ECC 2015

Examining NSCLC responses to durvalumab monotherapy

Brandon Higgs - MedImmune, Gaithersburg, USA

Brandon, you’re working with interferon gamma and PD-L1 expression and particularly in the context of non-small cell lung cancer. Can you tell me what you were doing in the study with a new agent?

Sure. We were looking at durvalumab monotherapy and when we measured PD-L1 pre-treatment in non-small cell lung cancer patients the positive patients have an increased response rate. Similarly for interferon gamma we see the same result, an increased response rate. So both independent markers at baseline the positive patients have an increased response rate to all comers. Then, of course, the combination of both of them provide an increased even more response rate.

So can you tell me a little bit about durvalumab, what is it and what is it doing?

Durvalumab is an anti-PD-L1 molecule, it blocks binding of PD-L1 to PD-1 and CD80. PD-L1 is expressed on tumour cells as well as immune cells so it basically activates effector T-cell function which then has allowed the T-cells to conduct anti-tumour activities.

So it’s an immunotherapy for lung cancer and from what you’re saying it seems to have an effect. Tell me about the study, how many patients did you look at and what exactly did you do?

We looked at 200 patients who were available for response. These are non-small cell lung, both histologies of squamous and non-squamous. The stages are stage 3b – 4, so late stage patients. We measured at baseline PD-L1 using immunohistochemistry on tumour cells and we had a threshold by which a patient was positive. Then we did the same thing with transcriptomics, so we measured the gene interferon gamma and once again we had a threshold to identify patients being positive for interferon gamma at pre-treatment. Then we looked at the response rates in those patient subsets, both independently of PD-L1 interferon gamma and then the combination of both.

So there are two distinct biomarkers for effectiveness?

Correct.

And how big an effect did you get off the drug?

So it’s a 46% response rate in the double positives but just as relevant is that double negative population, so patients who were interferon gamma negative and PD-L1 negative at baseline, the combination. They had only a 3% response rate.

So is this potentially helping you to individualise patients with lung cancer for this form of immunotherapy?

Remember these data are exploratory, as we presented this morning. So we’re continuing to collect more data. But the idea is that it’s a punitive biomarker that we want to continue to monitor in other lung trials to understand can we enrich for patients who are likely to respond to durvalumab as well as combinations.

What are the potential and actual toxicities of durvalumab?

Durvalumab has an acceptable safety profile, as we published in this past year.

In comparison to other options, what do you see patients getting if this drug does prove its worth in the future?

This drug with a biomarker can be quite effective if this biomarker, like I said, pans out and we see that we can employ this. But once again this is an exploratory analysis at this point. We’re collecting a host of data to confirm what we’ve identified.

So what should busy cancer doctors read into these interesting data right now?

I think the key is that biomarkers are a huge strategy, an important strategy and we’re of course pursuing biomarkers to identify the patient subsets to focus on. This idea of a one size fits all or one treatment across the population is an old paradigm and so we’re very invested in identifying patient subsets where we can enrich that response rate. The work that we’re doing here is one example of showing exploratory work where we’re trying to pursue that effort.

How do you think this agent, the action of it, fits in with other immune approaches to lung cancer going on at the moment? Quite a few exciting ones around.

Yes, there’s a host of PD-1 and PD-L1 targeting agents, this happens to be one that targets PD-L1.

Do you see this fitting in perhaps in combination in the future?

Absolutely. So we have a host of combinations; one that we’re speaking of today in a poster session, tremelimumab, with durvalumab in non-small cell lung. But we have multiple combinations we’re paring durvalumab with, very exciting opportunities. And bringing it back to this work we presented today, as we talk about that double negative population where the response rate is quite low, this would be something we’d like to understand a little bit more about, these patients with a combination therapy treatment. Can we, for example, identify responders in that group?

A quick take-home then for doctors?

This work is very exciting but it is preliminary, it is exploratory and we hope to confirm the results in subsequent lung trials. And that’s it.

Brandon, thank you very much.

Thank you.