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BTOG 2021 | MiST: personalized approaches to mesothelioma treatment

Dean Fennell, PhD, FRCP, University Hospitals of Leicester NHS Trust, Leicester, UK, gives an overview of the Phase II MiST trial (NCT03654833) investigating stratified therapy for the treatment of mesothelioma. Prof. Fennell outlines how mutations in BAP1 and BRCA1 can be used to predict response to PARP inhibitors such as rucaparib. The study will also explore the impact of mutations of the gene CDKN2a on CDK4/6 inhibitor therapy with abemaciclib, and the role of immunotherapy with pembrolizumab plus bemcentinib, atezolizumab plus bevacizumab or dostarlimab and niraparib in the relapsed setting is being investigated. This interview took place during the 19th British Thoracic Oncology Group (BTOG) Annual Conference 2021.

Transcript (edited for clarity)

Across multiple cancers, we’re very aware of the need to take account of the fact that patients differ. Differ genetically, differ in the behavior of these cancers and their drug responses and this sort of interpatient heterogeneity, the best way to deal with that, best way to maximize benefit for patients is to try and target those individuals using personalized therapy approaches.

So, the aim of MIST and our goal really in mesothelioma going forward is to see whether or not we can identify based on biology subgroups that may benefit from individualized therapies...

Across multiple cancers, we’re very aware of the need to take account of the fact that patients differ. Differ genetically, differ in the behavior of these cancers and their drug responses and this sort of interpatient heterogeneity, the best way to deal with that, best way to maximize benefit for patients is to try and target those individuals using personalized therapy approaches.

So, the aim of MIST and our goal really in mesothelioma going forward is to see whether or not we can identify based on biology subgroups that may benefit from individualized therapies. The approach we’ve taken with MIST is really to try and identify what could be described as low hanging fruit, in terms of these groups that I mentioned. Over the last number of years, there’s been an increasing body of knowledge around the genetics of mesothelioma, and this has provided now opportunities for us to develop targeted strategies.

So, what we’ve done with MIST is really as a first effort, I think, to try and stratify therapy and to deliver stratified therapy through what we call an umbrella design. This is an approach in which we will take patients really with I would say three key molecular characteristics. So, the first of these is a group of patients that have a very common mutation, probably the most common mutation in mesothelioma, called BAP1. We believe or have believed that this and another alteration that we see, which is loss of a gene called BRCA1, when present in patients with mesothelioma ought to sensitize these patients to a drug that’s already licensed for varying breast cancers called a PARP inhibitor. So, patients who have the presence of these abnormalities, inactivation of BAP1 or loss of BRCA1, these are eligible for the first arm of this trial and receive rucaparib. Now we’ve actually completed enrollment of patients into that trial and we’ve published that data, so that’s something that I’ll be able to talk a little bit about to the audience.

In terms of the second arm, this is data now that we’ll be presenting in ASCO a little later this year and this is now taking another very common mutation, which occurs within mesothelioma that affects chromosome nine, 9p21.3. It’s a mutation involving a gene called CDKN2A and that mutation we believe will sensitize to a drug called a CDK4/6 inhibitor.

There was a number of years ago actually, experiments showing that in mesothelioma specifically, when you put back the missing gene that gets deleted from the cancer, you’re able to actually have a very, quite marked anticancer effect, particularly in mouse models, they were able to demonstrate this. Now, a number of years later, the development of this so-called CDK4/6 inhibitor. This actually is a way of us replacing the gene. Functionally what the gene that gets deleted does is inhibits CDK or cyclin-dependent kinases four and six and because that’s what the gene does when the gene is gone, we can now restore what we call phenocopy, that gene being put back by using a small molecule.

So, we’ve done that and I will present some images actually from patients who have responded to the drug. So, we know that there’s some activity there but we’re not able at this point in time to present all that data, that I will be presented at an international conference in just over a month I think also.

The two other arms of the trial of immunotherapy treatments and we know immunotherapy has been already shown to have some positive benefits in patients with mesothelioma. That is now one of the new standards of care or most recently FDA approved in the frontline. We’re interested still in the relapse setting and we’re looking at two novel combinations. One is with what is known as a AXL inhibitor, which is predicted to have a favorable synergistic interaction when combined with an anti-PD-1 inhibitor. So, we’re looking at a drug called bemcentinib with pembrolizumab in arm three. And arm four we’re using a more evidenced-based combination, which is the use of the VEGF inhibitor and an anti-PD-L1 inhibitor atezolizumab. So those two will be combined in four and in five, which is due to open very shortly we’re taking arm one drug, which is the PARP inhibitor, and combining that with immunotherapy. So, it’s almost evolving the therapy actually or taking what we think are positive results and now trying to think about rational synergistic interactions for that fifth arm.

You mentioned the three stages, and this is extremely important because what we want to do is select patients either based on the molecular makeup of their tumor. So BAP1, BRCA1, p16ink4a, these are for arms one and two. For arm five, what we’ll be doing is only selecting patients who have had shrinkage or stabilization of their cancers with chemotherapy, because that’s a very useful predictor for when the PARP inhibitor is going to work at all.

And so yes, we have this first stage of really patient identification where we receive the tissue blocks into our translational hub. We’ll do the molecular profiling of all the patients and then in stage two, they’ll get their treatment, we measure their clinical activity and then in stage three, which is most exciting to me actually, is that we will be able to now look in great detail at the genetics of these tumors and begin to start correlating drug response with the genotype of the patients. So we’re able to now, with technological advances, to conduct whole exome sequencing of these patients tumors and use machine learning now to try and see whether we can build some sort of model or pattern of responders versus non-responders.

And by correlating this with other experiments in the lab, for example, in cells, in patient derived explants, we believe we can generate some form of universal model to predict sensitivity. So, that third bit is still critical to the whole, you know personalized therapy story, and this often, often gets missed – that wasn’t a pun, sorry. We have many trials which have happened over the years where you know drugs, very unusual drugs actually, very interesting drugs have shown partial responses, really good activity in the minority of patients. We just haven’t had the biology to give us any indication as to why that happened and in thinking about future development, randomized trials, really trying to maximize benefit for a particular drug and understanding of that drug-gene interaction is absolutely key. So, that’s stage three.

And the final thing to say is that for the immuno studies, there’s a big interest at the moment in the bowel microbiome. So, these are bacterial within the gut. There is a lot of published data now that’s come out in the last few years suggesting that the composition diversity of gut microbiome, this flora in the bowel, has a profound influence on whether immunotherapies work and so we’re sequencing, we’re conducting 16S rRNA sequencing of bowel flora in arms three and four. We’ll be correlating mass as well in stage three, to see if that has a meaningful effect for predicting outcomes.

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