Biological insight in new drug combinations

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Published: 11 Sep 2017
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Dr Elena Garralda - Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

Dr Garralda talks with ecancer at the ESMO 2017 Congress about the need for a better framework and system in order to increase the effectiveness of developing new drug combinations.

Noting the national and international barriers to designing and implementing trials of novel drug combinations, she describes how better genomic understanding of tumour origins and vulnerabilities may expose novel pathways to be targeted, and indicate cancer subgroups with the best chance of response.

Given the number of patients receiving immunotherapies who do not respond, and the progress in understanding these populations based on genetic sequencing, Dr Garralda describes new combinations as a highly worthwhile means of cornering cancer, regardless of hetereogeneity or development of resistance.

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

The realities we are seeing in cancer, it’s a very complex disease, there are many vulnerabilities that need to be attacked in order for us to get a response. We are seeing that only some patients will actually benefit from monotherapy targeted agents so we really need combinations if we want to achieve better responses and improve the clinical outcome of our patients. There are several barriers to actually get combinations approved; there are barriers in the complexity of cancer, so selecting the most proper combinations that need to be tested. There are barriers in drug development as most of our drug development trial designs are designed for monotherapy. There are, of course, some barriers, regulatory barriers and collaborations that need to be established between pharma, between academic research and between institutions in general to get these types of drugs approved.

Which leads you to the biological insight aspect. Can you tell us more about that?

Yes, right now we have such a big drug pipeline that the first thing we really need to know is which combinations we need to test. So only if we understand the genetic alterations of an individual cancer are we going to be able to make combinations from a rational point of view, in a rational way, combinations that stand behind proper scientific hypotheses. So if we have this insight we’re going to be able to predict or to think which are the best combinations. These can be in the targeted area and this would be more the genetic alterations or we are seeing right now also in the immune field, so probably there are different characteristics of each tumour that will make some patients respond better to some combinations and others would respond to monotherapy. So only if we understand this are we going to know which combinations are better for each patient.

So much like tailoring a therapy based on sequencing.

Exactly, in the end we are seeing monotherapy is only going to benefit some patients, even in those patients they’re probably going to have a mechanism of resistance that makes the response short-lived and probably even then they will have to have a combination. For most patients it’s going to be probably combinations that are going to make a difference.

That might also open up new treatment opportunities when someone sees a vulnerability to an existing treatment or a new combination with, for example, repurposed medicines.

Exactly. This is a big opportunity for the patients and for drugs. There are cancers that are going to be addicted to one pathway but we are seeing that the complexity is so much and there are so many alternative pathways that can be activated at the same time that probably drugs that themselves didn’t have such a single agent activity, in a combination they can be approved. For example MEK inhibition in melanoma – even if there was some single agent activity the reality is that the combination of BRAF and MEK inhibition is what actually got approved because it enhanced the target inhibition and created a synergistic effect. So this is a possibility of drugs that by themselves would not reach an approval.

You mention that this needs to be happening on the level of institutes and are there any plans to maybe take this for international collaborations, working between countries and pharmaceutical outlets to try and work on this more active use of sequencing data?

I think there are. There are many initiatives to actually share data and especially when we are finding small patient populations to actually be able to find the small patient populations and make the combinations in them. All the community is raising the knowledge that this is the only way forward if we want to find this population. So there is a big collaboration right now and we are starting to see the fruits of the efforts, also of different pharmas working together to find the best combinations which don’t necessarily need to be of two drugs of the same company.

That covered all my questions, was there anything else that we haven’t mentioned yet?

No, just that right now it’s an exciting moment, we have many drugs coming along. We have an increased knowledge of tumour biology and we have also new technologies that are enabling the screening of these combinations to be done in a more rational way. So it’s really our responsibility to really push forward those combinations that make sense because in the end that’s where we are going to create an impact on our patients.