ASH 2014

Blocking PD-1 activity could be safe and effective in classical Hodgkin lymphoma

Dr Phillippe Armand - Dana-Farber Cancer Institute, Boston, USA

You’ve been investigating a PD1 pathway, the PD1 pathway checkpoint inhibition. It’s quite big news, isn’t it, and you’ve been using nivolumab. Can you tell me what you were doing and which disease context, first of all?

This was a phase I study of nivolumab. The study itself enrolled patients with a number of haematological malignancies: Hodgkin lymphoma and non-Hodgkin lymphoma and myeloma. This particular presentation, this work, focussed on the Hodgkin lymphoma sub-group of 23 patients. The reason that Hodgkin lymphoma was included in this study was based on scientific work that was done a few years ago, mostly in Dr Shipp’s lab at Dana Farber, which showed that Hodgkin lymphoma… Hodgkin lymphoma we’ve known for a long time, it seems to attract immune cells which surround the malignant Reed-Sternberg cells and somehow impair their function because it survives in the host despite this brisk immune infiltrate around it. So many of us have wondered for a long time what it was about Hodgkin lymphoma that allowed it to control the immune response against it. What the work from Dr Shipp and her colleagues showed a few years ago is that Hodgkin lymphoma frequently had a genetic abnormality, amplification of genetic material at the 9p24 locus, which results in overexpression of the PD1 ligand, PDL1 and PDL2. There are other reasons why the PD1 ligands get overexpressed in Hodgkin lymphoma but leads to the thought that Hodgkin lymphoma may have this genetically determined dependence on PD1 for survival.

Now PD1 has been a crucial target in solid tumours, hasn’t it, so there’s some track record in this.

Correct. So the original intent of this work was to bring PD1 blockade to the haematological malignancies based on the astonishing results in the solid tumours. But there is something unique about Hodgkin lymphoma and that is, again, this genetic background which doesn’t exist for solid tumours. There is no other tumour that we know of, as of yet, that has a genetically programmed dependence on PD1, the way Hodgkin lymphoma seems to have. That was the reason why Hodgkin lymphoma patients were enrolled on these studies as separate expansion arms.

So what did you do? The patients you chose and how did you treat them?

Those were patients with relapsed refractory Hodgkin lymphoma and they were quite heavily pre-treated, patients with advanced disease. They were treated with nivolumab, so single agent monoclonal antibody therapy against PD1.

And what happened?

And what happened is many of them responded. Actually, all of them had some reduction in their tumour as their best response, and the response rate in this population was 87%. 17% of patients achieved a complete remission, 70% a partial remission and it seems, even though the follow-up is still short, that the responses can be durable. We’ve had responses over one year and most of the responses happen early.

Now, big claims are starting to be made of this but this is quite a small study, isn’t it?

Correct. So I’m not making any big claims and I’m the first to say that these results need to be confirmed and expanded. But you now have two studies of PD1 blockade in Hodgkin lymphoma, the one from nivolumab, the one from pembrolizumab, both showing extremely encouraging response rates in very heavily pre-treated patients. So I think the results are here to stay. Where this drug will fit in the management of patients, what it can be combined with, how early we can move it up, those questions remain to be answered.

What about toxicities, for example?

The safety profile overall of nivolumab is something that we know quite well because it’s been used so extensively in solid tumours. I think what we can say from those studies, it seems like the toxicity profile is similar in haematological malignancies which is overall quite good, especially compared to chemotherapy. So on this particular study there were no drug related fatal events, no drug related grade 4, life-threatening, events and the severe events, for the most parts, were manageable.

So what should happen now?

We obviously have much to learn on many fronts. Those findings are being extended in a large phase II study of nivolumab that’s now on-going. The interest is in moving it earlier in the treatment course of patients; using it in combination with other treatments; learning if the patients who do not respond, why they don’t respond; what’s the biology behind absence of response or what’s the biology behind progression for patients who lose their response and how do we target that to increase further the response rate and its duration.

What would you say doctors can learn from your findings so far?

At this point what I would say is it means PD1 blockade is a very promising treatment for patients with classical Hodgkin lymphoma and with further work I hope it can really become an important part of the treatment arsenal against this disease.

So what’s the take home message for doctors as far as treating their own patients might be concerned?

All the treatments are still done in clinical trials. This drug does not have FDA approval for treating Hodgkin lymphoma at this point. What the FDA gave on the basis of those results is breakthrough designation. So it will be a little while before the drug is FDA approved or before doctors can use this in clinic to treat their patients. It may be a little early to do that but certainly to encourage participation in clinical trial with those drugs so that we can learn more about it and hopefully reach more patients.