AACR Annual Meeting 2013

Next generation PI3 kinase inhibition

Dr Maurizio Scaltriti – Massachusetts General Hospital, Boston, MA, US

Maurizio, you are experimenting, you’re working in a whole lot of exciting areas and very much at the heart of what we’ve been hearing about here at the AACR, these mechanisms. Let me ask you about PI3 kinase inhibition because you’re looking at this, you seem to understand it quite well and also potentially how to combine that as a therapeutic approach with other interventions to beat cancer. What are you doing with PI3 kinase inhibition?

PI3K inhibitors are exciting molecules and they’ve really gained momentum in the last few years. The rationale to inhibit this important pathway is that, especially in subtypes, in cancer subtypes like breast or head and neck cancer, for example, we see activation, hyper-activation, of this pathway. And this pathway is a complex pathway and you can have many inhibitors inhibiting this pathway at different levels, so the PI3K levels and the EKT levels, but what is coming from the first preclinical studies and the first phase I, first of many clinical studies, is that alone they do inhibit the pathway but they don’t work so well.

Why?

Well because either you need too much compound to inhibit the pathway and you reach toxicity or the cell, the cancer cell, we know is very smart and they’re very smart, they find a way to compensate the inhibition of this PI3K pathway, maybe activating other pathways. They can actually overcome this inhibition.

What is it about the PI3K pathway that attracts you?

It did because it’s one of those targeted therapies that they can not serve only for one subtype or one cancer. For example…

It can be a variety of cancer care.

Exactly. PI3K inhibitors are used, for example the new PI3K inhibitors, they look more promising than the first one. The alpha inhibitor, the p110-alpha inhibitor, since they are more specific they are less toxic and the therapeutic window is higher and we see now more responses in the clinic. For example, we know now that these kind of inhibitors work in those cancers that have mutations, activated mutations in the gene, that actually codes for PI3K, for p110α, the PIK3CA mutation which is found in more than 30-40% of all breast cancers.

You mentioned that it’s difficult to get them to work optimally. Are there any that are looking close to the clinic at the moment?

As I was saying, the alpha inhibitors are very promising because they allow you to push the dose. Still, we do not expect them to work in a large proportion of patients as single agents but we do expect them to work combined with other molecules that might be inhibiting other pathways.

What’s the theory behind that joint use with another compound? Why is that better?

The theory is that, especially in the last year, our lab together with other labs like, for example, Neal Rosen’s lab in Memorial Sloan-Kettering, we’ve found that every time you inhibit a pathway, in this case the PI3K pathway but we know that it happens the same with the ERK pathway, another important pathway in cancer, every time you do inhibit this pathway the cells try to compensate this stress, activating something else. It’s like one of those toys, one of those boy toys, that you push one thing and something else pushes up. And it happens very, very early, as early as a few hours in the clinical models.

So the cell has redundancy built in to it so that it can come and fight back?

It has redundancy, exactly, and so we need to identify what these are. And if these compensatory pathways are targetable, we can actually use another molecule and inhibit both at the same time.

OK, which molecules are you looking at? I know HER2 is one of them, isn’t it?

For example, we saw that in HER2 cancer, in preclinical model HER2 cancers, they are resistant to lapatinib or trastuzumab. If we combine PI3K inhibitors with lapatinib we see spectacular responses – complete tumour regression of both cell based or even patient reaction to the drug. And these are a very promising combination. Another example, very more recent, is that we are finding in triple negative breast cancer, a nasty cancer, young women, very aggressive, we see that even those cancers that they don’t respond that much on PI3K. There is a subset of those cancers that if you combine a PARP inhibitor, which is used in this subtype that are BRCA mutant, that are a mutation in a protein important for DNA repair, these occur only in 10%. But we see that if you combine with PI3K inhibitors you can actually achieve a benefit in more than the 10%, you don’t need this mutation any more for the combination to work.

What’s the theoretical basis of this? You’re not just trying things out.

The theoretical… no, no, we don’t try things out, the patients are too important for trying things out. What we do see are two things: PI3K inhibitors, first of all, increase DNA damage so they increase the dependency of the cells of those mechanisms to repair and PI3K inhibition itself also down-regulates, decreases the amount of some of those proteins that are important for DNA damage. And, of course, if you use PI3K inhibitors, you inhibit an important pathway and you debilitate, you impair another pathway and then with the PARP inhibitor you just give the final hit to achieve, what is called broadly, synthetic lethality. It means that A B, it means that you killed the cells essentially.

And how does it work with the anti-HER2 agents?

With the anti-HER2 we already know since many years already, almost a decade, activation of the PI3K pathway is correlating with resistance to anti-HER2 because if you block the upstream PI3K pathway, the PI3 pathway has an engine itself inside the cells that goes by itself. Even if you block the upstream engine the lower engine still goes and if you block the two of them you achieve cell death.

And you’ve got other combinations with aromatase inhibitors, anti-oestrogen therapies?

We are actively working on that. This is an important story, this is a story that rarely happens but now it is happening. Now we know that from the last phase III trial, it’s called the BOLERO 2 trial, that they combine an AI, I think it was letrozole, together with an anti-mTOR1 molecule, which is everolimus. Now, thanks to this phase III, it’s actually FDA approved in breast cancer. We know that combining inhibition of the ER pathway, the oestrogen receptor pathway, together with the mTOR pathway, and we believe the PI3K in general, you see spectacular clinical benefit in patients. Funnily enough, we don’t know yet the mechanism why is that and we need to understand this mechanism because if we understand the mechanism we can a) select better those patients that can actually benefit from this combination and, second, predict which are the mechanisms of resistance that may arise with time.

Of course, spectacular responses are not enough because the history of cancer medicine shows that you can have a spectacular response, the durability matters, the development of resistance matters. How do you feel about all of this with your combinations?

So the combinations are, most of the time, we do early discovery and therefore we do phase I. We provide information for the better designing of phase I clinical trials. Phase I clinical trials, those patients are already heavily pre-treated so achieving those responses in patients that already experienced maybe three or four, sometimes even eight lines of therapy is, for me, spectacular. Because it gives you a hint, it gives you some insight that if you do this combination way earlier, way before, you can actually cure patients. This happened, it happened with trastuzumab, it happened with trastuzumab/lapatinib, with trastuzumab/pertuzumab. Fifteen years ago HER2 breast cancer was a very nasty subtype and now if you have a diagnosis of HER2 breast cancer that is not metastatic, you have a nearly 90% probability to get cured, I mean cured, not delayed. And now with the new combination, the dual HER2 blockade combining two different molecules with non-overlapping mechanism of action, you can actually see spectacular responses and cure even in the metastatic setting.

Right. Now, how does this impact the cancer doctor who will be intrigued, fascinated by these developments but also, perhaps, a little confused?

I don’t think they’re going to be very confused. I think that there are a few problems here. The FDA must accelerate approval of this drug. It’s happening with trastuzumab/pertuzumab. José Baselga was the corresponding author of the CLEOPATRA trial that showed spectacular responses with the combination and a few months later this combination was approved. Trastuzumab and lapatinib, I believe it will be approved soon and I think an oncologist that is updated, and fortunately most of them are, I don’t think they’re going to be very confused about using the combination rather than the single agent. Now, which combination, that we still don’t know because they probably work in a different way. We are actively working on that and actually now we know we know that many of these patients, they could probably spare chemo. And actually I, personally, now I’m personally working on a project in collaboration with other people to identify those patients that you can actually cure by anti-HER2 therapy without a drop of chemo.

OK, so what’s from among this very interesting science, what’s your hot tip for cancer doctors? What’s coming down the autostrada?

I believe, I don’t want to be repetitive, but I believe that alpha PI3K inhibitor specific, they’re going have an impact. And this is also a suggestion to MDs that maybe they are not so familiar with lab guys – don’t be scared or don’t be afraid of new and maybe sometimes weird combinations. In the next two or three years we’re going to propose new combinations that you probably would never have thought before and trust us, it’s because we know what we’re doing and there is a rationale behind it and we did a lot of study on this. So yes, I would say alpha inhibitor and combination with other molecules.

So what’s your take home message that you’d like to leave doctors with?

I think we are living in a fantastic time to do targeted therapy. I believe also with the genomic advance that we are really close to personalised medicine. Ourselves, for example, in the molecule category  we are already doing this, we are already taking advantage of these technologies and doing targeted therapy a la carte. Now, there are problems here, the problems are money. These therapies, these targeted therapies are expensive so I’m just a little bit afraid, I’m an optimist person and I think we’re going to really improve the cure of cancer in the next ten years. But the problem is I’m not sure everyone will be able to actually get this drug because of this problem. I believe the politicians, pharmaceutical companies and the whole community have to do our best to make an effort to drop and to make these accessible to everyone.

Well we wish you very well in this mission, an exciting one indeed. Maurizio, thank you very much for joining us.

Thank you so much.