WIN 2016

Combination trial designs: efficient, effective and tolerable regimens

Dr Susan Galbraith – AstraZeneca, Macclesfield, UK

I’m talking about how to develop effective and tolerable combinations. If you actually think about the cancers that we have a reasonable cure rate in, childhood leukaemias, testicular cancers and the lymphomas and even early stage breast cancer, those all improved the outcomes through developing effective combinations of drugs. Because most cancers have multiple mutations they rapidly develop resistance mechanisms to any one individual therapy so combinations are essential if you really want to improve the cure rate which is the ultimate goal. In order to do that you’ve actually got to understand how to create tolerable combinations because most drugs when you try and put them together, if you’ve already dosed one drug to its highest maximum tolerated dose it can be very difficult to add in even a normally tolerated additional drug; the two together can often result in additive side effects that mean that patients won’t stay on them for long periods of time.

So one of the topics I’m talking about is the fact that you don’t necessarily need to dose both drugs continuously in order to get an effective regimen but in fact we should be testing intermittent schedules of combination therapies in order to get a tolerable regimen. In fact, if you look at the hitting the pathway that you want to achieve with the individual drugs you can sometimes do that more effectively by actually dosing it intermittently, so a kind of hit and run on the cancer and allow the normal tissue to recover. In fact we’ve been doing this for decades already with most chemotherapies but we haven’t necessarily applied that same thinking to the era of targeted therapies. So I’ll give a couple of examples of ways in which we can do that and the regimens that are coming out.

When people started looking at the targeted therapies and looked in vitro and then in in vivo models, because they have a better therapeutic index than many chemotherapies, you could get tolerable continuous monotherapy regimens. In fact if you look at examples like the epidermal growth factor receptor inhibitors, patients can stay on those drugs for many months and years as monotherapies. But, as I said, you’re unlikely to achieve cure in any but a really tiny fraction of patients with a monotherapy, even an effective one, against a driver oncogene because most patients have many mutations in their cancer at the start and what you do is you apply clonal selection pressure and those clones, even if they’re in a very small allelic fraction at the start of therapy, will grow out over time and become the resistant mutation that will drive progression.

So the best way of trying to look at that is try and either prevent resistance and what we’re going to find is you’re going to move well tolerated combination regimens up front. To do that you need to be able to put these two or three drugs together. So I think it’s only really in the context of trying to solve that problem that people are starting to go back and say, well actually do we really need to have continuous exposure to a drug in order to effect anti-tumour cell kill. The answer is you don’t.

What are the next steps?

Immunotherapies are a paradigm changer, particularly the PD-1, PD-L1 antibodies but actually the biggest unmet need we’re going to have very shortly is all the patients that don’t respond to a PD-1 or PD-L1 antibody and how do you make the next step forward. As you rightly say, the next step forward will be through combinations. Again what we need to understand is what additional mechanisms are required to enable checkpoint inhibitors to work in those patients who don’t currently respond to monotherapy checkpoint inhibitors. So there’s a lot of work we need to do there about understanding what those mechanisms are, selecting the right patients for the particular drug or the particular combination of drugs and then working out again tolerable regimens to enable those to go forward.

You mentioned some successful combinations?

I’m going to talk about a dual TORC1/2 inhibitor, AZD2014 or vistusertib, which we’re developing in ER positive breast cancer in a combination with fulvestrant. So ER positive breast cancer is obviously driven by signalling through the oestrogen receptor and that’s a lineage marker that’s important throughout the lifetime of the cancer so it’s important that you have a really good hormonal backbone. But we know that signalling through the PI3 kinase pathway can generate endocrine resistance so looking at that combination, and we’ve compared intermittent and continuous dosing regimens of vistusertib on the background of fulvestrant, and then we’re looking, having developed a tolerable doublet combination, to then move to a triplet combination with the CDK4/6 inhibitors. Again the important thing to look at is the long-term discontinuation rate due to adverse events and the maintenance of anti-tumour activity over weeks rather than just looking at an initial response rate.

So that’s one example I’m going to talk about. The second is looking at the class of agents called DNA damage response inhibitors. We already have a PARP inhibitor, Lynparza, which is approved on the market in ovarian cancer. But actually again if we want to target the DNA damage response effectively, preclinical data that we have suggests that combinations of cell cycle pathway inhibitors, such as a WEE1 inhibitor, together with a DNA damage response inhibitor like a PARP inhibitor, prove to be very effective. Again, looking at the regimens of those and the schedule in order to avoid intolerable side effects on bone marrow or GI side effects are really important.

Are there concerns that bringing in new combinations will increase the likelihood of toxic events?

If you really understand which patients have tumours that are driven by a particular pathway you can tailor the combination to the right patient and still drive a difference between the sensitivity of the tumour and the sensitivity of the normal tissues. So we see that’s possible in, again, tumours like the EGFR driven tumours with the combinations of EGFR and MET inhibitors; it’s clearly possible in ER positive breast cancer, we’ve shown chronically tolerable regimens. And with the DNA damage response inhibitors actually if you select the right patients, patients that have, for example, a BRCA mutation, there’s actually a much better therapeutic index for those compounds than there is for traditional chemotherapy. So you can stay on the drugs for longer and we’ve had people staying on olaparib for many years in fact. So that’s a better tolerated backbone then to add in another therapy and produce a long-term tolerable regimen. So I don’t think it’s necessarily true to say that by introducing new drugs you’re going to worsen the side effect profile; I think you have to understand which patients, how to use the combination effectively and in which situations it’s likely to be better than currently available therapy.

Do you have a take home message?

I think the future is very optimistic. This is a golden age for cancer drug discovery and development. As I said, I think the immunotherapies are going to be changing the paradigm but let’s not forget that there are multiple other mechanisms. What we need to learn is how we put those together so we can actually improve the cure rate for patients with cancer.