Dr Steven Anderson, Chief Scientific Officer, Covance
Dr Anderson, from the early-stage studies you are supporting at Covance, what do you see as the major research avenues which will come to a head in immuno-oncology in late 2017/2018?
There are a few areas that I think will be very important in the area of immunotherapy development and trial execution. One is really having a good understanding of the biomarkers that are predictive of response, drug efficacy, or toxicity and adverse events.
Right now we have some biomarkers in common use for checkpoint inhibitors such as PD-L1 expression status, which is a good biomarker in some tumour indications, but not universally so. We have other genomic biomarkers, like tumour mutation burden and microsatellite instability, that appear to be predictive in, again, some tumour types, but not all. So having a focus on what the relevant biomarkers are for specific indications will be one area.
A second area is having appropriate model systems - such as animal xenograft and patient derived xenograft (PDx) models - to support immuno-oncology drug development. Those are limited right now compared to what we have available for targeted therapies. Both of these areas - model systems, biomarkers of disease, predictors of response, and predictors of adverse events - are important in today's market, in which we are looking at one immunotherapy at a time. When we start to look at combinations of immunotherapies, they will become even more important.
The ongoing advances in cancer immunotherapy, together with precision medicine, may promise a bright future for patients. By merging these two approaches, how can we increase the percentage of patients that respond to drugs and have an even more durable and lasting response?
When we look at the history of targeted therapies and immunotherapy, they have some distinct differences as well as areas of potential overlap. For targeted cancer therapies, because the drug was targeted specifically to a molecule expressed by the tumor or a genetic alteration in the tumour cells, we often saw significant responses therapy. In examples like with BRAF mutations in melanoma or EGFR mutations in non-small cell lung cancer, early significant responses but not durable responses are observed in patients whose tumors have the appropriate genetic alteration. However, often these patients would relapse or have disease recurrence. Their tumours would evolve pathways of resistance, i.e., mutations that allowed the tumor to bypass the effect of the targeted therapy.
Immunotherapies, on the other hand, patients who respond often show a long and durable response. For example, that was the case for the first checkpoint inhibitor, anti- CTLA-4 (ipilimumab, or Yervoy) used in melanoma - in which no biomarker was used to stratify patients. When those studies were done, patients that responded show a long and durable response to the therapy. This similar type of response has also been shown with subsequent immunotherapies.
Precision medicine, understanding biomarkers of therapy response, with specific targeted therapies and then potentially coupled with the broader scope of an immunotherapeutic approach where it's both the tumour and the immune system that are interacting with one another, promises significant impact for many cancer patients.
Covance's central laboratory was the provider of testing for PD-L1 expression in recent pivotal phase III registration trials, which led to the FDA-approved diagnostic test associated with the therapy. From this work, what has been learnt from a) innovative trial design for studying immunotherapies and b) taking a collaborative approach to research?
We've had the privilege to be involved in the key clinical trials for both pembrolizumab, where a companion diagnostic is used to select patients for considerations for that therapy, and nivolumab, where a complementary diagnostic is used in the risk-benefit analysis for the individual patient and how they might respond to a therapy.
There are a couple of things we've learned. One is the role of the various diagnostic tests, i.e., companion, and complementary diagnostics and how they are used by clinicians in making immunotherapy treatment decisions. For these type of clinical trials studies, the collaborative approach involved a pharmaceutical company, a CRO, and a diagnostic company, so a three-way partnership in order to achieve success and the end goal, which is improving patients' lives with these new and novel therapies.
Trial design is an area where we'll continue to see a lot of innovation, mainly because this is a highly competitive area, biomarkers are becoming more relevant, and specific patient populations are in high demand. So, understanding how you can use adaptive trial design so that you can make early go/no-go decisions, particularly in combination therapies or around using a given biomarker or biomarkers to guide treatment decisions, will be extremely important. This is magnified by the fact that there are over 1,000 trials being conducted or planned for immunotherapies, with many of the studies potentially competing for that same pool of patients.
As new immuno-oncology agents are being investigated and there is a greater investment in combinational studies in solid-tumour indications, how is Covance utilising clinically relevant models to screen immuno-oncology therapies and translational strategies?
Again, that goes back to an earlier question where we talked about having the appropriate model systems - in vitro and in vivo models - to do some of the preclinical work before you move into humans subects, assessing what potential combinations of agents might be most relevant.
The other area that we have is looking at extensively, is how we leverage the data that exists within the Covance and LabCorp system, in order for us to provide advice and consultation around trial design, and execution, including how you might find the right and appropriate patients to power a trial to be a potential success.
So having appropriate model systems, that speed early development, and using data to help facilitate trial design, and execution will be highly relevant in this exciting area of cancer immunotherapy.