watch very carefully this space because we will see data evolving in both the second line setting and then potentially in the first line setting for patients with relapsed metastatic head and neck cancer.