WIN Symposium 2013

Improving predictability of clinical trial outcomes

Dr Robert Kerbel - Sunnybrook Research Institute, University of Toronto, Canada

I think our big problem in oncology is that when a new target is discovered and a new drug is developed against that target a recurring theme has been that when that drug is used alone, up front as a single agent in patients with metastatic disease very often these drugs do not seem to be effective. They have a very low response rate, they don’t increase survival in any meaningful way. So very successful drugs such as Herceptin, trastuzumab, bevacizumab or Avastin, cetuximab, Erbitux, amongst others, a lot of those successful antibody drugs when they were initially evaluated didn’t seem to be particularly active on their own in phase I trials – a very low response rate.

In metastatic disease?

In metastatic disease. In a sense what saved those drugs from a marketing point of view, getting them approved, was chemotherapy which was kind of ironic because twenty years ago when you would read grant applications or scientific papers about the genetic basis of cancer and the development of new targeted therapies that were much more specific than chemotherapy, the rationale was that one day, and maybe this will happen one day, they would replace chemotherapy. Chemotherapy is very non-specific, it’s highly toxic, and these new drugs would be much more effective because they’re more specific. Well for the most part that hasn’t turned out to be the case; a lot of these new drugs, for one thing, are still toxic and on their own they were not very effective when first tested so they had to be combined with what was already known to be somewhat effective, chemotherapy, and the combination proved to be superior to chemotherapy alone. So a lot of these new drugs seen to be what I call enablers – they enable chemotherapy, conventional chemotherapy, to work somewhat more effectively than the chemotherapy alone. Now some of the new therapies, targeted therapies, can be used alone but in what’s called the maintenance setting which means while patients get conventional chemotherapy plus a targeted agent up front and if they benefit in some way, and the benefit again might be small, it might be stable disease or a partial response, then they may go on to the targeted therapy like trastuzumab or bevacizumab as a maintenance, as a long-term maintenance treatment where now it seems to have… it adds on to the initial benefit that was achieved early on. In that case, once you debulk or get some sort of major tumour response, then these drugs can be used in some cases alone.

But you say maintenance therapy so it would be a lower dose. Is it metronomic therapy?

In some cases the targeted agent is used alone so there are situations now where trastuzumab, Herceptin, bevacizumab, for example, Avastin, are used alone in the maintenance setting. At the American Society for Clinical Oncology meeting there was also a trial result in ovarian cancer of an anti-angiogenic tyrosine kinase inhibitor called pazopanib which was used after traditional up-front chemotherapy. Then after that therapy was completed then the pazopanib was initiated as a sort of follow-up maintenance therapy. But in addition now I think there is increasing consideration being given to metronomic chemotherapy being used in a maintenance setting. The reason is a) it might be effective and b) patients able to tolerate it. You can’t keep giving traditional conventional maximum tolerated dose chemotherapy that you use up front and just keep it going and going and going. It’s too toxic. But there might be a benefit in continuing the same chemotherapy drugs or different chemotherapy drugs but given in a way that are less toxic. So that, again, might mean or could mean giving them at lower doses on a per treatment basis so that the toxicity is less, so there’s less vomiting, less hair loss, less myelosuppression and you can keep the therapy going either using it alone or in combination, say, with some sort of new targeted agent.

So is that the reason the patients will live longer because they’re not going to have adverse effects or is there a biological reason why?

The rationale or the reasoning behind when you get a positive effect, a survival effect, is it’s a biologic effect; it’s not just related to the toxicity. But clearly the reduced toxicity might allow patients to receive the therapy for a longer period of time and not stop taking the therapy or, in some cases, maybe even die from the toxicity caused by the therapy. So it’s really based, at least partly, on the idea that cancer is a chronic disease, it develops over a long period of time and in some cases, depending on the cancer, for example breast cancer can last for a long period of time, and therefore maybe the therapy in some cases should be chronic as well. But it can’t be chronic if it’s highly toxic so that again is part of the rationale behind the metronomic chemotherapy dosing concept which has to be validated in prospective randomised clinical trials. I think we’re getting closer to that now.