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October 27, 2017

Of Biomarkers and CDxes

Companion Diagnostic Development Gets More Complex for Immune Therapies and Other Indications Outside Oncology

Of Biomarkers and CDxes

Source: JK1991/GettyImages

  • With emphasis in oncology shifting significantly to immune therapies, the days of companion diagnostics testing for one marker to prescribe one drug are rapidly changing. Pharmaceutical companies are dipping into the past to examine forgotten biomarkers and are looking to new analytical platforms and methods to provide definitive information on new drugs. Clinical OMICs recently asked five different questions to five leaders in biomarker and companion diagnostic development for their views on this quickly evolving area.

     

  • Clinical OMICs: With recent events including the continued emphasis on immuno–oncology, and the introduction of a multi-drug, multi-marker companion diagnostic, are we at an inflection point with CDx development?

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    Marielena Mata, Ph.D.

    Marielena Mata, Ph.D., Head of Precision Medicine and Companion Diagnostics, GSK: I don’t know. We thought so, and then we shifted to immuno-oncology and things shifted again. It is fluid again. It is interesting because the Thermo Fisher collaboration actually started here at GSK, and it was a collaboration between GSK, Pfizer, and Thermo Fisher when the focus was on targeted therapies.

    But now, if you look at oncology, the focus is shifting away from targeted therapies and to immuno-oncology targets. In the targeted therapies, the idea of multiple markers and multiplexing diagnostics makes sense, and I think the standard of care in that space calls for multiplexing. But as we move in the immuno–oncology space, and we start to see more of the drugs approved, we are going to go back to the drawing board to try to figure out what the right companion diagnostics are going to be.

    If you look at PD1, the current companion diagnostic is an immunoassay and it is very hard to multiplex those. They are starting to find out that other markers may be more appropriate: tumor mutational burden and MSI which has been approved for pembro. Can you multiplex that? Not really.

    Immuno–oncology is shifting. We are looking at a lot of different biomarkers and being very exploratory. We are looking at gene signatures, we are working with a number of biomarker firms out there looking for different options.

  • Clinical OMICs: Are there particular challenges around creating companion diagnostics for immuno therapies and might this area require multianalyte tests?

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    Dan Snyder

    Dan Snyder, Chief Executive Officer, Molecular MD: I think when you are looking at diagnostics associated with the immune system versus diagnostics tied to an oncogene, which is either
    there or not, it tends to be much more black and white. There tends to be a lot more gray area in the immuno area, and it tends to be more iterative. PD-L1, while it is certainly helpful, I think that plus other modalities are going to move things forward with greater certainty in terms of response.

    The other piece of this is that drug companies, they like grey areas, in some ways because for them it’s not a trial and error thing, but they want to use these IO therapies in terms of combinations and they want to continue to have the freedom to test these combinations without necessarily being restricted by some of these biomarkers. With targeted therapies, you get response or no response. With IO, you may not be able to get optimal response but you can still get partial response. In terms of the risk to patient, you never want to prescribe a targeted therapy is going to have zero response. In that case, regulatory has a different approach in terms of IO.

    Multi-analyte tests get more challenging in terms of how physicians are going to use the data, how you combine the tests and the expense that goes into that. When you are looking at more targeted data versus IO data and combining that, I think it is going to be heavily dependent upon how far pharma wants to push this in terms of the diagnostics piece and what their trials effectively demonstrate. In some cases, they just want enough to get the indication versus if you have a really strong biomarker you are going to get maybe that much more efficacy. For most of them, they just want to get the indication and go from there.

  • Clinical OMICs: Most companion diagnostics are for oncology, what needs to happen for the development of CDx in your field of central nervous system disorders?

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    Andreas Jeromin, Ph.D.

    Andreas Jeromin, Ph.D., Scientific and Medical Advisor for Quanterix: One of the challenges in CNS disorders for companion diagnostics is understanding the biology. Alzheimer’s disease is not a single disease, it is a continuum of a disease that is based on a clinical diagnosis that is not necessarily reflected in disease mechanism.

    For Alzheimer’s disease, the holy grail in CNS has been the detection of biomarkers in cerebral spinal fluid. Over the last two or three years we have continuously engaged in studies where we described and quantified some of these proteins not just to have diagnostic utility, but to really understand what Alzheimer’s disease is. We are going from understanding the biology, understanding the mechanisms, validation of assays, into an LDT type strategy, all the way to companion diagnostics. But we need a lot of clinical data. Just running a 3,000-patient clinical trial, which seems like a lot of patients, doesn’t generate the clinical data needed to develop a companion diagnostic.

    Large datasets will come into the public domain, this is what is going to change. The way we are running clinical trials is not just based on these clinical outcome measures, but subjective measures. Everyone is interested in wearables now, as well. So there are multiple elements where we will see a lot of demographic normative data being utilized in the design of clinical trials, hopefully resulting in shorter approval and clearance of a companion diagnostics.

  • Clinical OMICs: When it comes to diagnostics there is always the question of will it be reimbursed by payers. How are payers responding to the advances in immuno-oncology and testing for markers like tumor mutational burden?

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    Charles Mathews

    Charles Mathews, Vice President, Boston Healthcare Associates: Payers like it when there is a lot of clarity—things like definitive guidelines. What is happening in immuno–oncology is the guidelines are trying to keep pace. So they will mention things like TMB, they will mention here is a marker PI3-kinase and all of a sudden the payers wonder “do I pay for it or not pay for it?”

    I think from a marketing perspective, what has happened with TMB is it has been layered as an add on to the tumor panels. So the bigger payer question is “do I pay for panels?” Then they maybe pay for TMB that is coming along for the ride. But when it clicks for a specific indication I can see them paying for patients that have shown the TMB results for that indication. The scary thing for them in IO is to pay for all things, for all patients, all the time.

    Although chemotherapy isn’t as effective as they want it to be, because much of it has gone generic, it is more cost appropriate in their minds. The idea of firing IO and IO combinations at everything is quite daunting, so they will be looking for excuses and ways to tease out of the data that only the TMB patients are the ones to respond.

    This is where you start to see global differences. In the U.S., payers historically have been deferential to oncology care and they have looked at alternative approaches to reining in the total cost of care like payer pathway programs.

    But I can see authorities in Europe—NICE for instance, and the INCA program in France—looking at TMB and deciding they are only going to give this drug to people with [certain] TMB rates, because that is what was observed in the trial. But in the U.S. they will say this is added cost without any benefit. I think that some of the labs will say it is not added costs, they are doing it as a throw in with their panel, and want the panel covered.

    It will be some time before TMB actually shows [proof to payers] because right now it is still experimental. So I think there will be a phase where the labs are almost giving it away and where people are looking at it as part of the tumor panel. Eventually, more data might come out to indicate the patient population where TMB should be leveraged, somewhat similar to what has happened with MMR/MSI.

  • Clinical OMICs: What do you see as the big issues in the complementary and companion diagnostic area in the next few years?

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    David Parker, Ph.D.

    David Parker, Ph.D., SVP, Diagnostics Solutions, Precision for Medicine: There are a number of things. It will be technologies that, when applied to biological specimens, allow multiple markers to be assayed simultaneously. I’m thinking specifically about mass spec. It’s been around a long time. It is not typically applied to biomarker analysis, but increasingly it is, in part because it allows multiple analytes to be assayed in the same sample and the same assay. So enabling technologies like that that allow multiple biomarkers to be assayed simultaneously is one.

    The other is informatics in a couple of dimensions. It is applications of digital technologies that allow correlation and measurements to be made that never could be previously. Another could be identifying biomarker signatures out of multiple streams of omic data: proteomic, genomic, and the like. They are disparate streams, but can you find patterns that are in and of themselves a biomarker. And the third is the Foundation [Medicine] deep curation. Can we correlate every single piece of scientific knowledge known about this mutation in a way that might reveal some clinical utility?

    All of those are informatics technologies, that are enabling measurements and correlations to be drawn that couldn’t be drawn previously. 

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