PD-1 inhibitor pembrolizumab shows promising clinical activity for triple-negative breast cancer

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Published: 12 Dec 2014
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Dr Rita Nanda - University of Chicago Medicine, Chicago, USA

Dr Nanda talks to ecancertv at SABCS 2014 about the results of a phase Ib clinical trial which sought to evaluate the efficacy and tolerability of pembrolizumab in patients with metastatic triple-negative breast cancer.

The drug was shown to be well tolerated and yielded durable responses.

Read the news story for more.

Checkpoint inhibition is something we’ve been hearing quite a bit about and you’re harnessing it in a phase I study, an early study primarily looking at safety but also showing, perhaps, other things on pembrolizumab. Can you tell me what you were doing in this study, what you were trying to achieve?

Yes. This was a phase I study primarily looking at the safety and tolerability of pembrolizumab in heavily pre-treated triple negative breast cancer patients. Obviously we also looked at response to therapy in these patients and were pretty excited to see some quite durable responses despite the heavily pre-treated nature of these patients.

Can you give me the back story? This is a PD-1 receptor ligand inhibitor, what’s it all about and what’s it doing in your patients and what sort of patients were you looking at?

Pembrolizumab is a humanised monoclonal antibody which binds to the PD-1 receptor and it disrupts binding of PD-1 to its ligands, PDL-1 and PDL-2. We enrolled patients with triple negative breast cancer who had PDL-1 positive tumours onto this trail. Patients received pembrolizumab every two weeks for as long as they were tolerating therapy and benefitting from it.

So that’s monotherapy?

Correct, monotherapy.

What results did you get, then?

We enrolled 32 women on this clinical trial with triple negative breast cancer that was PDL-1 positive. Based on central review 27 of these 32 patients had evaluable disease and of these 27 patients 5 had a response to therapy. We had 1 complete response and 4 partial responses.

Now I need to ask you first of all about the tolerability of the drug. What sorts of side effects did you get?

In general the vast majority of patients who developed side effects from this therapy had very mild side effects, the most common being fatigue, some mild nausea, arthralgias, myalgias, overall very well tolerated. We did see a few higher grade toxicities, some to be expected immune related but, again, quite easily managed. However, one patient did develop decreased blood fibrinogen and developed DIC and died of her disease… I’m sorry, died of disseminated intravascular coagulation. To put this in context, however, this was a patient with a very rapidly progressive breast cancer; she had developed a recurrence very shortly after completing therapy for early stage disease and had progressed very rapidly on her two prior chemotherapy regimens.

But you did get what might be called an efficacy signal. How strong a signal was that?

It’s quite impressive, while it was only an 18.5% response rate in this heavily pre-treated population it was really quite impressive when you think about the fact that the vast majority of these patients received more than three lines of chemotherapy in the advanced cancer setting and it’s very unusual to see responses at that late stage.

So on the strength of this, looking ahead, obviously it sounds as if you’re going to be investigating this further. What do you hope to see?

Obviously the next step would be to consider using this in patients with earlier stage disease, still in the advanced cancer setting, maybe moving it up into the neoadjuvant setting perhaps. And also looking at combination therapy to try to enhance the response rates.

So you can go straight to neoadjuvant or adding it to existing regimens rather than expanding the numbers in the refractory situation?

When you look at many of the trials that will be a follow-up to this one, it will really be looking to move into the phase II or early stage settings.

So what messages would you give cancer doctors at this point?

Certainly the responses that we’ve seen, while a modest response rate, are quite exciting and we certainly do believe that therapies like this will play a role in the future for at least a subset of women with triple negative breast cancer and perhaps even other subtypes of breast cancer.

To get one in five women respond in this heavily pre-treated group, do you think that suggests that that rate could be higher if the patients had not been treated?

It’s possible that catching these patients earlier could lead to higher responses. It also, as you probably saw from the presentation, the time to response was 18 weeks and in patients who are heavily pre-treated, who have a higher tumour burden, oftentimes these patients don’t have 18 weeks to wait for a response to therapy. So certainly catching patients with a lower tumour burden earlier in their disease course of metastatic disease might increase the response rates.

So what would be the very brief summary that you would give doctors in terms of practical implications of this finding about checkpoint inhibition in this setting?

While the findings are quite exciting there is still a fair bit of work that needs to be done to, one, identify the right patient population for this type of therapy and also to determine if combination therapy might perhaps be better than single agent therapy and to also evaluate biomarkers that might correlate better with response to therapy.

Do you think this sort of inhibition could be combined with other immunotherapy approaches?

I think it’s certainly possible and we’ve seen great success from that in the melanoma world. So I certainly think that is an area that’s going to be an active area of investigation.