Novel fusion proteins to target PD-L1 in HPV associated cancers

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Published: 4 Jun 2018
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Dr James Gulley - Center for Cancer Research, Washington, USA

Dr Gulley speaks with ecancer at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting about the phase I study of M7824 for patients with HPV associated cancers.

He comments on how this could change clinical practice in certain settings and highlights the importance of using novel fusion proteins to target PD-L1.

For more on this study watch Dr Strauss discuss it further with ecancer here.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.
 

I’d like to talk a little bit about M7824.

This is a novel bi-functional fusion protein targeting PD-L1 and TGF-β. TGF-β is a very important negative regulator of both the immune system as well as other cancer biology mechanisms.

Not only does it decrease the effector cells that can eliminate the tumour and has impact on the regulatory cells but it can impact angiogenesis, it can impact epithelial to mesenchymal transition, which is how the cancer cells spread, and it can impact fibrosis and drug resistance.

So this is a very important part of the tumour biology that has not had an adequate inhibitor made that could have clinical activity to this point.

The idea of combining the two agents on one molecule is interesting because it allows for the concentration of the TGF-β and of the molecule within the tumour because of the PD-L1 expression within the tumour.

The antibody binding to that and concentrating within the tumour and then allowing all these positive effects of the TGF-β inhibition to go on within the tumour microenvironment.

This is an antibody against PD-L1 on the FC portion of the antibody, the tail of the antibody, has two TGF-β receptor 2 molecules that combine to and sequester TGF-β 1, 2 and 3.

What we found is that in our initial dose escalation study done at the National Cancer Institute, we found that this could safely be given and that the toxicities seen were very similar to toxicities one might observe with PD-1 or PD-L1 inhibitors with the addition of one toxicity and that is keratoacanthoma.

This is a low-grade skin tumour that typically does not require any treatment.

In addition what we found was that at all levels tested we could see a saturation of the PD-L1 in the peripheral blood and we also saw that when you measured TGF-β in the circulation when you released all TGF-β from the serum you could sequester all of that TGF-β by the excess of antibody around at all the dosing time points.

So what we then did was a series of dose expansion cohorts, one of which was presented at the American Society of Clinical Oncology meeting in lung cancer. 

This was a rather large expansion cohort with 80 patients, 40 of them were treated at the 1200mg flat dose level, which is the recommended phase II dose, and 40 were treated at the 500mg dose level.

The idea here was to get some idea of the dynamic range of the pharmacokinetics, pharmacodynamics and see if there’s objective responses in both groups.

What we found was indeed there was objective responses in both groups but I want to focus on the dose that we’re taking going forward which is the 1200mg dose level.

There, in this second line lung cancer setting, and this was presented by Dr Paz-Ares, we saw objective response rates of 28%.

When we looked at the PD-L1 positive cells, and that’s about three-quarters of the patients with second line lung cancer, we saw an objective response rate of 41%.

If you look at the PD-L1 high that’s seen in about 15-20% of the patients we saw objective response rates approaching 70%.

So we think that this is a really interesting early signal that suggests strong activity in patients with lung cancer.

How will this be used in clinical utility going forwards?

This is still an experimental therapy.

We hope to do additional studies that prove the efficacy and safety of this agent, hopefully in tumours like lung cancer.

We’re going to see other expansion cohorts that will be presented over the coming months and years and we’re also really interested in taking this forward in combination approaches at the National Cancer Institute.

We’re working on multiple investigator initiated trials that are combining this with other IO agents to really improve the outcomes of patients.