September 13, 2024 • 13 mins
Welcome to episode two of three, where Dr. John Hamack from MD Anderson Cancer Center and Dr. Millie Doss from Stanford University discuss the latest advancements and ongoing challenges in treating locally Advanced or Metastatic EGFR+ Non-Small Cell Lung Cancer (NSCLC). Explore the unmet needs in first-line therapy, the variety of resistance mechanisms, and the evolving landscape of treatment strategies.
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Episode Transcript
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(00:04):
Welcome to the Mechanisms of Resistance in Locally Advanced or Metastatic EGFR
Positive NSCLC episode of the Practice to Practice podcast series.
This educational podcast is brought to you by Johnson & Johnson and is not certified
for continuing medical education.
The consultants in this podcast were paid by Johnson & Johnson and must present
(00:26):
information in compliance with FDA requirements applicable to Johnson & Johnson.
Hi, I'm John Hamack. I'm a thoracic medical oncologist and I'm chairman of Thoracic
Head and Neck Medical Oncology at MD Anderson Cancer Center in Houston, Texas.
We have a large medical oncology practice. We see more than 3,000 new patients
(00:48):
a year with a heavy emphasis on new clinical studies and multidisciplinary care.
Hi, I'm Millie Doss. I am chief oncology at the VA in Palo Alto and a clinical
associate professor at Stanford University.
I am also a thoracic medical oncologist, and I have the privilege of having
clinic at both the VA in Palo Alto and at Stanford University.
(01:10):
John, when you're thinking about the patients that you're managing and treating,
what do you believe is the unmet need around first-line therapy for our patients
with locally advanced or metastatic EGFR-positive non-small cell lung cancer?
It's a great question, Millie. And, you know, I think it's important to say
from the onset that we've made tremendous progress in the field in recent years.
Now a patient with advanced or metastatic EGFR mutant disease who's on a TKI
(01:33):
could expect on the median to go more than a year and a half before the disease
is progressing, and in some cases, many years.
And that really is substantial progress, but it isn't curative and it isn't good enough.
So I think the first major unmet need are better therapies, therapies that can
extend that period even longer while maintaining an excellent quality of life.
(01:54):
The second major unmet need are finding ways to tailor the therapy or personalize it more effectively.
Not everybody should get the exact same approach. Dr. I think that we've had
tremendous progress with multiple generations of the EGFR tyrosine kinase inhibitors.
None of these drugs are actually considered to be cured. And I think we're,
of course, working on strategies to try to prevent or delay resistance to treatment
(02:19):
and really to allow our patients to live longer and live better lives. But I think...
We're just not quite there yet. John, what percentage of your patients with
locally advanced or metastatic non-small cell lung cancer are positive for the common EGFR mutations?
In my practice personally, and we've got a lot of clinical studies,
so my practice is probably enriched, it's about 25% to 30% EGFR mutations,
(02:41):
so a little higher than the general population.
And I think similar to the general population, about 70% of patients with EGFR
mutations are are the common LH58R or exon 19 deletion.
We do have studies for different mutations as well, but the bread and butter
here for EGFR mutant are those classical mutations.
I'd say I have a similar percentage in my Stanford practice where,
(03:05):
again, sort of enriched, especially living in the Bay Area, I would say 30%
to 40% of the patients that I'm seeing will have an EGFR mutation.
And most of these patients, as you mentioned, are going to have sensitizing
EGFR or the common EGFR mutations. Dr.
Amelia, I know the majority of your patients have the common mutations,
the exon 19 deletion or L858R, but what other types of mutations do you end
(03:27):
up seeing in your practice?
Yeah, you know, I think for those of us who see a lot of these patients with
EGFR mutations, we do at times come across patients who have some of the less
common or uncommon EGFR mutations.
The ones I've seen more commonly are the G719X mutation in exon 18 and the L861Q
EGFR mutation in exon 21.
(03:48):
And then we also, of course, see patients with EGFR exon 20 insertion mutations.
Yeah, well, we tend to see a pretty diverse set of atypical EGFR mutations.
One group are the exon 20 insertions, you know, and within that group,
you've got sort of near-loop and far-loop mutations.
We also do see some of the other atypical mutations like the G719X,
(04:09):
the L861s, and the S768Is.
Those are the most common atypicals outside of the common ones.
And then finally, it's worth pointing out that we often see compound mutations
where you put two mutations together.
Those are commonly with the G719X plus another mutation or G709 plus another mutation.
(04:32):
So common mutations tend to go along with those two exon 18 mutations.
We have been seeing improved outcomes for patients with common EGFR mutations.
What do you think are the big contributors to that improved survival that we're seeing?
Yeah, I think the main contributors to improved survival outcomes is really
trying to understand resistance mechanisms in patients who have progression on a TKI therapy.
(04:58):
We're now performing biopsies at the time of disease progression to try to understand
what is the underlying resistance mechanism and is there a treatment that we
can individualize for that patient.
And I do think that now that we're doing that more in clinical practice,
that our patients are doing better and some of them are being able to receive
additional targeted therapies at the time of disease progression?
(05:19):
DR. I think there's a few major contributors, I think. One is that our therapies
are getting better. Our tyrosine kinase inhibitors are getting better.
Secondly, doctors are getting more experienced at how to manage patients with these treatments.
That's in part how to manage side effects. Even though these drugs tend to be
well-tolerated, it still takes some experience to manage side effects.
(05:41):
And finally, I think identifying the different ways the tumor can become resistant
and developing strategies to combat that resistance is something we've got a
long way to go at, but we are improving.
John, what can you tell us about resistance mechanisms in patients treated with the EGFR-TKIs? Yeah.
Well, unfortunately, most patients do eventually develop disease resistance.
(06:05):
And we've learned a lot about this in the last several years, about how it emerges.
So many, if not most cases, we can identify a clear mechanism of resistance.
I like to group them into three major buckets of resistance mechanisms.
And this grouping isn't perfect.
Sometimes they They cross over into different ones. Sometimes there's completely different ones.
(06:26):
But the first bucket would be EGFR-dependent or on-target resistance mechanisms.
And this is where there's an additional EGFR mutation that causes resistance
to the tyrosine kinase inhibitor.
And there may be different resistance mutations depending on the drug or the generation of drug.
And those are pretty well characterized. We have a good sense of which mutations
(06:48):
cause resistance to what generation of drug.
The second grouping are what I think of as bypass mechanisms.
So you turn on another pathway that sort of substitutes for EGFR or complements EGFR.
The most common of these by far and away is MET. The third category of resistance
(07:08):
is a less well-defined one.
This one, I put it under grouping of lineage change or histologic change.
And this is where the tumor cell is going, usually from being well-differentiated
adenocarcinomas to having a different histology.
And therapeutically, this can often be one of the most challenging ones.
Yeah, I tend to think about the on-target, off-target, and then the histologic transformation.
(07:33):
So yeah, I think whenever possible, we try to do either liquid and or tissue
biopsies at the time of disease progression to look specifically at the different
resistance mechanisms that may be at play.
We do oftentimes see on-target EGFR resistance mechanisms, such as the EGFR
C797S. We also will see these off-target pathways.
(07:58):
MET amplification is something we see commonly. We also see other pathways such
as ERBB2, sometimes the acquisition of fusion proteins and pathways at the time of resistance.
And what's nice is when we see these off-target pathways, we can potentially
target them as we're individualizing a treatment plan for that patient.
(08:18):
And then I've certainly seen histologic transformation as well in my clinical
practice. And that really does, really reinforces the need to be performing
repeat tissue biopsies whenever possible in these patients who have disease
progressions at some point.
Or in a lot of cases, we are able to offer patients sort of more tailored therapy
at the time of disease progression.
(08:38):
Yeah. You know, the old days, by which I mean, you know, just five or 10 years
ago, we would commonly just, when a patient became resistant,
just look at EGFR itself.
And that was the only characterization we did.
But now I think it's important to look at, you know, a much broader panel because
sometimes we see, for example, other fusions that get turned on.
I don't know, have you had this experience where other driver oncogenes get turned on?
(09:00):
Absolutely. Yeah, yeah. I mean, it's unusual, but we do see it.
So I've seen ROS1 or ALK fusions that occur in cases of acquired resistance to EGFR-TKi. Yeah.
I've seen a number of cases of RET fusions also. so. Do you think the pattern
of resistance is changing over time compared to what we saw,
let's say, five or 10 years ago?
(09:21):
Absolutely. I mean, we've seen even with use of the different generations of
EGFR TKIs, we're seeing new and I would say more complicated mechanisms of resistance
as we're using some of the later generation TKIs.
And so I do think it's becoming increasingly important to perform these biopsies,
to really investigate, to see what's going on and to see if there is something
(09:42):
that we can do to potentially target that resistance pathway.
Yeah. I think my sense is we're well served never to underestimate the resiliency
or the resourcefulness of tumors to sort of escape the blockades we put up.
And it seems like as we're better at blocking some resistance pathways,
it sort of finds other ones, you know, to get around it.
(10:04):
So this is really feels like it's going to be a never-ending conquest to block
more and more of these resistance pathways, but hopefully as we do that,
therapies will get better and better. Yeah, and I think that's really the...
The reason why we're having difficulty curing this disease is because these
tumor cells get smart and they develop these resistance pathways.
And I think one of the goals, of course, is to try to delay or even prevent
(10:27):
the resistance from occurring in the first place.
John, what are some approaches that can be used to improve treatment outcomes
for our patients with metastatic EGFR-positive non-small cell lung cancer in
the first-line treatment setting?
Yeah, it's a great question. And we spend a lot of time thinking about this.
You know, I think in general, two major approaches we can take is either try
to kill more cancer cells up front, or we can try to block resistance pathways
(10:50):
before they even ever develop.
Now, for the first one, there's a couple ways you can do it.
Adding chemotherapy is one approach that will kill more of the cancer.
Again, not 100%, but it'll kill more of it.
Now, for blocking resistance pathways, there are, I think, combinations that
might block, you know, different resistance pathways. ways.
(11:10):
But it's important to point out there are multiple different ways,
and we don't have an approach right now to block all of them.
So that's something we have to keep in mind.
Yeah. And I think this is something that's certainly emerging and something
that a lot of academic centers are really focusing on and hopefully will lead
to better therapies and FDA approved options for our patients in the future.
Patients want to be cured. And, you know, so we have to do better than we're doing now.
(11:34):
But at least from my perspective, I think there's a clear path forward where
we can continue to make progress by taking things we already know and combining
them and developing new approaches to help extend the lifespan of patients with EGFR mutant disease.
John, it was really great to have this conversation with you today about EGFR-positive lung cancer.
(11:56):
I think, obviously, we talked a lot about resistance mechanisms and sort of
the path forward as we think about improving outcomes for our patients.
So I My hope is that we will all continue to work together to come up with better
treatments for our patients.
Yeah. No, I agree, Millie. I really appreciate the conversation we've had.
It's really breathtaking the amount of different changes and how much our understanding
(12:19):
of EGFR mutant non-small cell lung cancer has evolved.
And fortunately, there's been wonderful progress for patients.
But I think the more that we learn, the more we see that it's going to become
increasingly challenging to make progress as we go forward and learn about all
the ways the tumor can adapt.
But it's been great discussing this evolving field with you. Yeah.
Welcome to the Mechanisms of Resistance in Locally Advanced or Metastatic EGFR
Positive NSCLC episode of the Practice to Practice podcast series.
This educational podcast is brought to you by Johnson & Johnson and is not certified
for continuing medical education.
The consultants in this podcast were paid by Johnson & Johnson and must present
(00:26):
information in compliance with FDA requirements applicable to Johnson & Johnson.
Hi, I'm John Hamack. I'm a thoracic medical oncologist and I'm chairman of Thoracic
Head and Neck Medical Oncology at MD Anderson Cancer Center in Houston, Texas.
We have a large medical oncology practice. We see more than 3,000 new patients
(00:48):
a year with a heavy emphasis on new clinical studies and multidisciplinary care.
Hi, I'm Millie Doss. I am chief oncology at the VA in Palo Alto and a clinical
associate professor at Stanford University.
I am also a thoracic medical oncologist, and I have the privilege of having
clinic at both the VA in Palo Alto and at Stanford University.
(01:10):
John, when you're thinking about the patients that you're managing and treating,
what do you believe is the unmet need around first-line therapy for our patients
with locally advanced or metastatic EGFR-positive non-small cell lung cancer?
It's a great question, Millie. And, you know, I think it's important to say
from the onset that we've made tremendous progress in the field in recent years.
Now a patient with advanced or metastatic EGFR mutant disease who's on a TKI
(01:33):
could expect on the median to go more than a year and a half before the disease
is progressing, and in some cases, many years.
And that really is substantial progress, but it isn't curative and it isn't good enough.
So I think the first major unmet need are better therapies, therapies that can
extend that period even longer while maintaining an excellent quality of life.
(01:54):
The second major unmet need are finding ways to tailor the therapy or personalize it more effectively.
Not everybody should get the exact same approach. Dr. I think that we've had
tremendous progress with multiple generations of the EGFR tyrosine kinase inhibitors.
None of these drugs are actually considered to be cured. And I think we're,
of course, working on strategies to try to prevent or delay resistance to treatment
(02:19):
and really to allow our patients to live longer and live better lives. But I think...
We're just not quite there yet. John, what percentage of your patients with
locally advanced or metastatic non-small cell lung cancer are positive for the common EGFR mutations?
In my practice personally, and we've got a lot of clinical studies,
so my practice is probably enriched, it's about 25% to 30% EGFR mutations,
(02:41):
so a little higher than the general population.
And I think similar to the general population, about 70% of patients with EGFR
mutations are are the common LH58R or exon 19 deletion.
We do have studies for different mutations as well, but the bread and butter
here for EGFR mutant are those classical mutations.
I'd say I have a similar percentage in my Stanford practice where,
(03:05):
again, sort of enriched, especially living in the Bay Area, I would say 30%
to 40% of the patients that I'm seeing will have an EGFR mutation.
And most of these patients, as you mentioned, are going to have sensitizing
EGFR or the common EGFR mutations. Dr.
Amelia, I know the majority of your patients have the common mutations,
the exon 19 deletion or L858R, but what other types of mutations do you end
(03:27):
up seeing in your practice?
Yeah, you know, I think for those of us who see a lot of these patients with
EGFR mutations, we do at times come across patients who have some of the less
common or uncommon EGFR mutations.
The ones I've seen more commonly are the G719X mutation in exon 18 and the L861Q
EGFR mutation in exon 21.
(03:48):
And then we also, of course, see patients with EGFR exon 20 insertion mutations.
Yeah, well, we tend to see a pretty diverse set of atypical EGFR mutations.
One group are the exon 20 insertions, you know, and within that group,
you've got sort of near-loop and far-loop mutations.
We also do see some of the other atypical mutations like the G719X,
(04:09):
the L861s, and the S768Is.
Those are the most common atypicals outside of the common ones.
And then finally, it's worth pointing out that we often see compound mutations
where you put two mutations together.
Those are commonly with the G719X plus another mutation or G709 plus another mutation.
(04:32):
So common mutations tend to go along with those two exon 18 mutations.
We have been seeing improved outcomes for patients with common EGFR mutations.
What do you think are the big contributors to that improved survival that we're seeing?
Yeah, I think the main contributors to improved survival outcomes is really
trying to understand resistance mechanisms in patients who have progression on a TKI therapy.
(04:58):
We're now performing biopsies at the time of disease progression to try to understand
what is the underlying resistance mechanism and is there a treatment that we
can individualize for that patient.
And I do think that now that we're doing that more in clinical practice,
that our patients are doing better and some of them are being able to receive
additional targeted therapies at the time of disease progression?
(05:19):
DR. I think there's a few major contributors, I think. One is that our therapies
are getting better. Our tyrosine kinase inhibitors are getting better.
Secondly, doctors are getting more experienced at how to manage patients with these treatments.
That's in part how to manage side effects. Even though these drugs tend to be
well-tolerated, it still takes some experience to manage side effects.
(05:41):
And finally, I think identifying the different ways the tumor can become resistant
and developing strategies to combat that resistance is something we've got a
long way to go at, but we are improving.
John, what can you tell us about resistance mechanisms in patients treated with the EGFR-TKIs? Yeah.
Well, unfortunately, most patients do eventually develop disease resistance.
(06:05):
And we've learned a lot about this in the last several years, about how it emerges.
So many, if not most cases, we can identify a clear mechanism of resistance.
I like to group them into three major buckets of resistance mechanisms.
And this grouping isn't perfect.
Sometimes they They cross over into different ones. Sometimes there's completely different ones.
(06:26):
But the first bucket would be EGFR-dependent or on-target resistance mechanisms.
And this is where there's an additional EGFR mutation that causes resistance
to the tyrosine kinase inhibitor.
And there may be different resistance mutations depending on the drug or the generation of drug.
And those are pretty well characterized. We have a good sense of which mutations
(06:48):
cause resistance to what generation of drug.
The second grouping are what I think of as bypass mechanisms.
So you turn on another pathway that sort of substitutes for EGFR or complements EGFR.
The most common of these by far and away is MET. The third category of resistance
(07:08):
is a less well-defined one.
This one, I put it under grouping of lineage change or histologic change.
And this is where the tumor cell is going, usually from being well-differentiated
adenocarcinomas to having a different histology.
And therapeutically, this can often be one of the most challenging ones.
Yeah, I tend to think about the on-target, off-target, and then the histologic transformation.
(07:33):
So yeah, I think whenever possible, we try to do either liquid and or tissue
biopsies at the time of disease progression to look specifically at the different
resistance mechanisms that may be at play.
We do oftentimes see on-target EGFR resistance mechanisms, such as the EGFR
C797S. We also will see these off-target pathways.
(07:58):
MET amplification is something we see commonly. We also see other pathways such
as ERBB2, sometimes the acquisition of fusion proteins and pathways at the time of resistance.
And what's nice is when we see these off-target pathways, we can potentially
target them as we're individualizing a treatment plan for that patient.
(08:18):
And then I've certainly seen histologic transformation as well in my clinical
practice. And that really does, really reinforces the need to be performing
repeat tissue biopsies whenever possible in these patients who have disease
progressions at some point.
Or in a lot of cases, we are able to offer patients sort of more tailored therapy
at the time of disease progression.
(08:38):
Yeah. You know, the old days, by which I mean, you know, just five or 10 years
ago, we would commonly just, when a patient became resistant,
just look at EGFR itself.
And that was the only characterization we did.
But now I think it's important to look at, you know, a much broader panel because
sometimes we see, for example, other fusions that get turned on.
I don't know, have you had this experience where other driver oncogenes get turned on?
(09:00):
Absolutely. Yeah, yeah. I mean, it's unusual, but we do see it.
So I've seen ROS1 or ALK fusions that occur in cases of acquired resistance to EGFR-TKi. Yeah.
I've seen a number of cases of RET fusions also. so. Do you think the pattern
of resistance is changing over time compared to what we saw,
let's say, five or 10 years ago?
(09:21):
Absolutely. I mean, we've seen even with use of the different generations of
EGFR TKIs, we're seeing new and I would say more complicated mechanisms of resistance
as we're using some of the later generation TKIs.
And so I do think it's becoming increasingly important to perform these biopsies,
to really investigate, to see what's going on and to see if there is something
(09:42):
that we can do to potentially target that resistance pathway.
Yeah. I think my sense is we're well served never to underestimate the resiliency
or the resourcefulness of tumors to sort of escape the blockades we put up.
And it seems like as we're better at blocking some resistance pathways,
it sort of finds other ones, you know, to get around it.
(10:04):
So this is really feels like it's going to be a never-ending conquest to block
more and more of these resistance pathways, but hopefully as we do that,
therapies will get better and better. Yeah, and I think that's really the...
The reason why we're having difficulty curing this disease is because these
tumor cells get smart and they develop these resistance pathways.
And I think one of the goals, of course, is to try to delay or even prevent
(10:27):
the resistance from occurring in the first place.
John, what are some approaches that can be used to improve treatment outcomes
for our patients with metastatic EGFR-positive non-small cell lung cancer in
the first-line treatment setting?
Yeah, it's a great question. And we spend a lot of time thinking about this.
You know, I think in general, two major approaches we can take is either try
to kill more cancer cells up front, or we can try to block resistance pathways
(10:50):
before they even ever develop.
Now, for the first one, there's a couple ways you can do it.
Adding chemotherapy is one approach that will kill more of the cancer.
Again, not 100%, but it'll kill more of it.
Now, for blocking resistance pathways, there are, I think, combinations that
might block, you know, different resistance pathways. ways.
(11:10):
But it's important to point out there are multiple different ways,
and we don't have an approach right now to block all of them.
So that's something we have to keep in mind.
Yeah. And I think this is something that's certainly emerging and something
that a lot of academic centers are really focusing on and hopefully will lead
to better therapies and FDA approved options for our patients in the future.
Patients want to be cured. And, you know, so we have to do better than we're doing now.
(11:34):
But at least from my perspective, I think there's a clear path forward where
we can continue to make progress by taking things we already know and combining
them and developing new approaches to help extend the lifespan of patients with EGFR mutant disease.
John, it was really great to have this conversation with you today about EGFR-positive lung cancer.
(11:56):
I think, obviously, we talked a lot about resistance mechanisms and sort of
the path forward as we think about improving outcomes for our patients.
So I My hope is that we will all continue to work together to come up with better
treatments for our patients.
Yeah. No, I agree, Millie. I really appreciate the conversation we've had.
It's really breathtaking the amount of different changes and how much our understanding
(12:19):
of EGFR mutant non-small cell lung cancer has evolved.
And fortunately, there's been wonderful progress for patients.
But I think the more that we learn, the more we see that it's going to become
increasingly challenging to make progress as we go forward and learn about all
the ways the tumor can adapt.
But it's been great discussing this evolving field with you. Yeah.
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