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.