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ASCO in Action Podcast


Feb 12, 2019

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Welcome to this ASCO in Action podcast. This is ASCO's podcast series where we explore policy and practice issues that can impact oncologists, the entire cancer care delivery team, and those individuals we care for, people with cancer. My name is Clifford Hudis, and I'm the CEO of the American Society of Clinical Oncology.


I serve as the host of the ASCO in Action podcast series. And today, I am really pleased to have as my guest Dr. Richard Schilsky. He is ASCO's senior vice president. And chief medical officer, and Rich is here to talk about our new clinical cancer advances report, which was just released. In clinical cancer advances, ASCO identifies the most important clinical research advances of the past year across the full range of cancers, and from prevention to screening to treatment and survivorship.


The report also announces what ASCO has identified as our advance of the year. And for the first time in this year's report, we will debut what we believe are the research priorities with greatest potential to advance progress against cancer. Rich, welcome and thank you for joining me today.


Thanks, Cliff. Great to be back.


now let's start with what we always do. Every year, we announced the advance of the year, the one area of clinical cancer research that has demonstrated the most significant progress in a year's time. And we've seen tremendous progress in the treatment of rare cancers, earning it the 2019 advance of the year recognition. Rich, can you talk about why this area was chosen? Why is this particular line of research so important for individuals with cancer?


Well, first, let me start with a definition of what we mean by rare cancers. And generally, what we're talking about are cancers that are diagnosed with a frequency of less than six cases per 100,000 cancer diagnoses each year. Collectively, though, because there are many kinds of rare cancers, overall rare cancers comprise about 20% of all new cancer diagnoses every year.


But those numbers may not even tell the full story, because as we learn more and more about the molecular subtyping of cancer, what we're learning, of course, is that there are many very, very rare mutations and fusions and other genomic alterations that occur in a very small proportion of even common cancer diagnoses. So the patient with lung cancer, who has a RET fusion that occurs in about 1% of all lung cancer cases, that begins to become a very rare subset, even though it's overall a common disease.
So we're going to be dealing more and more with this general area of rare cancers. But the reason that it's so important to single this area out, of course, is because historically, we haven't been able to learn very much about these rare cancers, simply because they are rare. There aren't very many of them that occur each year. Therefore, they're difficult to study. It's difficult to complete clinical trials. It's difficult to find patient samples to be able to understand the underlying biology of these diseases.


And yet, many of them are refractory to standard treatments. Many of them have a very aggressive clinical course. And for patients who are affected by one of these rare cancers, they desperately need new treatments. And this year, we're seeing, for the first time, some real progress being made in a number of these rare cancers.
I'll give you some specific examples that we called out in the report. So for example, although thyroid cancer is a very common form of cancer, anaplastic thyroid cancer represents only about 2% of all thyroid cancers. And of those anaplastic thyroid cancers, about 16%-- so now we're talking 16% of 2% have a BRAF mutation. But it's clear now that treatment with BRAF directed therapy produces a very high response rate in this rare group of individuals who have BRAF mutant anaplastic thyroid cancer.


Another example, take the drug we're all familiar with, trastuzumab. We know now, of course, that trastuzumab is effective not only in breast cancer, but also in gastroesophageal adenocarcinoma that's HER2 amplified. And there's emerging data that HER2 directed therapy may be active in other tumor types, where the HER2 gene is amplified. And one of those is uterine serous carcinoma. So uterine serous carcinoma is a rare subtype of endometrial cancer. And about 20% or 30% of those patients have a HER2 amplified gene driving their tumor. And trastuzumab has been shown to be an effective therapy in those patients as well.
Last example I'll give you right now. A tumor that most oncologists probably will never confront in their practice, tenosynovial giant cell tumor. This is a very rare soft tissue tumor that occurs in the joints, typically of young adults, typically is refractory to all standard known cancer treatments. And yet, this year, we saw very promising results reported for a new class of anticancer drug, a CSF 1 inhibitor, called pexidartinib, that produced a 40% objective response rate in patients with these advanced tumors, compared to a placebo treated control group.


So we're starting to make real progress in treating these rare cancers, particularly when we can begin to understand their underlying biology, and develop a therapy that's directed at the key drivers.


It sounds to me-- I mean, in listening to that wonderful list of successes, that we've rolled up a process and an approach to drug development and science into a category that is appropriately called rare cancers. Because when you think about the way you presented it, which I think is lovely, first, rare cancers, as a group, aren't rare is what you said. Two, rare cancers cross from the rare histologies to include some of the common histologies.


But the underlying theme, if I think about the way we present this, is a deeper understanding of the driver mutations, allowing us to move a little bit off of histology towards genomics to define these diseases. And that's not to say that genomics is the only way we're going to make progress. But the unifying theme in these cancers is probably that shared trait of an alteration and a driver mutation and an available drug. And that's the advance that's helping us with rare cancers. Is that a fair roll up of that?


I think that is very fair. And you can think about it in terms of a common histology, like lung adenocarcinoma, having a large number of rare genomic subtypes, each of which comprises a rare cancer, if you will. Alternatively, you could think about it as in the trastuzumab example, of saying, well, if you look at the universe of HER2 driven tumors, those HER2 driven tumors comprise a whole bunch of different histologies. But they all are responsive to HER2 directed therapy.


And so you know, as we understand the underlying biology of cancer much more clearly, it's moving us away from the long held view that the way you diagnose cancer is looking under the microscope. And if you see something that you see only very rarely, you say it's a rare cancer, to we're not going to interrogate the cancer if we see a rare genomic alteration that occurs infrequently in the population of cancer patients. That's what we're going to call a rare cancer.


Yeah, I just say think it's almost like an introduction or a preview of an interesting future where more and more of the cancers we treat may be selected on this basis, rather than their conventional light microscopy appearance, right?


To be sure. I mean, we know still that context is important. Not all of these molecular drivers behave in the same way in every tumor type. We already have examples where not all the targeted therapies work equally well against the same alteration, again, in every tumor type. But slowly, but surely, I think the science is moving us toward a day where we will be identifying cancers, primarily, if not exclusively, by their genomic profile.


It may not be a single driver. It may be a signature. But that is ultimately is what we use to direct therapy.


So to some degree, this is a fulfillment of a multi-year view that we've had about where to invest in cancer research, and the fruits, I think, are obvious. But this wasn't the only advance that we reported on last year. It's the one we named as the advance of the year. But what were some of the other advances that we called out for recognition?


So as in the last several years, where we named some aspect of immunotherapy as the advance of the year, this year we continue to see progress in immunotherapy of cancer, particularly with extending the range of indications for many of the immune checkpoint inhibitor drugs, as well as new indications for CAR T cell therapies. So that continues to be a rapidly emerging area where there's a lot of progress continuing to be made. We continue to make progress how with the introduction of second and third generation targeted therapies.


We've come to understand, of course, that many targeted therapies although they work well for a period of time, cancers ultimately develop resistance, patients need additional treatment options after the first line of targeted therapy. And of course, the science has responded by giving us the insight as to the mechanisms of resistance, which has led to the development of second and third generation inhibitors that can effectively overcome the treatment resistance.


We're seeing this particularly in lung cancer, particularly with drugs recently introduced like osimertinib, which is effective against the T790M mutation, the common resistance mutation in EGFR mutated non small cell lung cancer. And interestingly, some of these drugs are also now showing much greater effectiveness in treating or even preventing the onset of brain metastases in lung cancers that commonly spread to the brain.


So this has opened up actually a whole new area of research on effectively treating and preventing brain metastases in those tumor types, where there's a high propensity for such metastases to occur. The last thing I'll mention as another area of continuing progress is the continuing development of new biomarker strategies to help us refine the way in which we select patients to receive treatment.
And certainly, this last year, the big news were the results of the so-called TLRX trial in breast cancer, a test, a gene expression profiling test, that clearly indicates that there is a substantial proportion of women with hormone receptor positive early stage breast cancer who can safely forego treatment with adjuvant chemotherapy with no detrimental effect.


And this type of test I think is now going to really move us even further down the road of precision medicine, because it's allowing us to identify those patients who are most likely to benefit from adjuvant chemotherapy. They should get treated, and they will certainly benefit. But it also is allowing us to identify those patients for whom adjuvant chemotherapy is unnecessary, and who can be spared both the physical toxicity and the financial toxicity of adjuvant treatment.


The more of those tests that we can develop, going forward, the better we'll be able to refine prognosis, the better we'll be able to apply adjuvant therapy in the future.


I think one of the subtleties here is this highlights something we almost touched on before, which is precision medicine doesn't have to be only about gene rearrangements. There are multiple paths towards some degree of precision in treatment selection for individual patients. And this is, I think, a good example of that.
It also is a good example of the fact that precision medicine is not actually just about treatment selection. It's about risk assessment, risk stratification, assessment of prognosis, identifying early recurrence, as well as directing patients to the right therapy at the right time, based on the biological characteristics of their cancer.
So one of the things that we've done this year, and it's a first for us, is to announce a set of research priorities. These represent areas that our leading volunteers and others have identified as needing urgent attention. They are areas where the progress is promising, but not fulfilled completely. Can you talk a little bit about the motivation for creating this kind of a research agenda, as well as a criteria for actually selecting the specific research priorities?
So obviously, you know, our field is advancing very rapidly. But there are still very many unmet medical needs. There are many clinical conundrums that oncologists face every day in practice. And we felt that given all the potential directions that research could take, ASCO is in a strong position to be able to at least begin to describe those areas, where we thought the potential benefits in patient care would be greatest, and could be realized soonest.
ASCO, because we are the physicians who treat patients with cancer, we have a pretty good sense as to what the unmet medical needs of our patients are, what the lack of evidence is that our doctors struggle with every day in making clinical decisions with patients, where the field needs to continue to grow and to develop new information, to help fill those evidence gaps.


So we felt that we could take a stab at setting a research agenda, and putting out there where we thought the unmet needs, where we thought the opportunities were ripe for investment in research, and trying to articulate how, if we were successful in fulfilling those research needs and priorities, the field would ultimately be transformed. So that's what we've done with the nine research priorities that we are offering this year.


So the nine priorities that's important for readers in a moment, if they go look at this or pick up our publication to recognize, they're not rank ordered. They just happen to be nine. Maybe next year, there'll be fewer or more. And the second thing is in no particular order, as I understand it, we've divided them into a couple or maybe three big buckets.


One is essentially the issue of who really benefits from IO, the advance that you already talked about, as a multi-year call out from us. The second is really a little bit about health care disparities and precision medicine all rolled up in the concept of special populations. And related to that is access to research itself.


And then the third is something which we always worry about, but have, I think struggled with as a field for decades, and that is reducing cancer risk, along with screening, which is surprisingly still controversial in many settings. We'll talk a little bit more about some of the specifics, but I would just remind everybody listening that you can find a list of these nine research priorities if you go to our website asco.org/cca.


So Rich, as you think about the nine areas that are rolled up in those three broad areas, can you talk a little bit about how specific research would potentially transform patient care? And you've set a relatively short timeline for results in introducing this. And what kind of resources might these projects need?


If you take the first area, for example, of essentially getting the right treatment to the right patient at the right time, you know, we've touched on some of these themes already. Look at the results so far with immune therapy for cancer. It's remarkable that a significant, although still small fraction of patients across multiple tumor types, who receive an immune checkpoint inhibitor, will have prolonged disease control, 20% or so of patients apparently surviving, without disease progression, or even disease free for many, many years in melanoma and diseases that previously were death sentences for patients.


The question is why is it only 20%, and who are they? Because these drugs are toxic. They're expensive. And what we'd like to be able to understand is, what are the characteristics of the tumor or of the host or of the treatment that makes the treatment so effective in a proportion of patients, so that we can then learn how to increase its effectiveness in those groups of individuals, where it has so far been less effective.


The same is true, as we touched on a moment ago, regarding adjuvant post-operative therapy. If you think about solid tumors, broadly speaking, roughly 50% of patients with a newly diagnosed solid tumor are cured by surgery alone. They don't need and can't benefit from adjuvant therapy. Of the remaining group, who are at higher risk of recurrence. Many of them will not benefit from whatever adjuvant therapy they might receive.
So what we observe in most clinical trials of adjuvant therapies are relatively small absolute improvements in say disease free and overall survival for the entire population of patients treated. But of course, what that likely represents is a substantial benefit for a small proportion of that population. So what we are suggesting in this research priority is additional research, similar to what we saw presented this year with the TAILORx study, that allows us to understand the biology, the biomarkers, the testing that can be done to identify the patients most likely in need of and those who will most likely benefit from adjuvant therapy.


And then the third area within this general theme goes back to immunotherapy and the enormous promise of CAR T cells, which so far, has been realized almost exclusively in patients with hematological malignancies. So that's wonderful. And we want to extend that benefit as far as it will go.


But the question is, can those treatments be effective in solid tumors, which generally have a much more complex biology than many human hematological malignancies, and how do we develop CAR T cell therapies that can be effective in the solid tumor setting, that can be delivered to a solid tumor patient population, and ideally, and this may still be a bit of a pipe dream, can we develop CAR T cell therapies then that can be developed and administered off the shelf, so that they don't have to be custom made for each individual patient, which drives up the complexity and the cost of treatment. So those are the key elements of this initial theme.


And in a similar way, we would have similar, or we would have short term plans for the other areas that we haven't gone into detail here. And again, I would remind listeners that they can go through our whole list of ideas in terms of areas of focus at asco.org/cca. Right?


Absolutely. And when they do that, what they'll find are that we are calling for increased research in precision medicine and pediatric cancer. We're calling for increased research that's necessary to optimize the care of older adults with cancer. We're calling for research on how to ensure more equitable access to cancer clinical trials, so that all patients can benefit from those studies, and we can make progress more quickly.


And then finally, of course, we're very interested in learning more about how to reduce the long term consequences of cancer treatment. The pediatric oncologists have actually been quite successful at this, because first of all, they've been very successful at curing children. And now, they've been able to show that they can begin to pull back on certain components of therapy in a very thoughtful and well studied way, so as to not diminish the chance of cure, but to diminish the risk of long term side effects of treatment.
We, of course, want to have more research done, addressing the challenge of obesity in this country and its link to cancer risk, cancer progression, and cancer treatment, and then finally, to identify strategies to better understand the biology of so-called pre-malignant lesions, so that we can understand which pre-malignant cancers are the ones that are destined, in fact, to become invasive cancer.


That latter touches on a theme we could talk about another day which is the building, the emerging drive to rename some of those cancers, as something less than cancer, because of their lack of at least acute life threatening potential, right?


We could talk about that another day, and we should.
Yes. So one of the things that I think is always important to point out is we can do all of this work, but of course, we are part of society, and we're dependent upon various sources of funding and other resources in terms of public policy. We are dependent on government ultimately for support, as well as private support. And I think this clinical cancer advances report highlights that there are policies that would help us improve and accelerate clinical cancer research.


Some of them are obvious. We talk about them in other podcasts, increasing access to clinical trials, covering the routine quest of care for trial participants, and indeed, increasing overall federal funding, not in an unpredictable way, but in a steady way, that allows us to make multi-year plans across our community. Given all of that, what steps do you think ASCO members, specifically, could take to support us? And I would take it a step further. What should they be telling their representatives in Congress in terms of these policies? What should they be telling them in terms of supporting these critical areas of cancer research and how can they make an impact?
It's clear that essentially all progress that we make in developing new treatments for cancer ultimately gets linked back to federally funded support for basic science research. All of the insights that we've developed in terms of what causes cancer, how it progresses, which are the high risk populations, so much of that information comes from data sets and other basic laboratory studies, funded by the NIH or the National Cancer Institute.


Of course, the NCI has in place a robust national clinical trials network publicly funded that supports clinical trials that would never be done by a commercial sponsor. In fact, three of the rare cancer studies that I mentioned earlier during this podcast were done with support from federal funding.


Those studies, because they are rare cancer, small populations are not studying tumors that represent a large market for a new pharmaceutical product. They're not going to be done by a commercial sponsor. We need federal support. And we need our members to point out these kinds of examples when they go to talk to their representatives in Congress. And I would urge our members to not only go to talk to your representative, but to bring a patient with you.


The patient tells a story far better than we can. And having the patient at your side and having the patient tell their own story about how they benefited from federally funded research is very powerful. In order to reach your member of Congress, ASCO's trying to make that as easy as possible, and you can do that by going to ASCO's Act network at asco.org/actnetwork.
That's great. I mean, we've covered a lot of exciting progress, I think, this year. And readers who take the time can dive far more deeply into this discussion with our publication. But what would you say is the main takeaway, the thematic takeaway that you hope people will get from this year's clinical cancer advances report?
To me, I think what we continue to see this year, and we have seen in recent years is that the more deeply we understand cancer biology, the more that will quickly lead us to new therapeutic approaches that will be far more effective, and hopefully, less toxic, and maybe most importantly, more enduring than the common therapies that we've had available to us in the past.


Our field is clearly moving to a day when immunotherapy will be central to cancer care, when every patient will have their cancer genotype well understood, and where therapy decisions will be informed by that deeper understanding of each patient's biology.
So you almost did this, but I'm going to push you a little more. In the same way that we're now calling for what should be done next in terms of research, if you could actually look into the future, what areas of progress against cancer would you expect or maybe hope to see, just 12 months from now, when we do this report again?
I hope that one of the things we'll see is rapid progress in developing, not necessarily novel biomarkers as unique tests, but novel biomarkers signatures. I think it's becoming increasingly clear that in order to select patients optimally to receive immunotherapy, and even to select patients to receive certain precision medicines, that a single biomarker is not necessarily the optimal selection strategy.


For immunotherapy, we may need to see a signature that represents some characteristics of the tumor, some characteristics of the patient, maybe even some characteristics of that patient's microbiome in order to figure out who is most likely to be susceptible to which immunotherapy approach, and the same is going to be true, I think, for even the now common precision medicine approaches with small molecules. We're trying to understand how molecular pathways and networks work inside the cell can suggest to us not which single targeted therapy to use, but which combination of targeted therapies to use for each individual person.


This kind of work is on the horizon. It's complicated, involves lots of complex algorithms. But my hope is that this will move us to a future where we can take the results of a test on a patient's tumor and integrate information of various sorts and come out with a more precise estimate of what's likely to be the best treatment for that person.
And you think that we could see some of those results even as soon as just 12 months from now, or is this a longer term hope?
I think we will begin to see some of these types of approaches appearing at an ASCO meeting in 2020.


Well, that's really exciting. I think it's really both uplifting, and I think challenging to hear where we are, because of course, as is always true in science, every answer begets many more questions. And in our world, every bit of progress identifies new challenges. And I think that's what's summed up in a lot of what's in this report now, right?


Absolutely. But you know, I think for the first time, you know, ASCO is trying to articulate where we see the greatest opportunity. And we hope to be able to do this each year in the coming years. As you said earlier, it may not always be nine research priorities. Some of that might even be repeated year to year, because we won't solve every one of these in a year from now.


But we will modify these. We will improve upon them, and they will change as the science advances, as the questions evolve, and as the opportunities continue to develop.


Well, rich I want to thank you for joining me today for this ASCO in Action podcast. I'll remind everybody, we have a mission at ASCO to conquer cancer through research, education, and promotion of the highest quality cancer care. And this clinical cancer advances report really does help us meet that mission, by increasing awareness of the progress we're making, but also, as you point out, identifying the critical importance of the entire community's engagement in research and high quality care. That is pointing out just how important all that is in terms of delivering on the promise of all of our progress.


I encourage listeners, again, to read the full report by visiting asco.org/cca. And until next time, I thank everyone for listening to this ASCO in Action podcast.