Hi, I'm Dr. Andrew Hahn, assistant professor of
Genitourinary Medical Oncology at MD Anderson Cancer
Center. I'm here with Dr. Pavlos Msaouel, associate
professor of Genitourinary Medical Oncology and
Translational Molecular Pathology.
And this is the Cancerwise Podcast.
Dr. Msaouel, thank you so much for being here today.
We're talking about kidney cancer, specifically renal cell
carcinoma or RCC.
It's biologically different from other cancers, and there
are exciting new treatments on the horizon.
For people who are new to kidney cancer, what makes RCC
different from other cancers?
And can you specifically talk a bit about histology?
Yeah, and this is the No.
1 question every time that we talk about kidney cancer.
It is a name that includes
many, many, many different type, subtypes, and
it is very important to distinguish between them.
We have the most common type, which is clear
cell kidney cancer.
The medical term is renal cell carcinoma.
Essentially that means kidney cancer.
So, clear cell kidney cancer is 75%
of all kidney cancer cases.
And in fact, many of the therapies
approved for kidney cancer, the FDA
often does not specify that
the studies that led to these approvals were predominantly,
or in many cases, exclusively performed and applied to
clear cell kidney cancer.
But then we have these other 25%
of cases that go under the umbrella term
non-clear cell kidney cancer that
represent many, many, many different types
like papillary kidney cancer, chromophobe
kidney cancer, renal medullary carcinoma, translocation
kidney cancer. Those are just a few names.
It's complex and what viewers need to know
is that they should only focus and care
about the one that they have,
and that should be the priority.
Why? Because each kidney cancer
is managed and treated very
differently. And with that said, I know
that there have been exciting developments
in how do we monitor
the various kidney cancer subtypes.
And perhaps you can talk to us about some of them?
Yeah, absolutely.
And to add on, when I'm thinking of histology or I'm trying
to describe them to patients, I totally agree with you.
And I would add into it that I like to just try to describe
it as flavors of ice cream for patient.
You know, it's if you have kidney cancer or RCC,
it's RCC. It is kidney cancer.
That's your ice cream. But there are lots of different
flavors of ice cream, and there are lots of different
flavors of kidney cancer.
And I always equate clear cell to the vanilla.
It's the most dominant. It's what most people are gonna
think about. But I fully agree with your sentiment that you
need to worry about the flavor that you have.
Now in terms of how do we detect kidney cancer and where do
things stand?
Kidney cancer, compared to some of our other GU tumors, is
a bit distinct in that we don't have a
blood-based screening biomarker.
So, for something like prostate cancer we can check PSAs,
and that's a screening biomarker.
We don't have that for kidney cancer or RCC.
So, typically kidney cancer is oftentimes
found as an incidental diagnosis.
So, someone goes in to get imaging of their abdomen
or pelvis for some other reason and they're incidentally
found to have a kidney mass, and it leads to the diagnosis
of RCC.
Occasionally patients will develop symptoms such as flank
pain, fevers, blood in urine, that can be the initial
presenting symptoms of RCC.
So, that's how the initial kind of presentation and
diagnosis occurs.
I think that then takes us into, well, how do we routinely
image RCC and how do we track RCC
over time?
So, I think one key point for patients and providers
is that we do not have a PET scan specific
to kidney cancer.
We don't have something like a PSMA PET scan.
The PET scans used for other cancers that's typically
FDG PET scans, they're not as helpful for kidney cancer.
So, I know most of our providers here are not routinely
performing FDG PET scans.
Most of us are using CT scans of the chest, abdomen,
and pelvis doing those at fixed intervals to monitor
for response or recurrence of kidney cancer.
Now, the two other spots that we'll think about imaging,
although there's a lot of heterogeneity across the field
even within our own group is how do you image bone?
How do you look for whether cancer has spread to the bone
or not? And you can do that with bone scans is one
potential option, but there's a lot of different potential
options there. Just know that there's heterogeneity and how
you can look for it, and kidney cancer is tricky to find in
bone. And then the other one is kidney cancer can spread
to many different places.
And so, you know, we'll oftentimes get MRIs of the brain
at initial diagnosis and then potentially
at fixed intervals thereafter, although that can vary
provider to provider.
So, I think that covers most from an imaging perspective
and initial detection, although please add if there's
anything I missed there. But I think going back to the
histology perspective, what
you know, is there a lack of understanding about some
subtypes versus others, or is there kind of, what
are your thoughts around that space?
Yeah, no. Beautifully stated, and this is something that
we've been highlighting for years.
And it is wonderful now to see the progress
on thinking about kidney cancer as
its own disease, its flavor of the ice
cream, exactly as you said.
And to your point, for example,
let's take one kidney cancer, renal medullary carcinoma,
abbreviated as RMC, which is
a major focus of our research program at
MD Anderson. It's a very deadly
kidney cancer that specifically afflicts young individuals
of African descent, and we have taken it upon
ourselves to make progress for that kidney cancer.
We've been able to essentially double the average survival
of these therapies exactly by
developing tailored therapies for
their disease. And to your point,
for renal medullary carcinoma, RMC,
we now do have a widely used
blood biomarker, CA 125,
that is typically used for ovarian cancer
in women. But we have found that it also
can be useful in about 60 to
70% of cases of renal medullary carcinoma.
And again, to your excellent point
about the diversity of the various images,
we have found, and we have been teaching clinicians
around the world, and hopefully we will be publishing more
of these data soon, that FDG PETs
can actually be remarkably useful
for renal medullary carcinoma and some
other subtypes as well.
They're rare ones. This is why it is so important
that we focus specifically to each patient's kidney
cancer. And again, to your point, there is also now
research emerging about dedicated PET
scan strategies for even the most common kidney cancer,
clear cell kidney cancer, even blood
biomarkers are emerging.
There's still research, but there is exciting developments
ahead for both clear cell kidney cancer and
the other subtypes. And having talked about that and
about all the exciting things ahead, let's also talk
about therapies.
Would you like to tell us a little bit more about
first-line therapies?
What would you usually recommend today
for a patient with kidney cancer and why?
Absolutely. And to be clear for everyone, I'm going to be
speaking about clear cell kidney cancer or clear
cell RCC when I talk about the recommended treatments or
the typical treatments that we're using, because this, as
Dr. Msaouel just so astutely pointed out, it is varies
enormously when you start getting into the variant
histologies of RCC or those other ice cream flavors,
you can get huge amount of variation there.
So, for clear cell kidney cancer, I think first-line
treatment is pretty straightforward in 2025.
We have four different combinations.
So, these are two drug combinations.
And all of them are going to have the backbone of a PD-1
checkpoint inhibitor.
People will refer to these as immunotherapy.
These are not chemotherapy.
These are trying to activate the patient's own immune
system to recognize and attack the kidney cancer.
So, that is a big part of the backbone for treatment of
clear cell kidney cancer as the first treatment.
And then you're going to add something else to that
medicine. You're going to either add another type of
immunotherapy that could be a CTLA-4 immune
checkpoint inhibitor or you're going to add a pill,
a targeted therapy. Again, not classic
chemotherapy. There's really no role for classic
chemotherapy in the treatment of metastatic
clear cell renal cell carcinoma.
But these targeted therapies there's three different pills
we can choose from. So, just to kind of cover the names of
the four different regimens in case a patient or their
loved ones are trying to think what are the options.
We've got nivolumab plus ipilimumab.
We've got pembrolizumab plus axitinib.
We've got pembrolizumab plus lenvatinib.
And then finishing it up we've got nivolumab plus
cabozantinib.
These four treatment options have never been compared
head-to-head. We likely never will.
There is some nuance in who do you choose, which
regimen do you choose for which patient with clear cell
kidney cancer. But I don't think we'll be diving too deeply
into that on this talk for today.
So, then I'll flip it over to you, Dr. Msaouel.
What happens whenever the first-line treatment
stops working? How do next, next lines
of therapy differ from those first-line treatments?
Yeah. And exactly to your point, while we, it's impossible
to share all the different strategies
that we come up with, and they constantly evolve
as we gain more data.
We're always very open and happy to talk
with oncologists from all over the world and brainstorm
and share our knowledge, learn also from their experience,
etc. this is something that we were literally doing earlier
this morning, communicating with people around both
the United States and around the world about challenging
cases of kidney cancer.
And exactly to your point, you focused beautifully
on the most common flavor of ice
cream, the vanilla one, clear cell kidney cancer.
For some of the other more rare ones, the exact
opposite thought process may apply.
So, for example, you said very correctly that for
clear cell kidney cancer, we essentially
never give chemotherapy.
But then there are other types like collecting
duct kidney cancer or renal medullary carcinoma
where we prioritize chemotherapy.
And in fact, for renal medullary carcinoma, the
standard immunotherapies that have transformed
the care of so many patients with clear
cell kidney cancer and other cancers may actually
not only not be effective, but they may actually be
harmful. This is why it is so important
that we specify.
Sometimes patients, you know may say, "Hey, why did Dr.
Msaouel or Dr. Hahn did this
to me?" And then the other patients say, "Oh, they did the
opposite for me." That is because each
case is unique.
Each patient deserves tailored
therapies for their particular situation
and disease. And this is exactly what also
applies to your question on what we do
next after the first therapy stops working,
or if it never worked, then we
will choose depending on the context.
For example, if we had chosen only
immunotherapy for a patient with clear cell kidney cancer,
and now we know that immunotherapy no longer is working,
then we might try the targeted therapies, the pills.
Sometimes patients call them chemo pills.
And I know that you have some exciting
progress in your research, Dr. Hahn,
on this topic.
And you will be presenting some of these results
at the European ESMO meeting?
We have run a clinical trial, a phase II clinical
trial called the LenCabo trial, where we
randomized patients, meaning kind of computer coin flip
them, to one of the two available pills, cabozantinib
as one of them, or lenvatinib plus
everolimus, actually two pills for that one, after
their cancer had gotten worse on immunotherapy.
And this was only for those patients who had that clear
cell renal cell carcinoma.
And we have the results of the study.
I'm, you know, optimistic or hopeful that it's
going to be helpful to everyone's, patient, or
doctors who are treating them and really help improve
things for patients with clear cell kidney cancer and
hopefully make the sequence of how we give treatments
clearer to providers.
So, really excited to share that at ESMO.
And then I'll follow up kind of back to what we were saying
with the standard treatments for clear cell kidney cancer.
I really think you're trying to think of like, what are the
big benefits, like what's happened in the last ten years
for clear cell kidney cancer, some of our mentors have been
instrumental in this, you know, Dr. Nizar Tannir being one.
These immunotherapies have the potential
to put patients into really, really
durable, deep responses where their cancer
is under deep control for many, many, many
years. I mean, we have patients out 8, 9 years now
from these immunotherapies, and that is something that did
not exist prior to these immunotherapies in 2015.
So, that is, I think, something for patients when they
think about what are the benefits of these treatments, what
are the potentials.
And then on the flip side, what are the potential harms, or
like what are the challenges that patients are interacting
with? I will be honest that all of our medicines, despite
the fact that we like to say they're not chemotherapy, they
definitely have real potential side effects.
Immunotherapy can over activate the immune system and
attack somebody's own body and cause
potentially life-lasting side effects.
And then the pills, the targeted therapies, have their own
class of side effects that really impact pretty much every
patient who takes them. It's just to what degree does it
impact them? So, there really have been over
the last eight, ten years, real benefits, but also real
challenges for patients.
But that being said, on the standard front, we've talked
about kind of the upcoming presentation at ESMO.
I'd like to hear more Dr. Msaouel about what kind of what
trials do we have going on at MD Anderson
for clear cell RCC that are kind
of exciting novel approaches?
And I'm going to set you up, but there's two that I'm
specifically thinking of. One of them called the IVORY
trial and then another one around cellular therapies.
But tell me more about that.
Yeah, and exactly. For the audience, it's, it's
good for them to know how much it takes a village to
move this research forward, including through patient
participation.
And one of the most fulfilling parts of
doing this research, in addition to seeing, obviously, the
patients respond, is the opportunity to
discuss them with you and our other colleagues.
We've been discussing, as you know, your
clinical trial data for the past few weeks, learning
from them, dissecting them, etc.
And you and I have been discussing about the trials I'm
going to talk to about now, which are trying
to push the field forward by
developing new mechanisms.
Are there ways that we can
crack open the kidney
cancer space with new ways to treat
patients with kidney cancer?
And one new way is to
modify antibodies.
We know that we can use modified
antibodies for years in
cancer therapy. And in fact, immunotherapy
that we've been using is a type of modified antibody, but
there is a new way to modify them to
target two different targets.
And this new way can be used to target
an immunotherapy target called PD-1.
It's the same target that pembrolizumab, Keytruda,
or nivolumab, Opdivo, also targets.
But at the same time, that same antibody can
target another target called VEGF.
So, an antibody engineered to target
both PD-1 and VEGF, and the
idea is that perhaps that antibody
can do better than the standard immunotherapies
that target only PD-1 alone.
And so, it's exciting to say that the first
ever clinical trial to
use a PD-1 VEGF bispecific
in clear cell kidney cancer in the world was
just activated, designed by our group with
your help, Dr. Hahn, and started treating patients just
a few months ago, and we're now
learning from that experience.
It's a wonderful opportunity for patients
to get exposed to the cutting edge of therapies
and for us to push the the field forward.
At the same time, in addition to those engineered
bispecific antibodies, and there's a lot of other
movement in that space, the other big one
is what we call cellular therapy.
So, we take immune cells, and these
can be either T cells or NK
cells. These are different type of immune cells.
They're essentially the little soldiers in our body that
our immune system uses to recognize and attack
cancer. We can take these T cells
or NK cells and engineer
them to make them even more likely to
specifically recognize the patient's cancer.
And we have been doing that in our group,
both for what we call CAR T
cells. So, when we engineer those cells, we call this CAR,
car. And when it's engineered T cells we call
it CAR T cells and then CAR NK
cells, so when we engineer the NK cells.
So, we have clinical trials
ongoing and upcoming, including one that we'll open,
the CAR NK one that will open in the next few weeks, that
we are exploring for our patients.
And we're very excited about those opportunities.
It will, of course, none of them will immediately
be the silver bullet that will
get us to cure 100% of patients.
However, it is progress, and
it shows that there is hope, even
for patients with kidney cancers that have been
resistant to the standard available strategies.
We need to remember many of these strategies didn't exist
10 or 15 years ago.
So, even during my time as a faculty, there has
been such an emergence of novel therapies
that can make a difference for our patients.
And exactly to this point, I would like to ask
you, Dr. Hahn, how do you think that
this evolution of our understanding
of kidney cancer might personalize
the treatment and surveillance strategies
in a way that changes our practice
and is impactful for our patients?
Absolutely. From a treatment perspective, I want to
highlight one thing that you just pointed out in both of
those studies, which is we are really trying here at MD
Anderson to try to add new tools to the toolbox
with our clinical trials, meaning totally new ways of
treating kidney cancer that are innovative and disruptive
in a positive way. And you can hear that highlighted in
both of the trials that Dr. Msaouel discussed.
Dr. Tang, one of our radiation oncologists, and Dr. Msaouel
have done some really nice work at trying to look at how to
personalize when to intervene with treatment
for kidney cancer.
So, to describe a situation for everybody.
There's a group of patients who will have a kidney cancer
that's, that gets limited to the kidney or maybe
just in the lymph nodes around it.
Oftentimes referred to as a stage III RCC, clear cell
RCC. And we think about using immunotherapy,
pembrolizumab, for about a year in those patients.
We consider it. We definitely do not do it for everybody,
and there's a huge amount of debate in our field about
this. Question here is: are there tools that
can help us better select patients who we
should and will benefit from intervening with a treatment
after their diagnosis of stage III kidney cancer to keep
them cured? And I think you can start to see that play out
with two new technologies that are coming down the
pipeline. One of them is the measurement of a protein in
blood or plasma called KIM-1.
KIM-1 seems to be
very closely associated with the burden of
kidney cancer that patients have.
And then another way to track them, whether there's any
residual kidney cancer present or not, or kind of residual
disease. Are these ctDNA tools, these bespoke
ctDNA tools, or tools that we take the tumor,
we do sequencing of the tumor, and we create a DNA tool to
check whether there's DNA from that tumor in the blood
still present. And if you start to detect it, maybe there's
a reason to intervene at that point.
So, both of those, I think, are ways that we can
personalize treatment and personalize intervention in the
future. There's going to be a lot more coming down the
pipeline. And I want to highlight another thing that Dr.
Msaouel said earlier, which is going to be the
personalization of cellular therapies and utilization
of cellular therapies, is another opportunity there for
clear cell kidney cancer.
So, that all being said, we talked a lot about clear cell
and what the future looks like for clear cell.
What in your mind is exciting in the non-clear
cell or variant histology space for RCC?
The beautiful thing to observe now
is how now people believe that
we can make a difference, particularly for each
non-clear cell subtype.
I think we now have enough practical examples
and people have seen that; indeed, we can develop
tailored therapies specifically for each subtype.
So, now there have been even randomized trials
performed for the papillary kidney cancer subtype,
which is the second most common kidney cancer
after clear cell.
We have the so-called fumarate hydratase-deficient
kidney cancer, which often can be part of
a syndrome known as HLRCC, a genetic
syndrome. There have been therapies now tailored
and developed for that kidney cancer.
For renal medullary carcinoma, we have developed
multiple strategies that have
now essentially doubled the survival of these patients.
And we went from less than 1% of
these patients being curable to now even up
to 10% being rendered
disease free, essentially cured.
It's not 100%, and that's what we're
working towards. Get it to 100%.
But that is progress.
Having people now alive and some of them rendered
disease free, that 5 or 10 years ago, that wouldn't be the
case. It is inspiring to see,
and this is what we're excited about, seeing
people motivated now and organizing,
including our patient advocates and patients, to
develop therapies and push for therapies for each
specific kidney cancer subtype.
And so, Dr. Hahn, for the patients and caregivers listening
now, what would you say are
the most important things to know
about kidney cancer and about advocating
for kidney cancer today?
Yeah, the first one I would say is get to know
your cancer and understand your cancer and
ask your doctor. Push him and ask questions to best
understand your cancer at diagnosis.
You've heard us both discuss how much variation
there is in imaging, treatment, surveillance,
etc., based simply upon the histology
that you have. And the same is true about stage.
So, it can be very empowering for patients and caregivers
if they understand what stage of cancer have I been
diagnosed with from the beginning?
If there is a recurrence, what's the intent of the
treatment? Is this treatment potentially curative, or is
this a treatment that's going to help me live longer and
help alleviate symptoms from my cancer?
That can be really powerful for patients.
And then it's always good to push.
Push your oncologist. Push each of us to understand your
treatment options.
Because as you've heard us both allude to, there are
options here. And then the final piece of advice I just
give for clear cell kidney cancer is that if you've been
diagnosed with metastatic clear cell kidney cancer and
you're getting first-line treatment, a simple takeaway from
today is that you should be getting an immunotherapy-based
combination with two drugs, and that's a simple way of
thinking about it. Any final remarks from you as you're
thinking about the future for your patients with both clear
cell and non-clear cell, or variant histology,
kidney cancer?
I would echo everything that you've excellently summarized,
and I will say that there is hope.
There is excitement.
There is research ongoing that I
believe will get us closer to one
day eradicating kidney cancer for every
patient, but it is going to take a village.
It will need the collaboration of all of us.
It will require the support of the research, patient
empowerment and I have been
so inspired to see
how patients can organize themselves
and advocate for themselves and push
for researchers and changes in clinical practice
that can make a difference.
I cannot emphasize that enough.
Everything counts.
Every act counts.
Every little push.
It might sound little, but it can make a difference
to advocate for kidney cancer research.
So, it's been a pleasure discussing about
this field with you, Dr. Hahn, today.
Thanks, Dr, Msaouel.
Thanks for tuning in today.
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