July 14, 2025 • 16 mins
Over the past decade, the landscape of systemic therapy has been transformed by the arrival of immunotherapy and highly effective targeted agents. Many of these drugs have significant intracranial activity, creating a new and complex challenge for the radiation oncologist: how do we sequence our treatments? The old paradigm of "radiation first" is no longer always correct. Today, we will provide a modern guide to navigating this new reality. We will discuss when it's appropriate to defer radiation entirely, compare the CNS efficacy of different systemic regimens, and detail the critical safety considerations and toxicity risks of combining SRS with these powerful new drugs.
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Episode Transcript
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(00:00):
Welcome to the Radon Smart Review CNS Cancer series.
Great to be here. Today we're tackling well a
really dynamic and sometimes perplexing area in Radon Sam.
Right now it's about sequencing stereotactic radio surgery, you
know, SRS with immunotherapy andtargeted therapy for brain Mets.
Yeah, it's a puzzle, isn't it? And one that seems to change
(00:22):
almost well, constantly. Absolutely.
These new systemic therapies, I mean, some have incredible
activity inside the brain. You really do.
It's completely rewritten the playbook.
So that old radiation first idea.
Yeah, that's often too simple now.
Sometimes it's even, well, the wrong call.
So our goal for this session is really to give you a practical
guide, sort of a modern take on navigating this new reality.
(00:45):
Exactly. We want to talk about when it
actually makes sense to defer radiation.
OK, Compare the CNS efficacy. You know how well different
systemic drugs work in the brain, right?
And this is critical, really detailed, the safety aspects,
the toxicity risks when you combine SRS with these potent
new agents. OK, to make this really
concrete, let's think about 3 hypothetical patients.
(01:08):
You know, the kind who could walk into your clinic any day.
Good idea. Each one has a bit of a
sequencing dilemma, but the basic question is the same.
Do we treat with SRS now or do we let the systemic therapy work
first? That's the $1,000,000 question,
right? Keeps us on our toes.
It really does. And honestly, the answer, it
really depends, depends on the Histology, the specific systemic
(01:30):
drug available, the whole clinical picture, you know?
So it's not one-size-fits-all. Not at all.
We can kind of break it down into maybe 3 main philosophies
or approaches that guide these decisions.
All right, let's start with patient A.
Imagine a 58 year old newly diagnosed EGFR mutant non small
cell lung cancer. OK, they've got three brain Mets
(01:51):
symptomatic. Just 5mm each.
Yeah, small, quiet. What jumps out at you there?
Well, for patient A, my first thought often leans towards a
systemic first approach, which we'll get into.
OK, but let's quickly paint the picture for the others too.
Patient B, 45 year old metastatic Melanoma, 5
asymptomatic brain Mets, about acentimeter each this time.
(02:12):
So a bit bigger, but still no symptoms.
OK. Melanoma 5 Mets and patient C.
Patient C is 52 HE R2 positive breast cancer single brain MET
1.5cm and she's about to start the antibody drug conjugate
trastuzumab duruxtican. Ah, OK, That one immediately
raises some red flags, doesn't it?
(02:33):
Yeah. Why is that specific drug
combination a concern? You're right to flag that one
patient C with that particular ADC needs extra caution.
We'll definitely circle back to why, but first, let's dive into
those 3 philosophies, starting with #1 systemic therapy.
First, deferring radiation. Right.
This idea of holding off on radiation, it feels relatively
(02:53):
new, but it's becoming much morecommon.
When can we actually feel confident doing that?
Holding SRS back upfront. We usually reserve this for
systemic agents that have, you know, a proven really high
chance of controlling the disease inside the brain.
OK. And a patient a our EGFR mutant
lung cancer case. That's like the textbook example
for this approach. Because of the specific drug.
(03:14):
Exactly the third Gen. TKI ossemertinib.
It just has outstanding CNS penetration and efficacy.
Really gets into the brain and works.
OK, out standing is a strong word.
What kind of numbers are we talking about?
What do the trials show for CNS response?
We're talking serious numbers. Trials like Flora and RA3 showed
(03:37):
CNS response rates around 66 to 70% in patients with measurable
brain Mets. 66 to 70% and. It's not just shrinking Mets.
The Bloom study looked at leptomeningeal disease, which is
notoriously tough, right? And it showed an overall
response rate of 62% there, too.That's just found activity
within the CNS. OK, with data like that
(03:59):
deferring upfront SRS for those little 5mm asymptomatic lesions,
it suddenly makes a lot of sense.
It does. What's the core thinking?
They're just keeping radiation in your back pocket.
Pretty much you've got such a high likelihood of shrinking
those brain Mets with the drug alone.
You buy time, you hold radiationand reserve, avoid potential
side effects until you really need it, maybe for progression
(04:19):
down the line. Makes sense.
And this same logic, this approach, it also applies really
well to ALK, a positive non small cell lung cancer,
especially when you're using potent inhibitors like lectinib
or lorlatinib, their CNS response rates can push close to
80%. 80%, yeah. It's really been a game changer
(04:40):
for these specific patient groups.
Right, let's flip the coin. Philosophy #2 Radiation first,
the traditional way. Right, standard practice for
years. Secure that intracranial control
upfront. When does that approach still
make the most sense today? Well, while it's maybe less of a
universal rule now, it's definitely still valid.
(05:00):
Crucial even if the patient has symptoms from their brain Mets.
OK, symptoms are key. Absolutely, or if the systemic
therapy you have available just doesn't have great or maybe
uncertain CNS response rates. You just don't want to gamble if
someone's symptomatic or if you're not confident the drug
will work well in the brain. Can you give us an example?
A scenario where radiation firstis clearly the kind of safer
(05:23):
bet. Sure.
A good example might be metastatic renal cell carcinoma.
OK. RCC.
Yeah, agents like cabozantinib, they do have some CNS activity,
but the response rates just aren't in the same league as
something like Osimoto nib for EGFR lung cancer.
Got it. Not as reliable.
Exactly. So in a case like that, hitting
those known brain Mets with SRS first is often the safest, most
(05:47):
reliable path to getting that intracranial control sorted out.
That makes sense, but you know, Speaking of EGFR lung cancer, I
seem to remember some data challenging that system.
First idea even there. Was there a Yale study?
Yes, you're probably thinking ofthe Magnuson paper from 2017.
That's the one. What did it find and how do you
sort of square that with the current practice?
(06:08):
That's a really important point.It was a retrospective study
looked at EGFR mutant non small cell lung cancer patients and it
actually found that patients whogot upfront SRS followed by a
TKI seemed to have better overall survival compared to
those who got the TKI first. Better survival with radiation
first. So how do we reconcile that?
Well, it highlights that this isstill an area of debate, right?
(06:31):
These aren't always simple blackand white decisions.
We're constantly balancing immediate intracranial control,
which radiation gives you quickly, with long term systemic
control and of course toxicity. So I think for many clinicians
with small asymptomatic lesions,the TKI first approach is often
still favored because Osmertina works so well and you want to
(06:52):
defer radiation if possible. But that Yale data serves as a
good reminder that securing thatlocal control early might offer
a long term survival benefit forsome patients.
It really comes down to a personalized risk assessment.
That's a great way to put it. OK, let's move to the third
philosophy, concurrent therapy, doing both around the same time.
(07:13):
Right, this one can feel a bit like high risk, high rewards
sometimes, especially combining SRS with immunotherapy.
Yeah, there's this fascinating idea about biological synergy
there, right? Exactly.
The preclinical data is really intriguing.
It suggests SRS can act like an in situ vaccine.
An in situ vaccine? How does that work?
So that high focused dose of radiation basically blasts tumor
(07:34):
cells open, releases a flood of tumor antigens and that release
seems to prime the immune system, wakes it up, makes it
more responsive to the checkpoint inhibitors.
So the local radiation treatmentmight boost the systemic immune
effect. That's the theory, potentially
turning a local ZAP into a systemic immune boost.
(07:54):
And are we seeing evidence for this in the clinic?
Does it actually play out? We are starting to see signals.
Yeah, yeah. There was a retrospective study
from Johns Hopkins, for example.What?
Did that show? It found that giving SRS and
immunotherapy concurrently or very close together was
associated with improved overallsurvival.
Improved survival. Wow.
And also a lower rate of new brain metastasis appearing later
(08:16):
compared to giving them non concurrently.
And importantly, it didn't seem to come with a significant
increase in radiation necrosis in that study.
OK. So better outcomes without more
toxicity in that analysis. Right.
And that kind of data has certainly encouraged the common
practice now of giving SRS and checkpoint inhibitors, you know,
pretty slow together concurrently or with minimal
(08:38):
delay. This brings us back to Patient
B, the one with Melanoma. What are the CNS response rates
we should know for immunotherapyin Melanoma single agent versus
the combination? Good question.
For Melanoma, if you use a single agent checkpoint
inhibitor like pembrolizumab, the CNS response rate is around
25%, which is, you know, OK, decent but not spectacular.
(09:03):
Only 5%. OK.
But the combination epilimab plus nivolumab, that's much more
effective in the brain. How much more effective?
The Checkmate 2O Four trial showed a CNS response rate of
about 55% for epinivo. 55% that's more than double the
single agent rate. Exactly.
It's a really significant jump in intracranial control for
those patients. That's a.
(09:23):
Huge difference. OK, OK.
But now while we're on combinations, we absolutely have
to go back to patient C. Right the her 2 positive breast
cancer patients starting trestizumab Duruxiken TDXD.
Yes, you flagged this earlier. This is where we need a big
flashing warning sign, right? Concurrent SRS with certain
ADC's. Absolutely critical safety
(09:45):
warning here. This is emerging data, but it's
consistent and concerning. What's the specific concern with
ADC's like TDXD and concurrent SRS?
There appears to be a significantly heightened risk of
symptomatic radiation necrosis when SRS is given concurrently
or very close in time with certain ADC's and trastuzumab
(10:05):
directican is kind of the posterchild for this concern right
now. Symptomatic radiation necrosis,
So serious brain swelling and damage, yes.
Potentially very serious. The exact Y isn't fully worked
out yet. Maybe it's increased drug
delivery to the irradiated area?Maybe enhanced inflammation?
But the bottom line is the combination seems to increase
the risk of bad tissue damage. That's the bottom line.
(10:26):
It's a combination you really want to approach with extreme
caution, and ideally avoid giving concurrently if you can.
So for patients like patient C needing both SRS and TDXD, yeah,
what's the recommendation? What's the safest way?
Based on what we're learning, the safest approach is to
separate the treatments createspace between them.
Separate them how? Either complete the course of
(10:48):
SRS before the patient starts the ADC, or if they're already
on the ADC, hold the drug for a period around the time of SRS.
We don't have exact optimal windows to find yet, but
creating that separation seems key.
So deliberate sequencing, putting time between the two
treatment. Precisely that separation
appears crucial to mitigate thatheightened risk of severe rad
(11:09):
necrosis. Timing is absolutely critical
here, OK. That is a hugely important
safety point. Let's pause here and maybe
distill some of these key takeaways.
Time for our clinical pearls. Sounds good.
Pearl #1. For those asymptomatic small
brain Mets in EGFR mutant or ALKpositive lung cancer, deferring
upfront radiation and going witha potent TKI first like
(11:32):
osmertinib or electinib is a standard justifiable strategy.
Right, justified by those reallyhigh CNS response rates over 65
even up to 80%. Exactly Pearl #2 for Melanoma
brain Mets. Remember those immunotherapy
numbers? Single agent checkpoint
inhibitors, around 25% CNS response, but the combination
iponivo jumps way up to about 55%.
(11:54):
Big difference. That combination really changes
the outlook for intracranial disease.
Got it. Pearl 3 concurrent SRS and
immunotherapy generally speakingwith checkpoint inhibitors is
common practice. It might even be synergistic
based on data like the Hopkins study.
OK, potentially beneficial. But, and this is a big but
extreme caution is needed with antibody drug conjugates,
(12:17):
especially Trustezuma deruxtican, because of that
heightened rad necrosis risk. Right IO combo OK ADC combo
danger zone. That's a good way to summarize
the current thinking. And that leads to Pearl 4 if you
have a patient needing both SRS and a higher risk systemic agent
like an ADC. Yeah, the safest plan involves
explicitly separating those treatments in time.
(12:40):
Build in a gap. Prioritize that separation for
safety. Excellent, Pearls.
OK, let's put some of this to the test.
Time for our board blitz. You ready?
Let's do it. Question one for you.
According to the Checkmate 2O Four trial, what was the
approximate overall intricate cranial response rate for
Melanoma brain Mets treated withthe combination of epilimab and
nivolumab? Was it a 26%, B 35%, C 57% or D
(13:03):
78%? OK.
Checkmate. 2O4, Ibanevo, we justtalked about this.
It was significantly higher thansingle agent.
I'm going with C 57%. That is correct.
C 57%. The Checkmate 2O four trial
really highlighted that impressive intracranial efficacy
for the combination. OK, Question 2.
According to that retrospective analysis from Yale on EGFR
(13:24):
mutant non small cell lung cancer patients, how did the
strategy of deferring radiation and using upfront TKI therapy
compared to using upfront SRS for brain metastases?
A upfront TKI was associated with superior overall survival.
B upfront TKI was associated with inferior overall survival.
C both strategies resulted in equivalent overall survival, or
(13:45):
D upfront TKI led to better distant brain control.
The Yale study, that was the onethat seemed counterintuitive,
right? It found starting with the TKI
was worse for survival, so B inferior overall survival.
That's right, the answer is B. The Yale retrospective study
found that initiating TKI therapy 1st and deferring
radiation was associated with inferior overall survival
(14:07):
compared to strategies that included upfront radiation in
their analysis. Definitely food for.
Thought it really is. OK, last one.
Last one, question 3. For a patient getting SRS for
brain meds, what's the clinical implication of the findings from
that Johns Hopkins retrospectivestudy on the timing of
immunotherapy? A Hold immunotherapy for at
least four weeks after SRSB. Concurrent administration of
(14:30):
immunotherapy and SRS may improve survival.
C Timing relative to SRS has no impact or D concurrent IO
significantly increases rad necrosis risk.
OK, the Hopkins study, that was the one suggesting synergy,
right? Better survival and fewer new
meds with concurrent treatment without more necrosis in their
data. So B concurrent admin may
improve survival. Exactly B is the correct answer.
(14:52):
The Hopkins retrospective data suggested concurrent
administration was associated with improved overall survival,
and fewer new brain myths without a corresponding increase
in rad necrosis in their cohort reinforces that potential
synergistic effect. Great questions.
So wrapping this all up, what's the big picture message here?
It feels like the main point is that the old one-size-fits-all
(15:14):
radiation. First rule for brain Mets is
definitely history. Absolutely.
It's history. We've seen how these powerful
new systemic agents, especially targeted therapies like AWESOME
or T NIB, can often take the lead, particularly for smaller
asymptomatic lesions. You can potentially spare
patients upfront radiation, right?
But we also learned that radiation, SRS specifically,
(15:35):
still has a crucial role, especially for symptomatic
patients or when the systemic drugs aren't as reliable in the
brain. And that Yale study reminds us,
early local control might still matter for survival in some
cases. Precisely.
And perhaps the most critical take away today is understanding
that delicate balance when combining therapies.
The potential synergy with immunotherapy is exciting, but
(15:55):
the very real danger with concurrent ADC's like TDXD means
timing isn't just important, it's absolutely paramount for
patient safety. You have to separate those
treatments. It's definitely a complex
landscape, challenging, but also, you know, incredibly
important to get right for our patients.
Staying up to date on these sequencing nuances is just
(16:15):
vital. It really is.
And as we look forward, you know, systemic therapies are
only going to get better, more diverse, constantly challenges
us to rethink what optimal sequencing means.
It makes you wonder, doesn't it?What do these complex,
personalized decisions really mean for the future of oncology
care? How might things like, say, AI
(16:36):
help us navigate this intricate dance between systemic treatment
and localized precision even better down the road?
Lots to think about. Indeed, thanks for tuning into
the RAD on Smart Review CNS Cancer series.
Yeah, thanks, everyone. Remember, you can get show notes
and complete practice oral boards over at RAD on
smartlearn.com. And definitely subscribe to RAD
on Smart Reviews so you don't miss our next session.
(16:57):
Thanks for listening.
Welcome to the Radon Smart Review CNS Cancer series.
Great to be here. Today we're tackling well a
really dynamic and sometimes perplexing area in Radon Sam.
Right now it's about sequencing stereotactic radio surgery, you
know, SRS with immunotherapy andtargeted therapy for brain Mets.
Yeah, it's a puzzle, isn't it? And one that seems to change
(00:22):
almost well, constantly. Absolutely.
These new systemic therapies, I mean, some have incredible
activity inside the brain. You really do.
It's completely rewritten the playbook.
So that old radiation first idea.
Yeah, that's often too simple now.
Sometimes it's even, well, the wrong call.
So our goal for this session is really to give you a practical
guide, sort of a modern take on navigating this new reality.
(00:45):
Exactly. We want to talk about when it
actually makes sense to defer radiation.
OK, Compare the CNS efficacy. You know how well different
systemic drugs work in the brain, right?
And this is critical, really detailed, the safety aspects,
the toxicity risks when you combine SRS with these potent
new agents. OK, to make this really
concrete, let's think about 3 hypothetical patients.
(01:08):
You know, the kind who could walk into your clinic any day.
Good idea. Each one has a bit of a
sequencing dilemma, but the basic question is the same.
Do we treat with SRS now or do we let the systemic therapy work
first? That's the $1,000,000 question,
right? Keeps us on our toes.
It really does. And honestly, the answer, it
really depends, depends on the Histology, the specific systemic
(01:30):
drug available, the whole clinical picture, you know?
So it's not one-size-fits-all. Not at all.
We can kind of break it down into maybe 3 main philosophies
or approaches that guide these decisions.
All right, let's start with patient A.
Imagine a 58 year old newly diagnosed EGFR mutant non small
cell lung cancer. OK, they've got three brain Mets
(01:51):
symptomatic. Just 5mm each.
Yeah, small, quiet. What jumps out at you there?
Well, for patient A, my first thought often leans towards a
systemic first approach, which we'll get into.
OK, but let's quickly paint the picture for the others too.
Patient B, 45 year old metastatic Melanoma, 5
asymptomatic brain Mets, about acentimeter each this time.
(02:12):
So a bit bigger, but still no symptoms.
OK. Melanoma 5 Mets and patient C.
Patient C is 52 HE R2 positive breast cancer single brain MET
1.5cm and she's about to start the antibody drug conjugate
trastuzumab duruxtican. Ah, OK, That one immediately
raises some red flags, doesn't it?
(02:33):
Yeah. Why is that specific drug
combination a concern? You're right to flag that one
patient C with that particular ADC needs extra caution.
We'll definitely circle back to why, but first, let's dive into
those 3 philosophies, starting with #1 systemic therapy.
First, deferring radiation. Right.
This idea of holding off on radiation, it feels relatively
(02:53):
new, but it's becoming much morecommon.
When can we actually feel confident doing that?
Holding SRS back upfront. We usually reserve this for
systemic agents that have, you know, a proven really high
chance of controlling the disease inside the brain.
OK. And a patient a our EGFR mutant
lung cancer case. That's like the textbook example
for this approach. Because of the specific drug.
(03:14):
Exactly the third Gen. TKI ossemertinib.
It just has outstanding CNS penetration and efficacy.
Really gets into the brain and works.
OK, out standing is a strong word.
What kind of numbers are we talking about?
What do the trials show for CNS response?
We're talking serious numbers. Trials like Flora and RA3 showed
(03:37):
CNS response rates around 66 to 70% in patients with measurable
brain Mets. 66 to 70% and. It's not just shrinking Mets.
The Bloom study looked at leptomeningeal disease, which is
notoriously tough, right? And it showed an overall
response rate of 62% there, too.That's just found activity
within the CNS. OK, with data like that
(03:59):
deferring upfront SRS for those little 5mm asymptomatic lesions,
it suddenly makes a lot of sense.
It does. What's the core thinking?
They're just keeping radiation in your back pocket.
Pretty much you've got such a high likelihood of shrinking
those brain Mets with the drug alone.
You buy time, you hold radiationand reserve, avoid potential
side effects until you really need it, maybe for progression
(04:19):
down the line. Makes sense.
And this same logic, this approach, it also applies really
well to ALK, a positive non small cell lung cancer,
especially when you're using potent inhibitors like lectinib
or lorlatinib, their CNS response rates can push close to
80%. 80%, yeah. It's really been a game changer
(04:40):
for these specific patient groups.
Right, let's flip the coin. Philosophy #2 Radiation first,
the traditional way. Right, standard practice for
years. Secure that intracranial control
upfront. When does that approach still
make the most sense today? Well, while it's maybe less of a
universal rule now, it's definitely still valid.
(05:00):
Crucial even if the patient has symptoms from their brain Mets.
OK, symptoms are key. Absolutely, or if the systemic
therapy you have available just doesn't have great or maybe
uncertain CNS response rates. You just don't want to gamble if
someone's symptomatic or if you're not confident the drug
will work well in the brain. Can you give us an example?
A scenario where radiation firstis clearly the kind of safer
(05:23):
bet. Sure.
A good example might be metastatic renal cell carcinoma.
OK. RCC.
Yeah, agents like cabozantinib, they do have some CNS activity,
but the response rates just aren't in the same league as
something like Osimoto nib for EGFR lung cancer.
Got it. Not as reliable.
Exactly. So in a case like that, hitting
those known brain Mets with SRS first is often the safest, most
(05:47):
reliable path to getting that intracranial control sorted out.
That makes sense, but you know, Speaking of EGFR lung cancer, I
seem to remember some data challenging that system.
First idea even there. Was there a Yale study?
Yes, you're probably thinking ofthe Magnuson paper from 2017.
That's the one. What did it find and how do you
sort of square that with the current practice?
(06:08):
That's a really important point.It was a retrospective study
looked at EGFR mutant non small cell lung cancer patients and it
actually found that patients whogot upfront SRS followed by a
TKI seemed to have better overall survival compared to
those who got the TKI first. Better survival with radiation
first. So how do we reconcile that?
Well, it highlights that this isstill an area of debate, right?
(06:31):
These aren't always simple blackand white decisions.
We're constantly balancing immediate intracranial control,
which radiation gives you quickly, with long term systemic
control and of course toxicity. So I think for many clinicians
with small asymptomatic lesions,the TKI first approach is often
still favored because Osmertina works so well and you want to
(06:52):
defer radiation if possible. But that Yale data serves as a
good reminder that securing thatlocal control early might offer
a long term survival benefit forsome patients.
It really comes down to a personalized risk assessment.
That's a great way to put it. OK, let's move to the third
philosophy, concurrent therapy, doing both around the same time.
(07:13):
Right, this one can feel a bit like high risk, high rewards
sometimes, especially combining SRS with immunotherapy.
Yeah, there's this fascinating idea about biological synergy
there, right? Exactly.
The preclinical data is really intriguing.
It suggests SRS can act like an in situ vaccine.
An in situ vaccine? How does that work?
So that high focused dose of radiation basically blasts tumor
(07:34):
cells open, releases a flood of tumor antigens and that release
seems to prime the immune system, wakes it up, makes it
more responsive to the checkpoint inhibitors.
So the local radiation treatmentmight boost the systemic immune
effect. That's the theory, potentially
turning a local ZAP into a systemic immune boost.
(07:54):
And are we seeing evidence for this in the clinic?
Does it actually play out? We are starting to see signals.
Yeah, yeah. There was a retrospective study
from Johns Hopkins, for example.What?
Did that show? It found that giving SRS and
immunotherapy concurrently or very close together was
associated with improved overallsurvival.
Improved survival. Wow.
And also a lower rate of new brain metastasis appearing later
(08:16):
compared to giving them non concurrently.
And importantly, it didn't seem to come with a significant
increase in radiation necrosis in that study.
OK. So better outcomes without more
toxicity in that analysis. Right.
And that kind of data has certainly encouraged the common
practice now of giving SRS and checkpoint inhibitors, you know,
pretty slow together concurrently or with minimal
(08:38):
delay. This brings us back to Patient
B, the one with Melanoma. What are the CNS response rates
we should know for immunotherapyin Melanoma single agent versus
the combination? Good question.
For Melanoma, if you use a single agent checkpoint
inhibitor like pembrolizumab, the CNS response rate is around
25%, which is, you know, OK, decent but not spectacular.
(09:03):
Only 5%. OK.
But the combination epilimab plus nivolumab, that's much more
effective in the brain. How much more effective?
The Checkmate 2O Four trial showed a CNS response rate of
about 55% for epinivo. 55% that's more than double the
single agent rate. Exactly.
It's a really significant jump in intracranial control for
those patients. That's a.
(09:23):
Huge difference. OK, OK.
But now while we're on combinations, we absolutely have
to go back to patient C. Right the her 2 positive breast
cancer patients starting trestizumab Duruxiken TDXD.
Yes, you flagged this earlier. This is where we need a big
flashing warning sign, right? Concurrent SRS with certain
ADC's. Absolutely critical safety
(09:45):
warning here. This is emerging data, but it's
consistent and concerning. What's the specific concern with
ADC's like TDXD and concurrent SRS?
There appears to be a significantly heightened risk of
symptomatic radiation necrosis when SRS is given concurrently
or very close in time with certain ADC's and trastuzumab
(10:05):
directican is kind of the posterchild for this concern right
now. Symptomatic radiation necrosis,
So serious brain swelling and damage, yes.
Potentially very serious. The exact Y isn't fully worked
out yet. Maybe it's increased drug
delivery to the irradiated area?Maybe enhanced inflammation?
But the bottom line is the combination seems to increase
the risk of bad tissue damage. That's the bottom line.
(10:26):
It's a combination you really want to approach with extreme
caution, and ideally avoid giving concurrently if you can.
So for patients like patient C needing both SRS and TDXD, yeah,
what's the recommendation? What's the safest way?
Based on what we're learning, the safest approach is to
separate the treatments createspace between them.
Separate them how? Either complete the course of
(10:48):
SRS before the patient starts the ADC, or if they're already
on the ADC, hold the drug for a period around the time of SRS.
We don't have exact optimal windows to find yet, but
creating that separation seems key.
So deliberate sequencing, putting time between the two
treatment. Precisely that separation
appears crucial to mitigate thatheightened risk of severe rad
(11:09):
necrosis. Timing is absolutely critical
here, OK. That is a hugely important
safety point. Let's pause here and maybe
distill some of these key takeaways.
Time for our clinical pearls. Sounds good.
Pearl #1. For those asymptomatic small
brain Mets in EGFR mutant or ALKpositive lung cancer, deferring
upfront radiation and going witha potent TKI first like
(11:32):
osmertinib or electinib is a standard justifiable strategy.
Right, justified by those reallyhigh CNS response rates over 65
even up to 80%. Exactly Pearl #2 for Melanoma
brain Mets. Remember those immunotherapy
numbers? Single agent checkpoint
inhibitors, around 25% CNS response, but the combination
iponivo jumps way up to about 55%.
(11:54):
Big difference. That combination really changes
the outlook for intracranial disease.
Got it. Pearl 3 concurrent SRS and
immunotherapy generally speakingwith checkpoint inhibitors is
common practice. It might even be synergistic
based on data like the Hopkins study.
OK, potentially beneficial. But, and this is a big but
extreme caution is needed with antibody drug conjugates,
(12:17):
especially Trustezuma deruxtican, because of that
heightened rad necrosis risk. Right IO combo OK ADC combo
danger zone. That's a good way to summarize
the current thinking. And that leads to Pearl 4 if you
have a patient needing both SRS and a higher risk systemic agent
like an ADC. Yeah, the safest plan involves
explicitly separating those treatments in time.
(12:40):
Build in a gap. Prioritize that separation for
safety. Excellent, Pearls.
OK, let's put some of this to the test.
Time for our board blitz. You ready?
Let's do it. Question one for you.
According to the Checkmate 2O Four trial, what was the
approximate overall intricate cranial response rate for
Melanoma brain Mets treated withthe combination of epilimab and
nivolumab? Was it a 26%, B 35%, C 57% or D
(13:03):
78%? OK.
Checkmate. 2O4, Ibanevo, we justtalked about this.
It was significantly higher thansingle agent.
I'm going with C 57%. That is correct.
C 57%. The Checkmate 2O four trial
really highlighted that impressive intracranial efficacy
for the combination. OK, Question 2.
According to that retrospective analysis from Yale on EGFR
(13:24):
mutant non small cell lung cancer patients, how did the
strategy of deferring radiation and using upfront TKI therapy
compared to using upfront SRS for brain metastases?
A upfront TKI was associated with superior overall survival.
B upfront TKI was associated with inferior overall survival.
C both strategies resulted in equivalent overall survival, or
(13:45):
D upfront TKI led to better distant brain control.
The Yale study, that was the onethat seemed counterintuitive,
right? It found starting with the TKI
was worse for survival, so B inferior overall survival.
That's right, the answer is B. The Yale retrospective study
found that initiating TKI therapy 1st and deferring
radiation was associated with inferior overall survival
(14:07):
compared to strategies that included upfront radiation in
their analysis. Definitely food for.
Thought it really is. OK, last one.
Last one, question 3. For a patient getting SRS for
brain meds, what's the clinical implication of the findings from
that Johns Hopkins retrospectivestudy on the timing of
immunotherapy? A Hold immunotherapy for at
least four weeks after SRSB. Concurrent administration of
(14:30):
immunotherapy and SRS may improve survival.
C Timing relative to SRS has no impact or D concurrent IO
significantly increases rad necrosis risk.
OK, the Hopkins study, that was the one suggesting synergy,
right? Better survival and fewer new
meds with concurrent treatment without more necrosis in their
data. So B concurrent admin may
improve survival. Exactly B is the correct answer.
(14:52):
The Hopkins retrospective data suggested concurrent
administration was associated with improved overall survival,
and fewer new brain myths without a corresponding increase
in rad necrosis in their cohort reinforces that potential
synergistic effect. Great questions.
So wrapping this all up, what's the big picture message here?
It feels like the main point is that the old one-size-fits-all
(15:14):
radiation. First rule for brain Mets is
definitely history. Absolutely.
It's history. We've seen how these powerful
new systemic agents, especially targeted therapies like AWESOME
or T NIB, can often take the lead, particularly for smaller
asymptomatic lesions. You can potentially spare
patients upfront radiation, right?
But we also learned that radiation, SRS specifically,
(15:35):
still has a crucial role, especially for symptomatic
patients or when the systemic drugs aren't as reliable in the
brain. And that Yale study reminds us,
early local control might still matter for survival in some
cases. Precisely.
And perhaps the most critical take away today is understanding
that delicate balance when combining therapies.
The potential synergy with immunotherapy is exciting, but
(15:55):
the very real danger with concurrent ADC's like TDXD means
timing isn't just important, it's absolutely paramount for
patient safety. You have to separate those
treatments. It's definitely a complex
landscape, challenging, but also, you know, incredibly
important to get right for our patients.
Staying up to date on these sequencing nuances is just
(16:15):
vital. It really is.
And as we look forward, you know, systemic therapies are
only going to get better, more diverse, constantly challenges
us to rethink what optimal sequencing means.
It makes you wonder, doesn't it?What do these complex,
personalized decisions really mean for the future of oncology
care? How might things like, say, AI
(16:36):
help us navigate this intricate dance between systemic treatment
and localized precision even better down the road?
Lots to think about. Indeed, thanks for tuning into
the RAD on Smart Review CNS Cancer series.
Yeah, thanks, everyone. Remember, you can get show notes
and complete practice oral boards over at RAD on
smartlearn.com. And definitely subscribe to RAD
on Smart Reviews so you don't miss our next session.
(16:57):
Thanks for listening.
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