Buparlisib helps overcome endocrine resistance in metastatic breast cancer: BELLE-2 trial results

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Published: 17 Dec 2015
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Dr Mario Campone - René Gauducheau Centre de Recherche en Cancérologie, Nantes, France.

Dr Campone talks to ecancertv at SABCS 2015 about the first results from the randomised, phase III BELLE-2 trial that assessed the the efficacy and safety of combining the PI3K inhibitor buparlisib with the endocrine therapy fulvestrant in postmenopausal women with endocrine resistant, hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. 

Activation of the PI3K pathway is a hallmark of resistance to endocrine therapy, Dr Campone explains. Early data suggest that using a PI3K inhibitor may be able to help reverse endocrine resistance and so the BELLE-2 trial was designed to look at this question further.

More than 1,140 women who were refractory to aromatase inhibitor therapy were enrolled into the study and stratified based on their PI3K pathway status measured in archival tumor tissue.

A 22% reduction in PFS was seen comparing buparlisib plus fulvestrant versus fulvestrant plus placebo in the full population, with respective median PFS of 6.9 and 5 months (p  < .001).

Pre-specified analyses showed that characterizing PIK3CA mutation in circulating tumour DNA at trial entry could identify patients that may benefit from the buparlisib/fulvestrant combination.

ecancer's filming at SABCS 2015 has been kindly supported by Novartis through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

You’re looking at PI3K status, a particular type of that, from circulating tumour DNA. What were you doing in this study of an anti-PI3K agent? What were you trying to investigate here?

One of the mechanisms of resistance in endocrine treatment is mediated by the activation of this pathway, PI3 kinase mTOR, and the idea of this clinical trial, the objective of the clinical trial, is to reverse resistance to endocrine treatment when using a PI3 kinase inhibitor combined with endocrine treatment.

So this drug, buparlisib, what does it do exactly and what is it?

It is a pan-inhibitor of the PI3 kinase protein.

And what did you do in the study?

In this study, the randomised phase III study, we compared the combination of fulvestrant plus this inhibitor of the PI3 kinase inhibitor to fulvestrant plus placebo.

And this is in which patients?

In the patients we were considering had resistance to endocrine treatment. All patients received an anti-aromatase inhibitor first; when they progressed the patients entered into the study.

And how many patients did you look at altogether and what did you find?

The number of patients is very important in this phase III. The primary endpoint is a PFS for the full population; the second primary endpoint is the same endpoint, is just in patients without activation of this pathway. You have experimental PFS in the selected patients with a PI3K mutation detected by liquid biopsy.

So you were monitoring what was happening by using a different form of sampling, the liquid biopsy?

Yes, exactly. For the patients with activation of the pathway, as it is in the primary tumour, you have to take active tumour, primary tumour, and for the liquid biopsies just before starting the treatment you take a blood sample to detect the free cDNA of the tumour.

Now, this was with patients who had inoperative or locally advanced breast cancer or ER positive.

Yes, all patients are ER or PR positive, HER2 negative, with local or metastatic setting exposed to prior endocrine treatment. This prior endocrine treatment is an anti-aromatase inhibitor. Some of the patients received just one line of chemotherapy agent but not all the patients received the PI3 kinase mTOR inhibitor or fulvestrant.

Now, it’s a phase III study, what was the total number of patients?

42 I think.

So what did you find? What’s the finding?

This clinical trial meets the primary endpoint. In the full population you have the benefits to combine the PI3 kinase inhibitor to the fulvestrant compared to fulvestrant plus placebo with 22% reduction of risk of progression. In the population where we have activation of this PI3 kinase pathway there are no theoretical differences between the two arms but I think the most important is in the exploratory PFS. You have large benefits when combining fulvestrant plus the PI3 kinase inhibitor compared to the placebo arm with a reduction of 44% risk of progression with the combination arm compared to the placebo arm.

So if you see the biomarker in the circulating DNA then it’s an indication that your drug, buparlisib, will work and resensitise or sensitise fulvestrant.

It will resensitise fulvestrant because when you have this mutation you are resistant to endocrine treatment, you are resistant to fulvestrant and when you give the drug you reverse this resistance. It’s very, very important.

What could this mean for doctors?

I think to select patients we have to combine treatment. If you have this mutation it’s probably fulvestrant and not active. Probably you can wait to select some mutation, it’s the same for, it’s one of the mutations we implicate in the mechanism of resistance to endocrine treatment. Probably you select the drug to combine to the endocrine treatment.

How near to prime time is the use of this agent?

In breast cancer, yes. It is the first in class, we demonstrated an activity.

So what do you recommend doctors to be thinking about this study finding now?

The problem is the balance between toxicity and efficacy. If you look at in terms of toxicity it’s very difficult to give the drug. But the next step is to develop another PI3 kinase inhibitor with less toxicity to confer this first result.

So what are the toxicities with this agent?

You have a specific class toxicity, hypoglycaemia, rash, and you have specific toxicity to the drug in the disorder and increased levels of the hepatic enzyme.

How optimistic should doctors be about overcoming resistance to endocrine therapy?

Yes, exactly. I think for the near future in the metastatic setting you never use endocrine treatment just in monotherapy. It is the third clinical trial which demonstrates that you have to combine endocrine treatment with other targeted therapies to reverse resistance. The first is when you combine exemestane plus everolimus in patients pre-treated with non-steroid anti-aromatases. You have where you combine fulvestrant plus palbociclib as an inhibitor of CDK in patients resistant to endocrine treatment, and this BELLE-2 we demonstrated in patients that are selected resistant to anti-aromatase inhibitors if you give fulvestrant in a selected population of patients with a PI3 kinase mutation you have to give another drug. One possibility is to give a PI3 kinase inhibitor.

In which category of patients with breast cancer, because surely you don’t have to have combinations for all?

No, it’s just patients with ER or PR positive breast cancer, HER2 negative.

So the brief take home message for doctors is what?

It’s now the new area when to reverse resistance to endocrine treatment you have some targeted therapy to add to this endocrine treatment to reverse resistance.