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Unveiling Cutting-Edge Eye On Research 2024 · The Eye Believe Podcast

0:00
Hi everyone.
0:00
Welcome to Eye
0:01
on Research
0:02
2024.
0:03
This is our
0:03
second annual
0:04
Eye on
0:04
Research
0:05
and we are
0:05
so thankful
0:06
to everyone
0:07
for
0:07
joining us.
0:07
So just
0:08
a special
0:08
thanks to
0:09
our sponsors.
0:10
We are,
0:10
sponsored by
0:11
Castle
0:11
Biosciences
0:12
as well
0:12
as IDEAYA
0:13
Biosciences,
0:14
Aura
0:15
Biosciences
0:15
TriSalus
0:16
Life Sciences,
0:17
Immunocore,
0:18
Delcath
0:19
and Replimune.
0:20
So thank you
0:20
to our
0:20
pharmaceutical ,Doctor Correa
0:22
I thank you
0:22
so much
0:22
for joining us
0:23
today.
0:23
We're so glad
0:24
to have you
0:24
and so excited
0:25
to hear
0:25
about some of
0:26
the primary
0:26
research
0:26
updates for,
0:27
primary ocular
0:28
melanoma.
0:29
So thanks
0:29
for joining
0:30
us.
0:31
Well,
0:31
thank you
0:31
so much
0:32
for this
0:32
opportunity.
0:33
it's really
0:34
great
0:34
to interact
0:35
with this
0:35
group.
0:36
You know,
0:36
so many
0:37
patients,
0:38
family members
0:39
and loved ones
0:40
that are
0:40
really
0:40
interested
0:41
and involved
0:42
not only
0:43
in the care
0:44
of patients,
0:44
but also
0:45
in the
0:46
advancements
0:47
of this area.
0:48
So that
0:49
brings me
0:49
great joy
0:50
to be part of.
0:50
So I'm
0:51
going to
0:51
go ahead
0:52
and I've just
0:53
prepared a
0:53
couple slides
0:54
just to kind
0:55
people
0:55
can follow
0:56
what I'm
0:56
talking about
0:57
and not be
0:58
a little bit
0:59
lost in
1:00
all of this
1:00
information.
1:01
I am,
1:02
an
1:02
investigator
1:03
for Castle,
1:04
IDEAYA,
1:04
and Aura
1:05
Biosciences.
1:06
What I'm here
1:06
to do
1:07
today
1:07
is to talk
1:08
about
1:08
general ocular
1:09
melanoma
1:10
updates
1:11
and touch
1:11
a little bit
1:12
about
1:12
potential new
1:13
developments
1:13
in neoadjuvant
1:14
treatments.
1:15
And finally,
1:16
update
1:16
everybody on
1:17
the radiation
1:18
retinopathy
1:19
trial.
1:19
That's called
1:20
the protocol
1:20
AL which
1:21
is sponsored
1:22
by the what
1:23
we call
1:23
the DRCR Net,
1:25
which is a
1:25
diabetic
1:26
retinopathy
1:27
network, and
1:28
and they
1:29
started out
1:30
looking
1:30
at diabetes,
1:31
and now
1:31
they have
1:32
verged into a
1:33
lot of blood
1:33
vessel
1:34
diseases of
1:35
the retina,
1:35
and now
1:36
including
1:37
radiation
1:38
retinopathy.
1:39
So before
1:40
I get started,
1:41
I just want
1:41
to share
1:41
some wonderful
1:42
news,
1:43
is that
1:43
finally,
1:44
our paper,
1:45
sharing the,
1:46
kind of
1:47
the validation
1:48
of the 15
1:49
gene
1:49
expression
1:50
profile
1:50
and PRAME
1:51
as an
1:52
integrated
1:52
prognostic
1:53
test for uveal
1:54
melanoma,
1:55
was just
1:56
published
1:57
the day
1:57
before
1:57
yesterday.
1:58
So,
1:58
you can see
1:59
here we're all
2:00
very excited.
2:01
This is the first
2:02
paper
2:02
by the COOG
2:03
Two group,
2:04
and I'm sure
2:05
when you
2:05
all browse,
2:06
you will
2:07
probably see
2:08
your ocular
2:09
oncologist
2:09
involved
2:10
there.
2:10
It was a big,
2:11
effort on
2:12
all of us
2:13
to get
2:14
this
2:14
information.
2:15
We enrolled
2:16
1500 patients,
2:17
and
2:18
it really provides
2:19
now
2:20
a good
2:20
framework
2:21
and a good,
2:21
valid,
2:22
prospectively
2:23
validated
2:24
framework,
2:24
and in
2:25
order to
2:26
kind of
2:26
come up with
2:28
studies
2:29
going forward,
2:29
enrollment
2:30
for adjuvant
2:31
treatments,
2:32
etc..
2:34
So what
2:35
are the
2:35
current
2:35
clinical
2:36
trials
2:36
for primary
2:37
posterior
2:37
uveal
2:38
melanoma?
2:38
Well,
2:38
first of all,
2:39
the IDE196.
2:42
The IDEAYA
2:42
trial
2:43
for localized
2:44
uveal
2:44
melanoma,
2:45
the Aura
2:47
011 trial
2:48
for the
2:49
intermediate
2:50
melanocytic
2:51
lesions
2:51
or small
2:52
choroidal
2:52
melanomas.
2:53
There's a
2:54
talk about
2:55
a neoadjuvant
2:55
tebentafusp,
2:56
for uveal
2:57
melanoma
2:58
that is not
2:58
yet
2:58
recruiting.
2:59
And then
3:00
there's
3:00
a new player
3:01
which is the
3:02
Sitravatinib
3:04
it's
3:04
the Sitra,
3:05
which can be a
3:06
potential
3:06
future target.
3:08
Right now,
3:08
they're using
3:09
that as
3:10
a target
3:11
for other
3:11
cancers
3:12
like lung
3:12
cancer.
3:13
They didn't
3:13
have such
3:14
a good result,
3:15
but this
3:16
medication,
3:16
probably
3:17
associated
3:18
with another
3:19
medication
3:20
may be
3:20
a good
3:21
potential
3:21
future target.
3:22
I'm sure
3:23
they will
3:23
look at it
3:24
first
3:24
for metastatic
3:25
disease,
3:26
and I know
3:27
that
3:27
we'll have
3:27
Doctor
3:28
Carvajal
3:28
and his team
3:29
talking
3:29
about it
3:30
a little bit
3:30
later,
3:31
but definitely
3:32
something
3:32
to be
3:32
on the lookout.
3:33
And then
3:34
finally,
3:34
I'm going
3:34
to talk
3:35
a little bit
3:35
about that
3:36
protocol, AL,
3:37
which is the
3:37
Intravitreal
3:38
Faricimab
3:39
or the
3:39
Fluocinolone
3:41
Intravitreal
3:42
vs Observation
3:44
to prevent
3:44
vision loss
3:45
after
3:46
radiation
3:46
treatment.
3:47
So I know
3:49
the idea
3:50
team is going
3:50
to be
3:50
talking about
3:51
their product
3:52
and
3:52
what their findings
3:53
are so far,
3:54
but I just
3:54
want to
3:55
kind of bring
3:56
to all of you
3:57
the potential
3:57
impact
3:58
of this
3:59
medication
4:00
in this
4:00
treatment.
4:01
If it proves
4:02
to be
4:02
successful,
4:03
as it's
4:03
promising to,
4:04
number one
4:05
is that
4:06
possibly
4:07
will improve
4:08
lobe salvage
4:09
tremendously
4:10
and as
4:11
a result,
4:12
limit vision
4:13
loss of
4:13
patients
4:14
associated
4:15
with radiation
4:16
treatment,
4:16
and that
4:17
will have
4:17
a huge impact
4:18
in quality
4:19
of life
4:19
and especially
4:20
for survivors
4:21
going forward.
4:22
It could
4:23
change
4:23
the systemic
4:24
outcomes of
4:25
these patients
4:25
because
4:26
targeting
4:26
GNA11,
4:27
which
4:28
we know it is
4:29
an upstream
4:30
mutation,
4:31
it could
4:32
really improve
4:33
the rates
4:34
or decrease
4:35
the rate of
4:36
metastatic disease.
4:37
So it would
4:38
work
4:38
both ways.
4:39
It would be a
4:40
primary
4:40
treatment,
4:41
and
4:41
it would be
4:41
also a
4:42
new adjuvant
4:43
treatment
4:43
in some ways.
4:44
And its
4:45
downstream
4:46
effect
4:46
could
4:46
potentially
4:47
improve
4:48
patients
4:48
survival, as
4:49
I mentioned.
4:50
The other one
4:51
that we're
4:52
excited about
4:53
is the
4:53
neoadjuvant
4:54
Tebentafusp
4:55
we know that
4:56
the
4:56
Tebentafusp
4:57
or Kimmtrak,
4:58
has been
4:58
used currently
5:00
for metastatic
5:01
disease,
5:02
but
5:02
the company
5:03
is now
5:03
trying to
5:04
think about it
5:05
as a primary
5:07
neoadjuvant
5:07
treatment.
5:08
And you know,
5:09
and this
5:10
is something
5:11
that will
5:11
probably be
5:12
launched here
5:13
in the near
5:13
future.
5:14
These are the
5:14
enrollment
5:15
criterias,
5:15
as you see,
5:16
they're going
5:16
to start
5:17
with very
5:17
large tumors
5:18
that
5:19
potentially
5:19
could not
5:20
be treated
5:21
other than
5:22
by enucleation
5:23
and they will
5:24
obviously make
5:25
sure the
5:25
patients are
5:26
all HLA
5:27
A0201 positive
5:29
that we know
5:29
only 50%, give
5:31
or take, of
5:31
the population
5:32
are positive.
5:33
and they want
5:34
to enroll
5:35
as they are
5:36
validating
5:36
this potential
5:37
trial.
5:38
All the patients
5:38
that are
5:39
in good
5:39
health
5:40
condition,
5:40
so that's
5:41
one thing
5:41
I tell
5:42
all of
5:42
my patients.
5:42
I always say
5:43
stay healthy.
5:44
That's what
5:44
you can do
5:45
to improve
5:46
your odds
5:46
and whatever
5:47
we do
5:47
going forward.
5:48
And also
5:50
they want
5:50
to make sure
5:51
this person
5:51
will be able
5:52
to adhere
5:53
to the
5:53
treatment,
5:54
etc.
5:55
and as you
5:55
all recall,
5:56
this is
5:56
the data
5:57
for the
5:57
Tebentafusp
5:58
metastatic
5:59
uveal
5:59
melanoma
6:00
setting.
6:00
And we just
6:01
think that
6:02
this
6:02
could have
6:02
another
6:03
huge impact
6:04
and possibly
6:05
improving
6:05
globe salvage,
6:06
possibly
6:07
limiting
6:08
the vision
6:08
loss
6:08
associated
6:09
with the
6:10
radiation
6:10
treatment
6:11
and
6:11
the downstream
6:12
effect
6:12
could
6:13
potentially
6:14
improve
6:14
patient
6:14
survival
6:15
and then
6:16
the question
6:16
is,
6:17
will there
6:18
be selection
6:18
bias by only
6:20
using
6:20
tumor size
6:21
instead of
6:21
genomic
6:22
profile.
6:23
And this
6:23
has been
6:23
something
6:24
that,
6:24
you know,
6:25
this company
6:26
has been
6:26
very honed in
6:27
to other
6:29
things
6:29
that are not
6:29
the genomic
6:30
profile.
6:30
Now that
6:31
we've had
6:32
the GEP
6:32
plus Prame
6:33
validated,
6:35
it would
6:35
be kind
6:35
of interesting
6:36
to see
6:37
how
6:37
it plays out
6:38
as far as
6:40
the validation
6:41
and its usage
6:42
going forward.
6:43
Then, the Aura
6:44
Bioscience
6:45
trial,
6:46
this is
6:46
something that
6:47
I know
6:47
Doctor Hopkins
6:48
will be
6:48
talking
6:49
about here
6:49
pretty soon.
6:50
I think
6:51
the exciting
6:51
thing is that
6:52
this is
6:52
a phase
6:53
three
6:53
randomized
6:54
trial.
6:55
And, you know,
6:55
we will be
6:56
seeing how
6:57
these
6:58
patients then
6:58
behave
6:59
compared to
7:00
no treatment.
7:01
I believe that
7:02
the new
7:03
suprachoridal
7:04
injection
7:04
will
7:05
definitely
7:05
optimize
7:06
the drug
7:06
delivery,
7:07
and I'm
7:07
excited to see
7:08
these results.
7:09
And,
7:09
this is
7:10
the phase
7:10
three study
7:11
schema.
7:11
The only thing
7:13
is that
7:13
it's a very
7:14
intense
7:14
treatment.
7:15
It really
7:15
needs a buy
7:16
in from
7:16
the patient.
7:17
And
7:18
understanding
7:19
that,
7:19
that you
7:19
may not
7:20
be randomized
7:21
to
7:21
get the treatment.
7:22
So you may
7:23
be randomized
7:24
to get
7:24
observation,
7:26
but
7:26
obviously you
7:27
will be taken
7:28
out of
7:28
the group
7:29
of
7:29
observation.
7:30
If the tumor
7:32
keeps on
7:32
growing
7:33
and then
7:33
you will get
7:34
the radiation
7:35
or whatever
7:35
else treatment
7:36
your physician
7:37
deems
7:37
appropriate.
7:38
Just letting
7:39
you know that,
7:39
you know, the,
7:40
the inclusion
7:41
criteria
7:42
is more
7:42
based on
7:43
growth
7:44
and this is
7:44
something that
7:45
in the past,
7:46
I have to
7:46
confess ,that
7:47
I was personally
7:48
a little
7:48
bit against
7:49
just having
7:49
that as
7:50
a, criteria,
7:51
but
7:52
the company
7:52
is giving
7:53
us now
7:53
some freedom
7:54
to do biopsy
7:55
the patients
7:56
before
7:57
enrolling
7:57
them,
7:58
and
7:58
I think that
7:59
that will
7:59
really make
8:00
the data
8:01
way more
8:01
robust.
8:02
Having that
8:03
information
8:04
again,
8:05
this just
8:06
kind of shows
8:06
that not
8:07
all tumors
8:07
are created
8:08
equal
8:08
and not all
8:09
patients
8:09
are equal.
8:10
So,
8:10
we have to account
8:11
for that
8:12
and
8:12
I think that
8:13
that will
8:13
be really
8:14
a game changer
8:15
for
8:15
those folks
8:16
that have very
8:17
small tumors
8:18
in a location
8:19
that radiation
8:20
can be
8:20
potentially
8:21
damaging.
8:21
So, stay tuned
8:23
because this
8:23
is going
8:24
to be
8:24
very exciting.
8:25
So, potential
8:26
impact of
8:27
this trial
8:27
is going to be
8:28
the early
8:28
treatment of
8:30
small
8:30
posterior
8:31
tumors
8:31
showing
8:31
progression
8:32
over a short
8:33
period of
8:33
time, expected
8:35
low risk
8:35
for vision
8:36
loss,
8:36
and possibly
8:38
mitigating
8:39
or eliminating
8:40
the radiation.
8:41
But the
8:42
possibility
8:42
of radiation
8:43
if the
8:44
treatment
8:44
fails, or
8:45
if
8:45
the observation,
8:46
deems that,
8:48
you know,
8:48
the tumor
8:49
continues
8:49
to grow.
8:50
The question
8:51
is, again,
8:52
are we testing
8:53
the efficacy
8:53
of the
8:53
treatment
8:54
for small
8:54
melanomas or
8:55
large nevi
8:56
and
8:57
I think
8:57
that now
8:57
that
8:58
the company
8:58
is allowing us
8:59
to biopsy
9:00
the patients
9:01
before
9:01
enrolling
9:02
them,
9:02
I think that
9:03
will be really
9:04
a game changer
9:05
and it's going
9:05
to make
9:06
that data
9:06
a lot
9:07
more robust.
9:08
Finally,
9:09
the protocol
9:09
AL,
9:10
the protocol
9:11
AL by the DRCR
9:12
Net is
9:13
going to
9:13
be very
9:14
impactful.
9:15
They're going
9:15
to test
9:16
what we call
9:16
the
9:16
intravitreal
9:17
faricimab
9:18
which is
9:19
already
9:19
commercially
9:20
available
9:20
as Vabysmo.
9:21
This medication
9:23
has been
9:23
approved
9:24
for age
9:25
related
9:25
macular
9:26
degeneration,
9:27
as well
9:27
as the
9:28
Fluocinolone
9:29
acetonide
9:29
implant, which
9:31
is called
9:31
lluvien also
9:34
by another
9:34
company, but
9:35
also
9:36
already
9:36
available
9:37
commercially.
9:37
So
9:38
we know both
9:39
drugs
9:39
are safe.
9:41
and then
9:42
the third
9:42
group would be
9:43
the
9:43
observation
9:44
for the
9:44
prevention of
9:45
visual
9:45
acuity loss
9:46
and so
9:47
they want
9:47
to see
9:48
how does
9:48
that impact
9:49
the blood
9:50
vessels
9:50
around the
9:51
radiated area.
9:52
How does that
9:52
impact
9:53
the occurrence
9:55
of blood
9:56
vessel events,
9:57
you know,
9:57
like
9:57
clogging up
9:58
the veins
9:58
and the
9:59
arteries
9:59
as a result
10:00
of the
10:00
radiation?
10:03
It's going
10:03
to be a very,
10:05
interesting
10:06
trial
10:06
because
10:07
right now
10:07
we don't have
10:08
any FDA
10:09
approved
10:10
medication
10:10
for radiation
10:11
retinopathy,
10:12
and many of us
10:13
do use
10:14
Avastin.
10:15
Sometimes,
10:16
Eylea,
10:17
but we have
10:17
to jump
10:18
through a lot
10:18
of hoops
10:19
to be able
10:19
to approve it
10:20
for
10:20
the patient,
10:21
especially if
10:22
it's a
10:22
younger
10:22
patient
10:23
that doesn't
10:24
have any
10:24
other diseases
10:25
or
10:25
comorbidities.
10:27
So having
10:27
that data
10:28
will
10:28
really push
10:29
the FDA
10:30
to approve
10:31
certain
10:31
medications
10:32
directly
10:33
for radiation
10:34
retinopathy,
10:34
and we're very
10:35
excited
10:36
about that.
10:37
Here's just
10:38
the things
10:38
that we'll
10:39
be doing,
10:39
the standard,
10:41
visual acuity,
10:42
lab exam,
10:43
etc., etc,
10:44
and we will be
10:45
monitoring
10:46
patients
10:46
every three
10:47
months.
10:47
We, the group
10:49
that gets
10:49
injections
10:50
will get
10:50
injections
10:51
every three
10:51
months,
10:52
and the group
10:52
with the
10:53
implant
10:53
will get
10:54
one implant
10:55
every
10:55
24 months.
10:56
And, the
10:57
observation
10:57
group
10:58
obviously
10:59
is not going
10:59
to get
11:00
any treatment.
11:01
The downside
11:02
of this study,
11:03
I have to
11:03
alert
11:03
everybody,
11:04
is that
11:04
they are not
11:05
going to be
11:06
enrolling
11:06
any patients
11:07
with tumors
11:08
around
11:08
the macula,
11:09
so around the
11:10
focusing point
11:11
and around
11:12
the nerve,
11:13
still, it's
11:14
going to
11:14
be useful
11:15
information.
11:16
It's not
11:16
going to be
11:17
as impactful
11:18
as we would
11:19
like,
11:19
but
11:20
I think
11:20
the the
11:21
idea behind
11:22
the protocol
11:23
would be
11:23
some very
11:25
striking
11:25
measurable
11:26
outcomes,
11:27
and that is
11:28
the only way
11:29
to avoid
11:30
the bias
11:31
of the
11:32
tumor
11:33
location.
11:33
So that's
11:34
that's the
11:35
whole
11:35
catch here.
11:36
So
11:38
the impact
11:38
of this
11:39
protocol
11:39
will be
11:39
providing
11:40
insight
11:41
into the
11:41
benefit
11:42
of
11:42
preventative
11:42
medication
11:43
to avoid
11:44
or minimize
11:44
radiation
11:45
retinopathy.
11:46
And because
11:47
of that,
11:47
improving
11:48
patient
11:49
visual
11:49
outcomes.
11:50
And hopefully
11:51
quality
11:52
of life,
11:53
especially for
11:54
those
11:54
surviving
11:55
the cancer,
11:55
determine
11:56
the success
11:57
of the
11:57
treatment
11:58
for radiation
11:58
retinopathy
11:59
and determine
12:00
the frequency
12:00
of treatment
12:01
that
12:01
right now,
12:02
you know,
12:03
we treat
12:03
kind of
12:04
by year,
12:05
not really
12:06
by year,
12:06
but by
12:07
experience
12:08
and by feeling
12:09
for how
12:10
the patient
12:11
is
12:11
coming along.
12:12
But
12:12
we definitely
12:13
need
12:13
a protocol,
12:14
something
12:14
that can be followed
12:15
in, something
12:16
that like,
12:16
as I said,
12:17
can be used
12:18
to, get
12:19
insurance
12:20
approval.
12:21
So
12:21
I believe that
12:22
that's
12:22
basically
12:23
my message.
12:24
Over
12:24
a century,
12:25
we had
12:25
no one change
12:26
the outcomes
12:27
of patients
12:27
with uveal
12:28
melanoma,
12:29
and we had
12:29
limited sight
12:30
saving
12:31
therapies
12:31
and now we're
12:32
seeing a
12:32
new era.
12:33
And it's just
12:34
so exciting
12:35
and I think
12:35
these webinars
12:36
are very,
12:37
very helpful.
12:38
So everybody
12:39
can stay
12:39
tuned
12:39
and understand
12:40
what's
12:40
coming down
12:41
the pipeline,
12:42
especially
12:42
for the
12:43
clinical
12:43
studies.
12:44
These clinical
12:45
trials
12:46
will
12:46
likely change
12:47
how we think
12:47
when we manage
12:48
patients,
12:48
and also
12:50
will change
12:50
how patients
12:51
do after
12:52
treatment in
12:53
the long term
12:54
and this is
12:54
the first step
12:55
to improve
12:56
survival
12:56
of patients
12:57
and improve
12:57
quality
12:58
of life
12:59
and their
12:59
visual
13:00
outcomes.
13:00
Thank you
13:01
so much.
13:02
We are
13:02
so thrilled
13:03
to have
13:03
you here
13:03
today, Dr Cole
13:04
thanks for
13:05
being here.
13:06
Well,
13:06
thank you
13:06
very much,
13:07
and I
13:07
appreciate the
13:07
opportunity
13:08
to present
13:08
what we're
13:09
doing at
13:10
IDEAYA
13:10
Biosciences
13:11
for uveal
13:12
melanoma.
13:13
So
13:13
this is our Safe
13:14
Harbor
13:14
Statement.
13:14
Just to let
13:15
you know that
13:15
everything
13:15
that I'm about
13:16
to discuss
13:17
is
13:17
investigational,
13:18
and
13:19
our molecule
13:20
is not yet FDA
13:21
approved for
13:22
marketing.
13:24
So I briefly
13:25
just wanted
13:25
to,
13:26
show everyone
13:26
our pipeline,
13:27
and the focus
13:28
of my talk
13:28
today will be
13:29
this top part
13:30
here,
13:30
Darovasertib.
13:31
This is what
13:32
we are
13:32
developing for
13:33
uveal
13:33
melanoma,
13:34
but we do have
13:35
a robust
13:35
pipeline
13:36
of other
13:36
molecules
13:37
that we are
13:38
developing,
13:39
for other
13:39
malignancies.
13:42
Very quickly.
13:43
Darovasertib,
13:44
how does
13:45
Darovasertib
13:46
work?
13:46
As we know
13:47
most uveal
13:48
melanoma
13:48
is driven
13:49
by mutations
13:50
in these two
13:50
genes over
13:51
here,
13:51
GNAQ and/or
13:53
GNA11,
13:54
and these
13:54
genes
13:55
with their
13:56
mutations
13:56
propagate
13:57
the signal
13:58
through PKC,
14:00
through RAF
14:01
and through
14:01
MEK,
14:02
which produces
14:03
our tumor,
14:03
which produces
14:04
our
14:04
malignancy.
14:05
Darovasertib
14:06
stops that
14:07
signaling
14:07
or inhibits
14:08
PKC right
14:09
here,
14:10
preventing
14:10
that signaling
14:11
from moving
14:12
forward
14:12
and also
14:13
preventing,
14:14
growth of
14:14
the tumor.
14:17
So our
14:17
first study in
14:18
terms of long
14:19
primary
14:20
uveal
14:21
melanoma,
14:22
we're looking
14:23
at
14:23
Darovasertib
14:23
in the
14:24
neoadjuvant
14:24
setting,
14:25
Darovasertib
14:26
in the
14:26
adjuvant
14:26
setting,
14:27
and a new
14:28
protocol
14:29
amendment for
14:30
this trial
14:31
is looking
14:31
at the
14:32
combination
14:32
of
14:32
Darovasertib
14:33
plus
14:34
Crizotinib
14:34
in the
14:35
adjuvant
14:35
setting.
14:38
So here's
14:38
a schema
14:39
of our trial,
14:40
and I would
14:40
say that
14:40
the overall
14:41
goal of our
14:42
trial,
14:42
we have a few of them
14:44
But we're
14:44
divided up
14:45
into sort of
14:45
two cohorts
14:46
if you would.
14:47
There is the
14:47
enucleation
14:48
cohort.
14:49
The goal
14:49
of that
14:49
cohort,
14:50
to see
14:50
if
14:51
Darovasertib
14:51
can save
14:52
the eye,
14:53
the
14:53
brachytherapy
14:54
cohort,
14:56
the idea
14:56
being
14:57
Darovasertib
14:58
can reduce
14:59
the amount
14:59
of
14:59
brachytherapy
15:00
that's given
15:00
to the eye.
15:01
And then,
15:02
adjuvant
15:02
setting sort
15:03
of afterwards,
15:03
as we say,
15:04
to save lives.
15:06
So our
15:06
primary
15:07
endpoints
15:07
in this phase
15:08
one two trial
15:09
and phase
15:09
two trial,
15:10
eye
15:10
preservation,
15:11
decrease
15:12
in radiation
15:13
dose,
15:13
and the
15:14
secondary
15:14
endpoints,
15:15
useful vision
15:16
meaning
15:16
improving the
15:18
visual acuity
15:19
or not,
15:20
loss of
15:21
visual acuity.
15:22
And I was
15:22
also seen in
15:23
relapse free
15:24
survival.
15:27
So in our
15:27
Darovasertib
15:29
company
15:29
sponsored
15:29
trial,
15:31
very,
15:31
very
15:31
preliminary
15:32
results here,
15:32
I'm able
15:33
to present
15:33
to you,
15:34
as everyone
15:35
knows, there
15:36
a couple of
15:36
different ways
15:36
in which
15:37
we can
15:37
measure,
15:38
decrease
15:38
in size
15:39
and tumor,
15:40
whether it be
15:40
a local high
15:41
basal diameter
15:42
and, or
15:42
the volume,
15:43
I'm happy
15:44
to say.
15:44
And,
15:45
our initial
15:46
look at our
15:46
data,
15:47
when we look
15:47
at eight
15:47
patients
15:48
who received
15:49
greater
15:50
than,
15:50
or equal
15:51
to four months
15:52
of treatment,
15:53
what
15:53
stimulated
15:54
Darovasertib
15:54
as we see
15:55
over here,
15:56
the majority
15:56
of these
15:57
patients,
15:57
we have
15:57
a median
15:58
reduction,
15:58
when we
15:59
look at this
15:59
by volume
16:00
about 72%.
16:02
And we look at
16:02
the light
16:03
blue,
16:03
these are
16:04
enucleation
16:04
patients.
16:05
We look at
16:05
the darker
16:06
blue here,
16:07
this is our
16:07
plaque
16:08
eligible
16:08
patient.
16:09
These patients
16:10
have had
16:10
a major
16:11
reduction
16:12
in the size
16:12
of their tumors
16:13
and we take
16:14
a pause here
16:14
for a second.
16:15
The idea
16:15
behind
16:16
that is
16:17
a patient
16:17
who
16:17
potentially
16:18
was scheduled
16:19
for
16:19
enucleation
16:20
now doesn't
16:20
need
16:21
enucleation,
16:22
patient who
16:23
is scheduled
16:23
for plaque
16:24
brachytherapy,
16:25
Now be getting
16:26
a smaller
16:27
amount of that
16:27
plaque
16:28
brachytherapy
16:29
and we'll have
16:29
some examples
16:30
of that
16:30
moving
16:30
forward.
16:32
So if we take
16:33
a look
16:33
at a couple
16:33
of case
16:34
studies now
16:35
a 50 year
16:35
old patient
16:37
uveal
16:37
melanoma,
16:38
receiving
16:38
four months
16:39
of
16:40
Darovasertib
16:40
treatment
16:41
in a dome
16:41
shaped tumor.
16:43
If we look
16:43
over here
16:44
at the
16:44
baseline,
16:44
their baseline
16:45
measurements
16:46
about five
16:46
millimeters
16:47
in April,
16:47
height
16:48
almost 15mm
16:49
in the
16:50
basal
16:50
diameter.
16:51
And their
16:51
volume is
16:52
shown below.
16:53
When we look,
16:54
when we
16:54
took our
16:55
measurements,
16:56
pretty
16:56
dramatic
16:57
decrease
16:57
in the size
16:58
of their tumor
16:58
with their
16:59
apical height,
17:00
basal
17:00
diameter,
17:01
and/or
17:01
the volume,
17:02
you know,
17:03
north of
17:03
40% decrease
17:04
or upwards
17:06
of the greater
17:06
than 80%
17:07
decrease
17:08
total.
17:09
When we
17:09
look at
17:09
another
17:10
patient
17:10
who is
17:10
scheduled
17:11
for
17:11
enucleation,
17:12
the first patient
17:12
was scheduled
17:13
for plaque
17:14
brachytherapy,
17:15
further on
17:15
we'll see
17:15
some more
17:16
slides about
17:16
why we're
17:17
excited
17:17
about this,
17:18
but here's
17:18
a patient
17:19
who was
17:19
scheduled
17:19
for
17:20
enucleation.
17:21
We see
17:21
their initial
17:22
baseline
17:22
measurements
17:23
over here 8
17:24
millimeters,
17:24
30mm, and,
17:26
almost 140
17:27
cubic
17:27
millimeters
17:28
of volume.
17:29
After four
17:29
months of
17:29
treatment,
17:30
we see
17:30
pretty
17:31
dramatic
17:31
decrease
17:32
in this,
17:33
tumor size,
17:35
whether it be,
17:35
almost
17:36
three
17:36
millimeters
17:37
in apical
17:37
height,
17:38
eight
17:38
millimeters,
17:39
and there's
17:39
a diameter,
17:41
90 cubic
17:42
millimeters
17:42
showing
17:43
percent change
17:44
from baseline,
17:45
almost 70%
17:46
for the
17:46
height,
17:46
40% for
17:47
the basal
17:47
diameter,
17:48
and almost 90%
17:49
for the
17:50
volume.
17:53
when we look
17:53
at some data
17:54
that has
17:55
recently been
17:55
presented
17:56
at ASCO
17:58
and this is
17:58
data from,
18:00
Anthony
18:00
Joshua,
18:01
this is
18:01
an
18:01
investigator
18:02
initiated
18:02
trial
18:03
or an IST,
18:05
we see that
18:06
same treatment
18:07
Darovasertib
18:07
in the
18:07
neoadjuvant
18:08
setting.
18:08
This is a
18:09
spider plot
18:09
over here,
18:10
and again Dr.
18:11
Josh was
18:11
looking at
18:12
volume two.
18:12
Over time,
18:13
we see
18:14
with these
18:14
15 patients,
18:16
all the patients
18:16
except for
18:17
maybe one
18:17
initially
18:18
from when
18:18
you took
18:19
the sample
18:19
size.
18:20
Excuse me,
18:20
when he took
18:21
the data,
18:21
all these
18:22
patients
18:22
are showing
18:23
a, decrease
18:24
in the volume
18:25
of their
18:25
tumor sizes.
18:26
When we look
18:27
at tumor
18:28
volume,
18:29
in terms of
18:30
eyes
18:30
preserved, of
18:31
12 patients,
18:32
75% of
18:33
those patients
18:34
had their eyes
18:35
preserved.
18:35
Again,
18:36
light blue
18:36
being eyes
18:37
saved,
18:37
dark blue
18:38
the one
18:39
patient
18:39
that was
18:40
enucleated,
18:41
we see
18:41
the median
18:41
reduction
18:42
again in terms
18:42
of tumor
18:43
volumes,
18:43
about 47%.
18:47
How does this
18:47
translate for
18:48
our plaque
18:48
brachytherapy
18:49
patients?
18:49
Again,
18:50
more of Dr.
18:51
Joshua's data
18:52
that was
18:52
just recently
18:53
presented
18:53
at ASCO.
18:54
Take a look
18:55
over here,
18:55
we have a patient.
18:56
This over here
18:57
represents her
18:57
tumor,
18:59
critical
18:59
structures
18:59
here, optic
19:00
nerve
19:01
and phobia.
19:02
We see this
19:02
as our
19:03
baseline
19:03
measurement
19:04
and we see
19:04
how close
19:05
the tumor is
19:06
to these
19:06
critical
19:06
structures.
19:08
Again
19:08
after
19:09
treatment with
19:10
Darovasertib,
19:10
we see a very
19:12
large increase
19:13
in the
19:13
distance
19:14
of the tumor,
19:15
to those
19:16
critical
19:16
structures,
19:16
whether it be
19:17
the fovea
19:17
and/or
19:18
the optic
19:18
nerve.
19:19
So, we can see
19:20
how much here
19:20
the tumor is
19:21
actually
19:21
shrunk,
19:22
greater
19:23
distance.
19:24
Why is this
19:24
important?
19:25
When we look
19:26
at the
19:26
potential,
19:26
radiation
19:27
field for
19:29
plaque
19:29
brachytherapy
19:30
treatment
19:31
baseline,
19:32
we see
19:32
how close
19:33
that radiation
19:34
field
19:34
is coming
19:34
to those
19:35
critical
19:35
structures.
19:36
Whereas after
19:37
treatment
19:38
we see that
19:38
radiation
19:39
field
19:39
is much
19:39
smaller.
19:40
Over here
19:41
we have
19:41
some more
19:42
specific
19:42
numbers
19:42
of that.
19:43
So if
19:44
we thought
19:44
about this
19:45
patient
19:45
initially,
19:46
the dose of
19:47
the optic
19:47
nerve
19:47
and or
19:48
the dose of
19:48
the fovea,
19:49
when we look
19:49
at the amount
19:50
of radiation
19:50
therapy
19:51
that was about
19:51
to occur,
19:53
78 Gys,
19:54
157 Gys
19:55
post baseline,
19:56
this is now
19:56
decreased
19:57
13 Gys.
19:58
That's an
19:58
83% change
20:00
to the fovea,
20:01
59 Gys,
20:02
which now is
20:02
62% change.
20:04
Now
20:04
when we look
20:05
at the
20:05
probability
20:05
of visual loss
20:06
from one year
20:07
and/or
20:07
three year,
20:08
through the
20:08
disease,
20:09
criteria,
20:11
we see that
20:11
at baseline
20:12
there is
20:12
almost a
20:13
70% chance
20:14
for visual
20:14
loss
20:15
and/or 95%
20:17
chance
20:17
of visual loss
20:18
at three years
20:19
from
20:19
the initial
20:20
settings here,
20:21
our post
20:22
baseline,
20:23
after
20:23
treatment
20:23
with
20:24
Darovasertib,
20:25
that
20:25
possibility of
20:26
visual loss
20:27
at one year
20:27
is now down
20:28
to 20%.
20:29
Three year
20:30
potential loss
20:31
is down to 43%
20:32
and this is
20:33
where I
20:33
will end
20:34
this part
20:35
of my
20:36
presentation,
20:37
because
20:37
the next part
20:38
is for
20:38
what we are
20:39
doing in,
20:41
metastatic
20:41
melanoma.
20:42
melanoma.
20:42
we have
20:42
an update
20:43
from Doctor
20:44
Hopkins
20:44
from Aura
20:45
Biosciences
20:46
regarding
20:46
their CoMpass
20:47
Trial.
20:47
Doctor
20:48
Hopkins,
20:48
thanks so much
20:49
for joining
20:49
us.
20:50
Tremendous.
20:51
Thank you
20:51
so much,
20:51
Danet.
20:52
It's,
20:52
such a
20:52
pleasure
20:53
to be here
20:53
and to
20:54
see the
20:54
incredible
20:55
activity
20:55
in research
20:56
and care
20:56
for patients,
20:58
with uveal
20:58
melanoma.
20:59
So thank you
20:59
for the
20:59
opportunity
21:00
to be here.
21:01
I'm Jill
21:01
Hopkins, I'm
21:02
the chief
21:02
medical
21:03
officer
21:03
at Aura
21:03
Biosciences
21:05
and I'll walk
21:05
you
21:05
through our
21:06
current
21:07
program
21:07
and our hopes
21:09
for changing
21:11
some of
21:11
the paradigm
21:11
of care
21:12
for people
21:12
living
21:12
with uveal
21:13
melanoma.
21:14
So,
21:15
disclosures,
21:16
much like
21:16
Doctor Cole
21:17
and IDEAYA,
21:17
we are
21:17
an
21:17
investigational,
21:18
virus like
21:19
drug
21:19
conjugate.
21:20
We are in
21:20
clinical
21:21
trials
21:21
and are
21:22
not yet
21:22
approved for,
21:24
use.
21:26
So, Bel-sar or
21:27
AU-011, but
21:29
we call it
21:29
Bel-sar, is
21:30
a novel
21:30
viral
21:31
drug conjugate
21:32
and this is
21:32
a very
21:33
novel
21:34
technology
21:35
that uses
21:35
a virus
21:36
like particle.
21:37
So this is,
21:37
similar
21:38
to, vaccines
21:39
using a
21:40
papilloma
21:40
virus,
21:41
but this is a
21:42
non
21:42
replicating
21:43
or empty
21:43
viral capsid,
21:44
doesn't
21:45
contain
21:45
genetic
21:46
material
21:47
and we're able
21:47
to demonstrate
21:48
that it has
21:49
a potential
21:49
to have
21:50
multivalent
21:51
binding
21:52
to these
21:52
heparin
21:53
sulfate
21:53
proteoglycans
21:55
on solid
21:55
tumor cells
21:56
and
21:56
this is important
21:57
because
21:57
these HSPGs
21:59
as we call
21:59
them,
22:00
are present
22:01
across a
22:01
range
22:02
of tumors.
22:02
So somewhat
22:03
agnostic
22:03
to genetic
22:04
subtype,
22:05
solid tumors
22:06
present
22:06
these HSPGs
22:08
on the on
22:09
the tumor
22:09
surface,
22:10
and we're able
22:11
to see
22:11
these VLPs
22:12
bind to them.
22:14
We then
22:14
add to that
22:15
a light
22:15
activated
22:16
molecule.
22:17
We conjugate
22:18
that on
22:18
the surface
22:19
of the VLP
22:20
and when we
22:21
activate that
22:22
with a laser,
22:22
we're able to
22:23
see selective
22:24
binding of
22:25
our drug
22:26
to the tumor
22:26
cell.
22:27
And additional
22:28
selectivity
22:29
brought about
22:29
by the
22:30
activation
22:30
only being
22:31
at the site
22:32
of where
22:32
the laser
22:32
is
22:33
administered.
22:34
So we're
22:34
able to see
22:35
very on target
22:36
tumor effects
22:37
with a
22:38
much better
22:39
looking side
22:40
effect profile
22:41
when we look
22:42
at trying
22:42
to treat
22:42
early tumors.
22:44
So we know
22:45
that,
22:45
this allows
22:47
for a dual
22:48
mechanism
22:48
of action
22:49
within the
22:49
Bel-sar
22:50
activity.
22:51
So we have
22:52
one mechanism
22:53
where as
22:53
we, bind
22:54
that VDC
22:55
to the HSPGs
22:57
on the
22:57
tumor cells,
22:59
we see tumor
23:00
cell necrosis
23:00
after late
23:01
activation
23:03
so the tumor
23:03
releases
23:04
these oxygen
23:04
spaces, it
23:05
disrupts
23:06
the cell
23:06
membrane,
23:07
and we see
23:08
tumor cell
23:09
killing via
23:10
mechanism one.
23:12
We secondarily
23:13
see as
23:14
mechanism two,
23:15
that these
23:15
damaged
23:16
tumor cells
23:16
release
23:17
neoantigens.
23:18
In these
23:18
DAMPs,
23:19
we call
23:19
them, damage
23:20
associated
23:20
molecular
23:21
patterns,
23:22
and these
23:23
bring immune
23:24
cell reaction
23:25
into the
23:26
tumor,
23:26
locale.
23:28
So here
23:29
we're able
23:29
to see
23:30
necrosis
23:31
or cell
23:32
killing
23:32
at the
23:32
time of,
23:33
of
23:33
the activation
23:34
and then the
23:35
secondary
23:35
mechanism
23:36
whereby
23:36
immune cells
23:37
come in.
23:38
And here
23:38
we're very
23:39
excited
23:39
by the
23:40
possibility
23:40
that long term
23:42
adaptive
23:43
immunity
23:44
can help
23:44
with ongoing
23:45
tumor control.
23:50
So what
23:50
are the goals
23:51
of treatment?
23:51
Well,
23:52
as Doctor
23:53
Correa
23:53
mentioned,
23:53
we are in
23:54
phase three,
23:54
which means
23:55
we're in
23:55
a stage
23:56
of development
23:56
that we are
23:57
hopeful
23:57
will lead
23:58
to
23:58
registration
23:59
and ultimate
24:00
access of this
24:00
therapy
24:01
for patients.
24:02
And
24:02
the hope is,
24:03
with
24:04
Bel-sar, is
24:05
that
24:05
we'll be able
24:05
to provide
24:06
local tumor
24:06
control,
24:07
we’ll preserve
24:08
vision, we’ll
24:10
move away
24:10
from the
24:11
radiation
24:11
related
24:12
morbidities
24:13
that are
24:13
well known
24:13
to
24:13
the community,
24:15
and that we’ll
24:15
see,
24:15
potentially,
24:16
an opportunity
24:16
to treat early
24:17
and reduce
24:18
the risk
24:18
of metastases
24:20
with a side
24:20
effect profile
24:21
that will
24:21
hopefully
24:22
improve
24:22
quality
24:22
of life
24:23
for patients.
24:24
So we're
24:24
very excited
24:25
by the
24:26
potential
24:27
here.
24:27
We are
24:27
looking at the
24:28
delivery
24:29
of Bel-sar
24:30
by injection
24:31
into the eyes.
24:32
So this is
24:32
done in
24:33
the office,
24:34
do not need
24:34
to go
24:34
to the
24:35
operating room
24:35
for this.
24:36
We use
24:37
a super
24:37
choroidal
24:38
injector
24:38
on the
24:38
white surface
24:39
of the eye.
24:40
We deliver
24:41
the Bel-sar
24:41
in that
24:42
location,
24:42
and we do
24:43
two
24:43
injections,
24:44
on either
24:45
side of
24:45
the tumor.
24:46
The blue drug,
24:47
as you
24:47
see there
24:47
on the slide,
24:48
kind of
24:48
distributes
24:49
back
24:49
around
24:50
the back
24:50
of the eye,
24:50
surrounds
24:51
the tumor
24:51
and
24:51
distributes
24:52
within it.
24:53
And we
24:53
then do two,
24:54
laser
24:55
treatments.
24:56
They take
24:56
about
24:56
five minutes
24:57
once the drug
24:58
has had time
24:59
to distribute
24:59
in the tumor.
25:00
Again,
25:01
all done
25:01
in office
25:02
as Dr Correa
25:03
mentioned,
25:03
it's a lot of
25:04
upfront
25:04
activity.
25:05
You do have,
25:06
three cycles
25:06
of treatment,
25:07
at the start
25:08
of the trial
25:08
and you’re
25:09
then followed
25:09
for an
25:10
additional
25:10
15 months,
25:12
but in-office
25:12
and as we say,
25:13
the potential
25:14
for,
25:14
side effect
25:15
profile
25:15
that allows
25:16
for
25:16
preservation
25:17
of vision.
25:20
This slide
25:20
talks
25:21
about how
25:21
we're
25:21
currently
25:22
managing
25:22
uveal melanoma
25:23
and I think,
25:23
whenever I
25:24
look at this,
25:24
and what
25:25
this webinar
25:25
absolutely
25:26
highlights
25:26
is the
25:27
activity
25:28
in research
25:29
and
25:29
advancement
25:30
across the
25:30
entire
25:31
spectrum
25:31
of care
25:32
for uveal
25:32
melanoma,
25:33
which I think
25:33
is the
25:33
most exciting
25:34
thing about
25:34
this slide.
25:36
I think
25:36
where we are,
25:37
seeing
25:37
the potential
25:38
for Bel-sar
25:39
is in
25:39
this local
25:40
or early
25:41
stage
25:41
of disease
25:42
when we have
25:42
either
25:42
these
25:43
indeterminate
25:44
lesions
25:44
or the
25:44
small
25:45
melanomas
25:46
where many
25:47
people are in
25:47
that watch
25:48
and wait.
25:48
So, so many
25:49
people
25:49
listening
25:50
or with
25:50
family members
25:51
impacted
25:51
by this,
25:52
you may have
25:53
been told
25:53
at some time
25:54
that you have
25:54
this pigmented
25:55
lesion
25:55
in your eye.
25:56
We're going
25:56
to watch
25:57
and wait
25:57
and see
25:57
what it does
25:58
over time,
25:59
because
25:59
available
26:00
therapies
26:00
are associated
26:01
with with
26:02
challenging
26:02
side effects.
26:03
It's always a,
26:04
trade off
26:05
of sorts
26:06
to say,
26:06
do I treat now
26:07
and know
26:08
that I'm
26:08
putting
26:08
someone on
26:09
a radiation
26:09
related series
26:10
of
26:11
complications?
26:12
Or do
26:12
I observe
26:13
and make sure
26:14
I'm seeing
26:14
growth,
26:15
or determining
26:15
that this is,
26:16
in fact,
26:16
going to
26:16
be a lesion
26:17
that will
26:17
require
26:18
treatment?
26:19
And I think
26:19
that's a
26:19
very important
26:20
point of what
26:21
Doctor Correa
26:21
mentioned in
26:22
her talk.
26:22
We do, in
26:23
the trial,
26:23
want to show
26:24
evidence
26:24
of growth,
26:25
because that
26:25
is a somewhat
26:26
irrefutable
26:27
sign of,
26:28
change
26:29
in the tumor.
26:29
So
26:30
to make sure
26:30
we are
26:31
treating
26:31
true melanomas
26:32
rather
26:33
than nevi,
26:33
that growth
26:34
aspect is
26:34
important
26:35
and as she
26:36
mentioned,
26:36
biopsies prior
26:37
to entering
26:37
the trial
26:38
are absolutely
26:38
fine to
26:39
determine,
26:39
additional
26:40
information to
26:41
help support
26:41
that,
26:42
but we are,
26:43
you know,
26:44
the thought
26:45
of being able
26:45
to move
26:46
into lesions
26:46
that are
26:47
earlier,
26:48
smaller,
26:48
that might be
26:49
in that watch
26:50
and wait,
26:50
aspect now,
26:52
with the
26:52
treatment
26:52
being explored
26:53
in phase
26:53
three, is,
26:54
is very
26:55
exciting
26:55
to us at Aura,
26:56
and we hope to
26:56
the community
26:57
as well.
26:58
Dr.
26:59
Cole did a
26:59
lovely job
27:00
describing
27:00
where IDEAYA
27:01
is in
27:02
terms of
27:02
the potential
27:02
in larger
27:03
tumors
27:04
and then the
27:04
systemic
27:05
therapy
27:05
we'll hear
27:05
about in
27:06
the next
27:06
session.
27:09
I think the,
27:10
as
27:11
I mentioned,
27:11
the high
27:11
morbidity
27:12
associated
27:12
with the
27:12
current
27:13
standard
27:13
of care,
27:13
which is
27:14
radiotherapy
27:15
and has
27:15
been the case
27:16
for decades,
27:17
and it's
27:17
successful
27:18
in, in
27:19
stopping
27:19
growth of
27:20
the tumor,
27:20
the
27:21
unfortunate
27:21
side effect
27:22
for people
27:22
living with
27:23
that is that
27:23
the vast
27:24
majority
27:24
of patients
27:25
treated with
27:26
radiation
27:26
do go on
27:27
to legal
27:27
blindness
27:28
over time
27:28
in the
27:29
treated eye
27:30
so we really
27:31
would,
27:31
would be,
27:33
excited to see
27:34
a paradigm
27:34
shift
27:34
that says
27:35
we can
27:35
treat early,
27:36
we don't have
27:37
the vision
27:37
loss
27:37
associated,
27:38
and we can,
27:39
look at
27:40
a shift
27:40
in how
27:40
we've been
27:41
managing
27:41
patients for
27:42
many
27:42
years now.
27:45
Tell you a
27:45
little bit
27:46
about
27:46
our phase
27:46
two trial.
27:47
So
27:47
the phase two
27:48
trial
27:48
is completed
27:50
and the data
27:51
from this
27:51
allowed us
27:52
to move
27:52
to our phase
27:52
three
27:53
registrational
27:53
program.
27:54
In phase two,
27:55
we again
27:56
looked at
27:56
super
27:57
choroidal
27:57
administration
27:58
to the eye,
27:58
activated
27:59
with laser
28:00
and this was
28:00
a dose
28:01
escalation
28:01
trial.
28:02
So
28:02
we were able
28:02
to move
28:03
quickly
28:03
through
28:04
cohorts
28:04
to show that,
28:05
increasing
28:06
either
28:06
the dose
28:07
of the Bel-sar
28:08
or the number
28:08
of lasers
28:09
was not
28:10
associated
28:10
with any, side
28:11
effect profile
28:12
that prevented
28:12
increasing,
28:14
and we were
28:14
able to
28:14
increase up
28:15
to our
28:15
therapeutic
28:16
regimen,
28:16
which is what
28:17
we're
28:17
exploring in
28:17
phase three,
28:18
which is
28:19
three cycles
28:20
of treatment,
28:20
two
28:21
injections,
28:21
two lasers.
28:22
And
28:23
our endpoints
28:24
were looking
28:24
at evidence
28:25
of tumor
28:26
progression.
28:26
So did
28:27
the tumors
28:27
grow over
28:28
time?
28:29
Was there
28:29
any loss of
28:30
visual acuity
28:31
measured
28:31
as 15 letters
28:32
or three lines
28:33
on the eye
28:33
chart
28:34
from baseline,
28:35
and any change
28:36
in the rate
28:36
of growth
28:37
of the tumor
28:37
over the
28:38
course of of
28:39
the treatment
28:39
cycle.
28:43
And what we
28:43
saw was, three
28:45
key outcomes
28:46
that
28:46
allowed us
28:47
to move
28:47
into phase
28:47
three.
28:48
First, 80%
28:49
tumor
28:50
control rate.
28:51
So when we
28:51
looked at our
28:51
therapeutic
28:52
regimen,
28:53
so
28:53
the three cycles
28:54
that are
28:54
being studied
28:55
in phase
28:55
three,
28:56
we had 80% of
28:57
those patients
28:57
had a
28:58
complete
28:58
cessation of
28:59
tumor growth
29:00
at the
29:00
12 month mark
29:02
compared
29:03
to our
29:03
sub
29:03
therapeutic.
29:04
That's not
29:04
a true
29:05
sham in
29:05
the sense
29:06
that patients
29:06
did receive
29:07
some drug,
29:08
but we know
29:08
it was
29:08
a very low
29:09
level of drug
29:10
and laser.
29:11
We're only 20%
29:12
of those
29:12
tumors,
29:13
achieved
29:13
control.
29:14
So we had
29:15
an 80%
29:16
tumor
29:16
control rate.
29:17
Very
29:17
importantly,
29:18
we were able
29:18
to demonstrate
29:19
that 90%
29:20
of the
29:21
patients
29:21
in the phase
29:21
two trial
29:22
maintain
29:23
their visual
29:24
acuity
29:24
so the vision
29:25
with which
29:25
they entered
29:26
the trial
29:27
was the vision
29:28
with which
29:28
they left
29:29
the trial,
29:30
and
29:30
very importantly,
29:31
these were
29:32
tumors in 70%
29:33
of them,
29:34
were tumors
29:35
that were
29:35
very close
29:35
to the macula
29:36
or the
29:36
optic nerve,
29:37
which, Dr.
29:38
Cole nicely
29:38
outlined
29:39
the importance
29:40
of those
29:40
structures
29:41
in maintaining
29:42
vision.
29:43
So even tumors
29:44
in that high
29:45
risk location
29:46
for vision
29:46
loss,
29:47
patients
29:47
were able
29:48
to preserve
29:48
vision
29:49
with the
29:49
Bel-sar
29:49
treatment,
29:51
and then
29:51
we saw
29:51
a very low
29:52
rate of of
29:54
adverse events
29:55
in the
29:55
trial, again,
29:56
supporting
29:57
our hypothesis
29:58
of the dual
29:58
selectivity of
29:59
this
29:59
treatment.
30:00
We had a little
30:01
bit of mild,
30:02
front of
30:02
the eye
30:03
inflammation
30:03
that was
30:04
managed
30:04
with topical
30:05
drops over
30:06
a few
30:06
weeks and,
30:07
resolved
30:07
without any
30:08
additional,
30:09
sequelae
30:10
or long
30:11
lasting
30:11
side effects
30:12
and no
30:13
other major,
30:13
side
30:14
effects
30:15
reported.
30:15
So we were
30:15
very,
30:16
encouraged
30:17
by the
30:18
favorable
30:18
safety
30:18
profile,
30:19
coupled with
30:20
the tumor
30:20
control rate
30:21
and the
30:21
preservation
30:22
of visual
30:22
acuity coming
30:23
out of our
30:24
phase two
30:24
trial.
30:26
So this has
30:27
allowed us
30:27
to move
30:28
into the phase
30:28
three CoMpass
30:29
trial.
30:30
We are looking
30:30
at these
30:31
small
30:32
choroidal
30:32
melanomas
30:33
or
30:33
indeterminate
30:34
lesions,
30:35
and we are
30:35
randomizing
30:36
patients 2
30:37
to 1 to 2,
30:38
which means
30:38
within the,
30:40
the main
30:41
comparator
30:41
groups,
30:42
we have the
30:42
80 micrograms,
30:43
the high dose
30:44
of Bel-sar
30:45
compared
30:45
to the sham
30:46
control arm.
30:47
And that is a
30:48
observation
30:49
arm.
30:49
This was very
30:50
important
30:50
in our
30:51
conversations
30:51
with the FDA
30:53
and the
30:53
European
30:53
Regulatory
30:54
agencies,
30:55
that we do
30:55
have treatment
30:57
compared
30:57
to sham
30:57
or
30:58
observation,
30:58
which is for
30:59
many of these
30:59
small lesions,
31:00
what the
31:00
current
31:01
standard of
31:01
care is.
31:02
And then
31:02
we have
31:03
the 40
31:03
microgram,
31:04
the lower dose
31:05
of Bel-sar
31:05
in there
31:06
for masking
31:07
so that
31:07
patients,
31:08
and physicians
31:08
are not aware
31:09
of which dose
31:10
they are
31:10
receiving.
31:11
This is very
31:12
important.
31:12
All
31:13
that sounds
31:13
complicated.
31:14
It's very
31:15
important
31:15
in terms
31:16
of a
31:16
registrational
31:17
trial
31:17
that allows
31:18
for regulatory
31:19
approval
31:20
and access
31:21
for patients.
31:22
And we're
31:22
pleased to say
31:23
we have
31:23
both fast
31:24
track
31:24
and orphan
31:25
drug
31:25
designations.
31:26
We have
31:27
a protocol
31:27
agreement
31:28
with the FDA,
31:29
and support
31:30
from the EMA
31:30
on our
31:31
endpoints.
31:31
so we're
31:32
looking at
31:32
enrolling 100
31:33
participants
31:34
around
31:34
the world.
31:35
We have
31:36
sites in North
31:36
America,
31:37
Europe,
31:38
Middle East
31:38
and Asia
31:39
Pacific,
31:39
so we are
31:40
truly global
31:41
in our
31:41
approach here,
31:42
90 sites
31:43
to enroll
31:43
100 patients
31:44
with the hopes
31:45
that we will
31:45
have,
31:46
regulatory
31:46
approval
31:47
following
31:48
enrollment
31:48
and a
31:48
15 month,
31:49
primary
31:50
efficacy
31:50
analysis.
31:52
So ongoing,
31:53
and this
31:53
map shows,
31:54
you can see,
31:55
both on the,
31:55
A Cure
31:56
In Sight
31:56
website,
31:56
Thank you,
31:57
Danet.
31:57
there's a
31:57
really
31:58
nice link
31:58
to the
31:59
CoMpass trial
31:59
and
32:00
any information
32:00
you want
32:01
there.
32:01
We’re also
32:01
on
32:01
ClinicalTrials.gov,
32:03
and this is
32:04
a map of the
32:04
current sites
32:05
that are open
32:05
and enrolling
32:06
in the
32:06
United States.
32:08
Still more
32:08
to come there.
32:09
We've just
32:10
been approved
32:10
in Canada,
32:11
the United
32:11
Kingdom
32:12
and Australia,
32:13
and we're
32:13
following,
32:14
in short order
32:14
with European
32:15
sites as well.
32:16
So a lot of
32:17
activity on on
32:18
a key trial,
32:19
and happy
32:20
to take
32:20
any questions.
32:21
Thank you
32:22
again
32:22
for
32:22
the opportunity
32:23
to share
32:24
our goals
32:25
at Aura
32:25
to change
32:26
how patients
32:27
with melanoma
32:27
are treated.
32:28
Thank you.
32:29
Hey, Danet,
32:30
how are you?
32:31
I'm great.
32:31
How are you?
32:33
Good.
32:33
Thank you for
32:34
having me.
32:35
Of course.
32:36
So, Doctor
32:36
Carvajal,
32:37
we are
32:37
so excited
32:38
to chat
32:38
about
32:38
metastatic
32:39
uveal
32:39
melanoma.
32:40
I know this
32:40
is a hot
32:41
topic, but,
32:43
do you have
32:43
any specific
32:44
thoughts
32:44
that you
32:44
want to
32:45
give us?
32:46
You know,
32:46
kind of going
32:47
from this
32:47
last section
32:48
into our
32:48
next section
32:49
Yeah, that's
32:49
exactly
32:50
actually what
32:50
I want
32:51
to focus on
32:51
Danet because,
32:52
I think
32:53
your point
32:54
that,
32:55
you know,
32:56
we're really
32:57
in a new place
32:58
in this ocular
32:59
melanoma
32:59
field, and
33:01
I have to
33:01
say is,
33:01
I guess, like,
33:02
kind of,
33:03
speaking
33:04
to patients
33:05
and other
33:05
researchers
33:06
and clinicians
33:06
now, I am
33:07
so much
33:07
more
33:08
optimistic.
33:08
I was always
33:09
optimistic.
33:11
but,
33:12
the degree of
33:12
optimism
33:13
is just
33:13
much higher,
33:14
and it just
33:15
reminds me,
33:16
I think
33:16
some of you
33:16
who have
33:17
heard me
33:17
speak before,
33:18
I kind of,
33:19
talk about
33:19
sometimes
33:20
where we were
33:20
in skin
33:21
melanoma,
33:22
when I started
33:23
as an
33:24
oncologist
33:24
in 2000, where
33:27
we really
33:27
didn't
33:27
have anything,
33:29
you know, and
33:31
fast forward
33:31
20 years
33:32
later,
33:33
with our
33:33
therapies,
33:34
where
33:34
we're carrying
33:35
patients
33:36
with
33:36
metastatic
33:36
melanoma
33:37
for not
33:38
everyone,
33:38
but 40 to
33:39
50% of them
33:41
with these
33:41
novel
33:42
immunotherapies
33:43
and these
33:43
novel
33:43
targeted
33:44
therapies.
33:44
And as you
33:45
said, as,
33:46
as these
33:47
effective
33:48
therapies
33:48
became
33:49
approved,
33:50
we had more
33:51
license
33:51
in terms of,
33:52
I would
33:53
say,
33:53
creativity
33:53
in the forms
33:54
of novel
33:54
clinical
33:55
trials, novel
33:56
combinations,
33:57
which really
33:58
just
33:58
accelerated
33:59
our ability
33:59
to improve
34:00
outcomes.
34:01
And I think
34:01
that's where
34:01
we are now
34:02
for uveal
34:03
melanoma,
34:03
so I'm
34:04
just I'm
34:05
really
34:05
excited.
34:08
Well, I'm
34:08
so excited
34:09
to hear
34:09
what you guys
34:10
have,
34:11
both you
34:11
and our future
34:12
guests
34:12
that we have
34:13
coming on.
34:13
So I'm
34:13
going to
34:14
go ahead
34:14
and let
34:14
you share
34:14
your slides,
34:15
and I will
34:16
step away
34:16
so that
34:17
you can
34:17
present
34:18
and we will
34:18
get going.
34:19
Perfect.
34:21
So I think so
34:22
this talk is
34:23
maybe a little
34:24
bit different.
34:24
So what I want
34:25
to do
34:25
is maybe,
34:28
talk a
34:28
little bit
34:29
about that
34:30
bridge,
34:30
I guess,
34:32
between,
34:33
you know,
34:33
kind of
34:33
treatment
34:34
of the
34:34
primary
34:34
treatment
34:35
of metastatic
34:35
disease,
34:36
and this is
34:36
more of
34:37
a conceptual
34:37
kind of
34:38
overview
34:39
because,
34:40
again,
34:40
I do think
34:41
we're moving
34:41
towards cure
34:43
the way
34:43
we're thinking
34:43
about this
34:44
disease
34:44
and developing
34:45
therapies.
34:46
It's
34:46
much different
34:46
than the way
34:46
thinking
34:46
of things
34:46
five years
34:46
ago, and so,
34:50
this will be
34:53
a little bit
34:57
of a
34:59
different talk
35:02
than I
35:04
usually do.
35:05
Here are
35:05
my
35:06
disclosures.
35:06
I do a little
35:08
bit of
35:09
consulting,
35:09
a little
35:09
bit of work
35:09
with IDEAYA
35:09
and Aura
35:09
so let me
35:10
start
35:10
with this
35:11
and this is
35:11
conceptual.
35:12
if we look at
35:15
cutaneous
35:16
melanoma,
35:18
we have been
35:18
able to
35:19
increase
35:20
the number
35:20
of patients
35:21
that we
35:21
can cure,
35:22
through
35:23
kind of three
35:24
large buckets,
35:25
I would say.
35:26
And the left
35:27
bucket is that
35:29
with our
35:29
novel
35:30
immunotherapies,
35:31
targeted
35:31
therapies and
35:32
so forth,
35:33
we're
35:34
actually
35:34
able to,
35:35
treat
35:36
patients with
35:37
widely
35:38
metastatic
35:38
cutaneous
35:39
melanoma.
35:40
So
35:40
this is skin
35:40
melanoma
35:41
that's gone
35:41
through
35:41
the liver,
35:42
bone, lungs,
35:42
wherever
35:43
brain,
35:44
and we can
35:45
treat them
35:45
with these,
35:47
immunotherapies
35:48
and
35:48
we can just
35:48
eradicate it.
35:50
Right.
35:50
We still have
35:51
work to do.
35:52
You know,
35:52
I want to be
35:53
able to
35:53
do that
35:53
for 100%
35:54
of people.
35:55
But,
35:56
you know,
35:56
20 years ago,
35:57
we were
35:57
carrying maybe
35:58
5% of people
35:59
with
35:59
metastatic
36:00
disease.
36:00
Now it's up
36:00
to 50%.
36:02
Okay.
36:03
And so one
36:03
path towards
36:04
increasing the
36:05
number
36:05
of people
36:06
we can cure
36:06
with uveal
36:07
melanoma is
36:07
just develop,
36:09
more
36:10
effective
36:10
therapies
36:11
that work
36:11
in the
36:12
metastatic
36:12
setting.
36:14
Okay.
36:14
So that's
36:14
kind of
36:15
that left
36:15
bucket.
36:16
The right
36:17
bucket is
36:20
using various
36:21
tools
36:22
to prevent
36:22
the
36:22
development
36:23
of cancer
36:24
in the
36:24
first place.
36:25
Right.
36:26
And so for
36:26
skin melanoma,
36:27
which
36:27
we know
36:28
is
36:28
predominantly
36:29
driven by UV
36:30
radiation
36:31
exposure
36:31
from the sun,
36:32
if we use
36:33
sunscreen,
36:33
if we use sun
36:34
safe measures,
36:35
stay out
36:36
of the sun
36:36
during kind
36:37
of noon.
36:38
wear
36:39
wide brimmed
36:39
hats,
36:39
all of that
36:40
stuff.
36:41
We can reduce
36:42
the risk
36:42
of developing
36:43
disease
36:43
in the
36:43
first place.
36:44
And frankly,
36:46
that's what
36:46
we have to do
36:47
for all
36:47
cancers,
36:47
right?
36:47
Prevent it.
36:50
I would say,
36:51
you know,
36:51
where we are
36:51
for metastatic
36:52
uveal
36:53
melanoma,
36:53
we have
36:54
some approved
36:54
effective
36:55
therapies.
36:56
We have to
36:56
enhance
36:57
what we're
36:57
doing right,
36:58
to actually
36:59
be able
36:59
to achieve
37:00
cure and a
37:02
high number
37:02
of patients
37:04
in terms
37:04
of prevention,
37:05
we have a bit
37:07
of work to do
37:07
because,
37:08
you know,
37:09
to prevent
37:09
cancer, it's
37:10
helpful
37:10
for us to know
37:11
what
37:11
causes it.
37:12
And,
37:13
that's
37:14
something
37:14
that we
37:14
still
37:14
have work
37:15
to do.
37:16
Okay.
37:17
But for this
37:17
talk, what
37:18
I want to
37:18
focus on
37:19
is the idea
37:19
of eliminating
37:20
what we call
37:21
micro
37:21
metastatic
37:22
disease.
37:23
Right.
37:23
And so,
37:25
can we treat
37:27
patients?
37:27
Can we
37:28
treat people
37:28
with primary
37:29
uveal
37:30
melanoma,
37:30
not just
37:31
with
37:31
enucleation
37:32
or radiation,
37:33
but can we
37:33
use
37:34
the medicine
37:34
either
37:35
before
37:36
treatment
37:36
with the eye
37:36
or after
37:37
treatment of
37:38
the eye,
37:39
to kill
37:40
any cells
37:41
that may have
37:41
escaped.
37:42
It might be
37:42
hiding out
37:43
in the liver.
37:44
Right,
37:44
and that's
37:45
what we call
37:45
micro
37:46
metastatic
37:46
disease
37:47
and we know
37:48
in skin
37:48
melanoma
37:49
and a lot of
37:50
other cancers,
37:50
breast cancer,
37:51
colon cancer,
37:52
if we
37:53
give medicine
37:53
around
37:54
the time
37:55
of surgery
37:57
either before
37:58
and or
37:58
after surgery,
38:00
we can
38:00
dramatically
38:01
decrease
38:01
the risk of
38:02
the cancer
38:02
coming back
38:03
and in
38:03
some diseases,
38:04
help people
38:04
live longer.
38:05
We can do that
38:06
in skin
38:07
melanoma
38:08
and I think
38:09
we're
38:09
getting close
38:10
to the point
38:10
of being able
38:11
to do that
38:11
in uveal
38:12
melanoma.
38:14
Okay,
38:14
so that was
38:14
that was a
38:15
big overview.
38:16
So, if
38:16
we take
38:17
that kind of
38:18
middle bucket
38:18
how do we
38:19
eliminate
38:20
micro
38:21
metastatic
38:21
disease.
38:22
There
38:22
basically
38:23
three ways
38:24
that we can
38:25
think about
38:25
developing
38:26
that. Right.
38:27
And one way
38:27
we can do that
38:28
is take
38:29
what we know
38:29
works
38:30
in people
38:31
with
38:31
metastatic
38:31
disease.
38:33
and then
38:33
try it
38:34
either before
38:35
treatment of
38:35
the eye
38:36
or after
38:36
treatment of
38:37
the eye
38:37
or in
38:38
combination
38:40
and see
38:40
if, it can
38:41
kill off
38:42
those, rogue
38:43
cells
38:43
that might be
38:44
in the liver,
38:45
reduce
38:45
the risk of
38:46
the cancer
38:46
coming back
38:47
in the future
38:47
and improve
38:48
outcomes.
38:50
and I'll
38:51
talk
38:51
a little bit
38:51
about the
38:52
Tebentafusp
38:52
story
38:53
in that space.
38:55
You know,
38:55
I'll go
38:55
through two
38:56
and three,
38:56
kind of a
38:57
little bit
38:57
later,
38:58
but so let's,
38:58
let's focus
38:59
on this
39:01
in the
39:01
metastatic
39:02
setting.
39:03
there are
39:04
kind of two,
39:05
systemic
39:06
approaches
39:06
that we think
39:07
about, one
39:08
is
39:08
Tebentafusp,
39:09
you’ve
39:09
heard a bit
39:10
about this.
39:10
And that's
39:11
an
39:11
immunotherapeutic
39:12
approach.
39:13
And the other
39:14
is the
39:14
Darovasertib
39:15
story,
39:16
which is
39:16
the targeted
39:17
therapy
39:17
approach.
39:18
I'm not
39:19
going to talk
39:19
too much
39:20
about the,
39:21
kind of
39:21
mechanism that
39:22
Darovasertib,
39:22
George did
39:23
a
39:24
fantastic job
39:25
about that.
39:26
I would just
39:27
say that
39:27
the targeted
39:27
therapy
39:28
approach
39:28
is basically
39:30
looking
39:30
at the
39:30
signaling
39:31
pathways
39:32
within
39:33
the cancer
39:33
cell, right.
39:34
Like the
39:35
things that
39:35
are telling
39:36
that cancer
39:36
cell to grow
39:37
and spread
39:37
and do
39:38
the things
39:38
we don't
39:38
want it to do.
39:40
and with
39:40
these pills
39:41
like
39:41
Darovasertib,
39:42
we can
39:42
shut down
39:42
those pathways
39:43
that kills
39:44
the cancer
39:44
cell,
39:44
improve
39:45
the outcome.
39:46
Okay.
39:46
With the
39:47
immunotherapeutic
39:48
approaches,
39:48
what we're
39:48
trying to do
39:49
is somehow,
39:51
increase
39:52
the ability
39:52
of our
39:53
immune system,
39:53
our immune
39:54
cells
39:54
in the body
39:55
to, recognize
39:56
and kill
39:57
off the
39:57
cancer.
39:58
And,
39:59
I don't think
39:59
we have an
40:00
Immunocore
40:00
speaker so
40:01
I'll talk
40:01
just briefly
40:02
about the
40:03
mechanism
40:03
about this.
40:05
It's kind
40:05
of
40:05
interesting.
40:06
Tebentafusp
40:07
is, in
40:08
this picture,
40:09
it's this
40:09
blue thing
40:09
here, and here
40:11
we have
40:11
the melanoma
40:12
cell up top
40:12
and immune
40:13
cell,
40:13
they're here.
40:14
And this
40:14
blue thing,
40:15
this tebe
40:16
thing,
40:17
it's what
40:17
we call this
40:17
bispecific
40:18
molecule
40:19
where one
40:19
half of it
40:20
binds to
40:22
this protein
40:22
gp 100
40:23
that's present
40:24
on virtually
40:25
all uveal
40:26
melanoma cells
40:26
in high,
40:28
concentration.
40:30
And if it's
40:30
expressed
40:31
in a
40:31
certain way,
40:33
in the context
40:34
of what
40:34
we call
40:34
HLA-A*02:01,
40:36
Tebe
40:37
can bind to
40:38
that really
40:38
tightly,
40:39
so binds
40:39
to the cancer
40:40
cell really
40:41
tightly,
40:42
and then on
40:42
the other end,
40:43
it has
40:43
this thing
40:44
that just
40:44
attracts
40:45
immune cells
40:45
that are in
40:46
that
40:46
environment
40:48
and basically
40:48
all it does
40:49
then is Tebe
40:50
brings
40:51
the immune
40:51
cells
40:52
just in close
40:52
proximity to
40:53
the cancer
40:54
cell,
40:54
and then
40:55
the cancer
40:55
cell dies.
40:56
Right?
40:56
So that's
40:57
pretty cool.
40:58
And it's
40:58
really cool
40:59
that this was
41:00
the first drug
41:01
that was
41:01
ever approved
41:02
for the
41:02
treatment
41:02
of uveal
41:03
melanoma
41:03
and this is
41:04
just in
41:04
January
41:05
of 2022.
41:06
Right.
41:06
Like why
41:07
am I so
41:08
optimistic?
41:09
There was
41:10
nothing
41:10
that was ever
41:11
proven to
41:12
meaningfully
41:12
improve
41:12
outcomes
41:13
in this
41:13
disease
41:14
before that,
41:15
which is mind
41:17
blowing to me.
41:17
Right?
41:18
That,
41:19
that was the case,
41:20
but finally
41:20
we have,
41:21
you know,
41:22
our first
41:23
approved
41:23
systemic aid
41:24
and that
41:24
really
41:24
meaningfully
41:25
improve
41:25
outcomes
41:26
in our
41:26
patients
41:27
with advanced
41:27
disease
41:28
if they are
41:29
HLA-A*02:01
41:30
positive.
41:32
Okay,
41:36
now I want to
41:36
kind of
41:37
shift to
41:37
how are we
41:38
applying this
41:38
and like that
41:39
prevented it
41:40
and
41:40
preventative
41:41
type setting.
41:43
And one of
41:43
the things
41:43
that we
41:44
noticed,
41:45
when
41:45
we treated
41:46
patients with
41:47
metastatic
41:48
disease
41:49
is that,
41:50
the likelihood
41:51
of
41:51
significantly
41:52
shrinking
41:52
the cancer
41:53
wasn't
41:53
that high.
41:54
And so up
41:55
top here,
41:56
this kind
41:57
of bar thing,
41:58
this is
41:58
what we call
41:59
a waterfall
41:59
plot.
42:00
Every patient
42:01
is a bar.
42:02
And
42:02
if the tumor
42:02
shrinks,
42:03
the bar
42:03
goes down.
42:04
If the tumor
42:05
grows,
42:05
it goes up.
42:07
And you can
42:07
see that,
42:08
we have
42:08
major
42:09
shrinkage
42:10
in orange
42:10
and a small
42:11
fraction of
42:11
patients,
42:13
we have
42:13
more modest,
42:14
shrinkage.
42:15
So
42:15
a little bit
42:15
of shrinkage
42:16
or maybe even
42:16
a little bit
42:17
of growth,
42:18
in the
42:18
majority
42:19
of the patients,
42:19
and then
42:20
we have major
42:20
growth in
42:21
kind of a
42:22
small subset,
42:25
in some
42:26
cancers,
42:28
drugs that
42:29
shrink cancer
42:30
better leads
42:32
to improve
42:32
outcomes
42:33
in terms
42:33
of having
42:34
of people
42:34
live longer.
42:35
Right?
42:35
Which is
42:36
ultimately
42:36
what we
42:36
want to do.
42:38
but for Tebe,
42:38
we didn't
42:39
see that
42:39
relationship,
42:40
really.
42:41
So,
42:42
whether or not
42:42
you shrunk
42:43
tumor,
42:44
the outcomes
42:45
were kind of
42:45
equally good
42:46
and so
42:47
even if you
42:47
had minor
42:48
shrinkage
42:48
or maybe
42:49
even just
42:49
a little bit
42:49
of growth,
42:50
there was
42:50
still that
42:51
sort of
42:51
benefit
42:52
in helping
42:52
people
42:52
live longer.
42:54
and so one of
42:55
the problems
42:56
with Tebe
42:56
then was,
42:58
well,
42:58
if size
42:59
doesn't
42:59
predict
43:00
overall
43:00
outcome,
43:01
right,
43:01
if our ability
43:01
to shrink
43:02
the cancer
43:03
doesn't
43:03
predict
43:03
overall
43:04
outcome,
43:04
is there a
43:05
better way
43:05
for us
43:05
to kind
43:06
of assess
43:07
that
43:07
rather than
43:07
scans,
43:08
which is
43:08
hugely what
43:09
we do?
43:10
And so,
43:11
what we
43:12
did in the
43:12
earlier
43:13
trials is,
43:14
we collected
43:15
something
43:15
called
43:15
circulating
43:16
tumor DNA
43:18
and
43:18
circulating
43:19
tumor DNA.
43:21
basically
43:22
the DNA is
43:23
kind of the
43:23
like the brain
43:24
of all cells
43:25
and all of our
43:25
cells have
43:27
DNA
43:28
and DNA is
43:29
can constantly
43:30
shed from
43:31
the cells,
43:31
and you can
43:32
detect it
43:32
in the blood.
43:32
If we do a
43:33
blood test,
43:33
we can find
43:34
fragments of
43:35
your
43:35
normal DNA,
43:36
but cancer
43:38
also
43:38
sheds DNA,
43:39
and we can
43:40
we can
43:40
separate
43:41
the cancer DNA
43:42
from normal.
43:43
And so
43:44
what was
43:45
kind of
43:45
interesting
43:46
here is
43:46
that in
43:47
all of
43:47
the people
43:48
we treated
43:48
with Tebe,
43:49
if the ctDNA
43:51
decreased or
43:51
if they
43:52
cleared
43:52
the DNA,
43:52
if it just
43:53
disappeared
43:53
and
43:54
we couldn't
43:54
find any
43:54
anymore,
43:55
all those patients
43:56
did well,
43:57
and so
43:58
there was
43:58
a really
43:58
strong
43:59
correlation
44:00
between our
44:00
ability to
44:01
get rid
44:02
of that
44:02
circulating
44:03
cancer DNA
44:04
and improved
44:05
outcomes.
44:07
and so
44:08
based off of
44:08
that data,
44:09
the first
44:10
of the
44:10
the seven
44:11
Tebe trials,
44:13
and adjuvant
44:13
just means,
44:14
treatment
44:15
after
44:16
treatment
44:16
with something
44:17
after
44:17
treatment
44:18
with the eye.
44:18
So the first
44:19
of these kind
44:19
of adjuvant
44:20
trials,
44:21
came
44:21
was developed
44:22
and this is
44:22
being led by,
44:23
Mark
44:24
Middleton,
44:25
Paul
44:25
Nathan, and
44:25
Joe Sacco
44:26
in the UK.
44:28
And what
44:28
they're doing
44:28
here is,
44:30
they're
44:30
identifying
44:31
individuals
44:32
with uveal
44:33
melanoma
44:33
that's high
44:34
risk by
44:34
cytogenetics
44:35
or gene
44:36
expression
44:37
usually
44:37
cytogenetics
44:38
and large size
44:40
who are treated
44:42
who are HLA
44:43
A*02:01
44:44
positive
44:44
because this
44:46
drug
44:46
only works
44:47
if you are up
44:47
to a
44:48
one positive
44:49
and then
44:50
they check
44:50
for ctDNA
44:51
over time.
44:53
If they
44:53
detect ctDNA,
44:54
then those,
44:55
folks get six
44:56
months
44:57
of Tebentafusp
44:58
and then
44:58
they can see
44:59
if we do that,
44:59
can we
45:00
actually clear
45:01
reduce that
45:01
the amount
45:02
of ctDNA
45:03
under the
45:04
hypothesis
45:05
that if we
45:05
decrease
45:05
the ctDNA,
45:07
overall
45:07
outcomes
45:07
or the better
45:08
likelihood of
45:09
the cancer
45:09
coming back
45:10
will be lower?
45:11
So, this is
45:12
kind of one
45:13
kind of
45:13
ongoing trial.
45:14
It's ctDNA
45:15
based.
45:16
It's kind of
45:17
it's
45:17
a big trial,
45:18
but it's still
45:19
going to be a
45:19
little bit
45:19
hypothesis
45:20
generating,
45:22
but what
45:23
what we
45:23
wanted to do
45:24
was really
45:25
design,
45:26
a trial
45:27
that would
45:28
more
45:28
definitively
45:29
answer
45:29
the question.
45:30
If we do Tebe
45:31
after
45:32
treatment at
45:32
the primary,
45:33
can we improve
45:34
outcomes
45:35
and so this
45:36
this is
45:37
probably 7
45:38
or 8 years
45:38
in the making.
45:39
And, it's
45:40
finally going
45:40
to open up
45:41
this,
45:41
this Fall,
45:43
but we are
45:44
beginning
45:45
this,
45:46
trial called
45:47
the ATOM
45:47
trial.
45:48
It's an
45:48
adjuvant
45:48
heavy trial
45:50
where
45:50
we're going
45:50
to take
45:50
individuals
45:51
with high risk
45:52
uveal
45:53
melanoma,
45:55
A*02:01
45:55
positive,
45:57
without
45:58
evidence
45:58
of metastatic
45:59
disease and,
46:01
they're going
46:01
to be
46:01
randomized
46:02
to either
46:02
six months
46:03
of Tebe
46:03
or
46:03
observation,
46:05
and then we're
46:05
going to
46:05
follow.
46:07
There's no
46:07
placebo here.
46:08
You know,
46:08
if you're
46:09
getting the drug
46:09
or if
46:10
you're on
46:10
observation,
46:11
observation
46:12
is the
46:12
standard
46:12
of care.
46:13
Right.
46:13
So that's why,
46:14
we feel like
46:15
this is a very
46:16
small trial
46:16
to do
46:18
and so
46:18
this will be
46:19
sponsored
46:20
by a group
46:21
called
46:21
the EORTC,
46:22
so it's
46:22
a European
46:23
group.
46:23
We're going
46:24
to open
46:24
this up,
46:26
and select
46:27
sites
46:27
in the US
46:27
as well,
46:28
hopefully up
46:29
to ten sites,
46:30
at least five,
46:31
and,
46:31
and hopefully
46:32
those sites
46:32
will be open,
46:34
hopefully no
46:35
later than
46:35
early
46:35
next year.
46:38
I also
46:39
just want
46:40
to highlight
46:40
that we
46:41
do have
46:42
what we call
46:42
regional
46:43
therapies
46:44
that,
46:44
can be
46:45
very effective
46:46
in this
46:46
disease.
46:48
So,
46:48
because
46:49
recurrence
46:50
tends to occur
46:50
in the liver,
46:51
and then in
46:52
some cases,
46:53
in many cases
46:54
it's what
46:54
we call liver
46:55
predominant
46:55
the bulk
46:56
of the cancers
46:56
in the liver.
46:58
A
46:58
lot of times,
46:58
what we do is
46:59
think about
46:59
is there a
47:00
treatment
47:00
we can put
47:00
right into
47:01
the liver,that
47:03
can fight
47:03
the cancer?
47:05
And,
47:06
there are
47:06
a lot of
47:06
different ways
47:06
to do that.
47:07
there's,
47:08
one technique
47:09
called
47:09
intrahepatic,
47:10
isolated
47:11
hepatic
47:11
perfusion.
47:13
and there's
47:13
another one
47:14
called
47:14
percutaneous
47:15
hepatic
47:15
perfusion.
47:16
The concept
47:17
between
47:18
both of
47:18
these
47:18
techniques
47:19
are kind of
47:19
the same.
47:19
Basically
47:20
we isolate
47:21
the liver,
47:23
vasculature
47:23
for. Right.
47:24
So you kind
47:25
of put the
47:25
liver on like
47:25
a bypass pump
47:27
and you
47:27
put in a
47:28
lot of
47:28
chemotherapy
47:29
into the
47:29
liver.
47:30
and because
47:31
of that
47:31
bypass pump,
47:32
the
47:32
chemotherapy
47:33
doesn't go
47:33
into the
47:34
rest of
47:34
the body
47:34
and cause
47:35
a lot of
47:35
side effects.
47:36
and with
47:37
that high dose
47:37
chemotherapy,
47:39
we can see
47:39
some really
47:40
nice,
47:41
tumor
47:41
shrinkage.
47:42
And so this,
47:43
platform
47:46
by Delcath
47:47
is the
47:48
second
47:48
treatment
47:48
that was approved
47:49
for uveal
47:49
melanoma
47:50
just
47:51
in August
47:51
of last year.
47:53
Okay.
47:53
And again,
47:54
this is
47:54
another tool
47:55
I, suspect
47:56
that we're
47:56
going to
47:57
be seeing,
47:57
trials about
47:59
can we do this
48:00
in the
48:00
preventative
48:01
setting?
48:02
to improve
48:03
outcomes.
48:04
nothing is,
48:07
open yet,
48:08
but there's
48:08
certainly
48:09
discussions.
48:11
Okay.
48:12
So that's
48:12
basically,
48:14
kind of
48:14
strategy
48:14
one let's,
48:15
let's see
48:16
what works
48:16
in the
48:16
metastatic
48:17
setting
48:17
and then
48:17
try it in the
48:18
preventative
48:18
setting.
48:20
Our option
48:21
two is
48:22
to perform
48:23
what I call
48:23
signal seeking
48:24
adjuvant
48:25
trials
48:26
and then
48:27
take the
48:27
most promising
48:28
therapies
48:29
forward
48:29
in
48:29
confirmatory
48:30
trials
48:31
and here
48:31
I want to talk
48:32
about IpiNivo.
48:33
The difference
48:35
between 1
48:36
and 2
48:36
is like it
48:37
for two here.
48:39
it may be that
48:40
we have to
48:40
take therapies
48:41
that we
48:41
have not
48:42
heavily
48:42
tested in
48:44
people
48:45
with
48:45
metastatic
48:45
disease.
48:48
or maybe
48:48
we think
48:49
the treatments
48:49
will work
48:50
better
48:51
when there's
48:51
only tiny
48:52
bits of cancer
48:53
in the body,
48:53
as opposed
48:54
to kind
48:55
a more
48:55
bulky cancer
48:56
that I can see
48:56
on the scans.
48:58
And so
48:58
that's what,
48:58
kind of
48:59
option two
49:00
is here.
49:01
And so,
49:03
at ASCO,
49:04
which is
49:05
the big cancer
49:06
meeting,
49:06
just a few
49:07
months ago,
49:07
we reported
49:09
the final
49:09
results of a
49:10
second trial
49:11
of two
49:12
immunotherapies,
49:14
one called
49:14
nivolumab
49:15
and one
49:15
called
49:15
ipilimumab
49:16
in patients
49:17
with high
49:17
risk of
49:18
melanoma, and
49:19
so this
49:19
was the
49:20
study design.
49:21
Basically,
49:21
we took people
49:22
who had a high
49:23
risk of
49:23
the uveal
49:24
melanoma
49:24
coming back
49:26
and all of
49:27
the patients
49:27
there got
49:28
these two
49:29
immunotherapies
49:30
IpiNivo,
49:31
immunotherapies
49:32
that are
49:32
commonly used
49:33
for cutaneous
49:33
melanoma.
49:34
This is the regimen
49:35
that gets us
49:35
the 45 to 50%
49:37
cure rate
49:37
in skin
49:38
melanoma,
49:39
and then
49:39
we followed
49:40
them.
49:41
This was not
49:42
a
49:42
randomized trial,
49:43
so
49:43
we used what
49:44
we call
49:44
a real world
49:45
data set
49:46
to create
49:46
a synthetic
49:47
control arm.
49:48
So, we kind of
49:49
we didn't
49:49
randomize
49:50
patients,
49:50
but we use
49:51
patients
49:51
who were
49:51
treated
49:52
previously,
49:53
and try to see
49:54
the patients
49:55
on this trial
49:55
do better.
49:57
I would say
49:57
that the
49:58
historical
49:58
outcomes
49:59
for IpiNivo
50:00
in this
50:00
disease,
50:01
has been
50:02
assessed
50:02
in a couple
50:03
of small,
50:04
prospective
50:05
trials.
50:06
And we've
50:06
looked at this
50:07
in a couple of
50:07
retrospective
50:08
trials
50:09
and the
50:10
likelihood
50:10
of major tumor
50:11
shrinkage
50:11
isn't that
50:12
great,
50:13
you know,
50:13
maybe 15
50:14
to 20%
50:14
at best.
50:16
The
50:16
likelihood of,
50:17
preventing
50:19
tumor growth,
50:20
not that
50:21
great, right?
50:22
It only seems
50:22
to control
50:22
cancer for a
50:23
few months,
50:25
but we
50:25
hypothesized
50:26
here that
50:28
if we
50:28
gave this
50:28
treatment
50:29
earlier, that
50:30
maybe
50:30
the outcomes
50:31
would be
50:31
better.
50:32
And in fact,
50:33
this is what
50:33
we saw
50:34
if we looked
50:34
at the
50:35
patients
50:35
treated
50:36
with IpiNivo
50:37
at three
50:37
years,
50:40
70% of
50:42
the patients
50:43
were doing
50:43
well,
50:44
no evidence
50:44
of cancer.
50:46
Whereas if
50:46
we look at
50:47
our control
50:47
arm,
50:48
it was 43%.
50:50
Right.
50:50
So that was a
50:51
significant
50:51
difference
50:52
or improvement
50:53
for IpiNivo,
50:55
versus
50:56
that
50:56
historical
50:56
control.
51:00
and so
51:00
there are
51:03
a number of
51:03
other signals
51:04
and trials,
51:04
but I just
51:04
wanted to
51:04
highlight
51:05
that one.
51:05
That's
51:05
one of
51:06
the more
51:06
recent ones.
51:08
and then
51:08
the third
51:09
thing
51:10
we've
51:10
already heard
51:10
a little
51:10
bit of
51:11
or a lot
51:11
about this
51:12
from is,
51:13
maybe
51:13
we can perform
51:14
what we call
51:15
signal seeking
51:15
neoadjuvant
51:16
trials
51:17
and
51:17
neoadjuvant
51:18
means
51:18
let's give a
51:19
medicine
51:19
before
51:20
treatment
51:20
of the eye,
51:22
and then take
51:22
the most
51:23
promising
51:23
therapies
51:24
forward.
51:25
The benefit
51:25
of giving
51:27
a treatment
51:27
with,
51:28
a medicine
51:29
before
51:29
treatment
51:29
for the eye
51:30
is that
51:30
we can see
51:32
does it work
51:33
in shrinking
51:34
that eye
51:34
tumor? Right.
51:35
Because maybe
51:36
if the
51:36
treatment
51:36
actually helps
51:37
to shrink
51:38
the tumor,
51:39
maybe
51:39
those are
51:40
the patients
51:40
who are going
51:40
to benefit
51:41
the most,
51:41
and maybe
51:42
those are
51:42
the patients
51:43
who should be
51:43
getting more
51:44
of that
51:44
treatment
51:45
after the eye
51:46
is treated.
51:48
And so,
51:49
I'll talk
51:49
a little
51:49
bit more
51:50
about the
51:50
Daro trial.
51:51
So again,
51:52
George spoke
51:52
a lot
51:53
about
51:53
the mechanism
51:54
so I'm not
51:55
going to,
51:55
kind of
51:56
harp on that.
51:57
I will say
51:57
we've been
51:58
looking
51:58
at the idea
51:59
of targeting
51:59
PKC for
52:00
a long time
52:01
in ocular
52:02
melanoma.
52:02
So
52:03
the early papers
52:04
came out and,
52:05
you know,
52:06
to 2010, 2012.
52:09
And so this
52:09
has been
52:10
definitely of
52:10
high interest.
52:11
We've done
52:12
trials
52:13
looking at
52:13
PKC inhibition
52:14
by itself.
52:16
Again, these
52:16
these were
52:17
published in
52:17
2020 and
52:18
2023, but,
52:19
you know,
52:19
we were doing
52:20
these trials
52:20
a long
52:20
time ago
52:22
and the
52:23
likelihood
52:23
of major
52:24
shrinkage
52:24
for PKC
52:25
inhibition
52:25
alone.
52:26
So that
52:26
one pill
52:27
by itself
52:28
is also pretty
52:28
modest, like,
52:29
you know, 3%
52:30
with this
52:31
first
52:31
generation
52:31
PKC
52:32
inhibitor, 13%
52:33
with, Daro,
52:35
which
52:35
was called
52:35
LXS196 before,
52:40
and there were
52:40
some toxicity
52:41
counts too.
52:41
So,
52:44
you know,
52:44
it was a
52:44
little bit,
52:48
I would have
52:48
liked to see
52:49
more,
52:49
but as,
52:50
as George
52:51
said,
52:52
IDEAYA
52:52
has done
52:52
a really
52:53
great job
52:53
looking to see
52:55
can we combine
52:56
Daro
52:57
with other
52:57
therapies
52:58
and will
52:58
that lead
52:59
to better
53:00
outcomes?
53:00
Right.
53:02
And so I want
53:02
you to look
53:03
at these
53:03
plots,
53:04
these
53:04
waterfall
53:04
plots. Right.
53:05
Again,
53:05
the lines
53:06
going down
53:06
means
53:07
the tumor
53:07
shrank.
53:08
So here
53:09
maybe a
53:09
third line
53:10
go down, here
53:10
maybe like
53:11
a little bit
53:12
more than
53:12
half of
53:12
the lines
53:13
go down,
53:15
but
53:15
this is the
53:16
waterfall plot
53:18
when Daro
53:19
is combined
53:19
with
53:20
another
53:20
pill called
53:21
Crizotinib,
53:21
and so we use
53:22
this
53:22
combination
53:22
therapy where
53:24
look at this,
53:24
almost
53:24
every single
53:25
patient
53:25
has tumor
53:26
shrinkage.
53:27
Right.
53:27
And then this,
53:28
this data
53:28
set, 30%
53:30
of patients
53:30
have major
53:31
shrinkage.
53:32
That's
53:32
really
53:32
durable.
53:33
Right,
53:34
and I
53:35
will say that
53:36
this sort of
53:36
waterfall
53:37
plot,
53:37
I've been
53:37
studying
53:37
this disease
53:38
for a
53:38
long time.
53:40
We've never
53:40
seen this
53:41
before.
53:42
so this
53:42
this is
53:42
really,
53:42
really
53:43
striking.
53:44
and so
53:45
what was also
53:45
really cool
53:46
is that in
53:47
some of the
53:47
early trials,
53:49
some of the patients
53:49
who were treated
53:50
still had
53:51
the eye
53:51
melanoma,
53:52
the primary
53:52
lesion
53:53
in place
53:53
that was not treated.
53:54
And so
53:55
George showed
53:55
some examples
53:56
here.
53:57
You know,
53:57
here's
53:57
some other
53:58
ones. Right.
53:58
So here's
53:59
a 70 year
53:59
old patient
54:00
who had
54:00
the primary
54:01
melanoma there
54:02
that
54:02
you can see
54:02
on PET scan,
54:05
and just
54:06
after
54:06
a couple of weeks
54:07
you can see
54:08
it's
54:08
the brightness
54:08
is bad.
54:09
That just
54:09
means it's
54:10
fairly active.
54:11
Here
54:11
the brightness
54:12
is much less,
54:13
right,
54:14
which shows
54:15
that it's
54:15
less active.
54:15
And it also
54:16
shrunk down
54:17
as well.
54:18
And then
54:18
here's
54:18
another
54:18
patient, 50
54:19
year old.
54:20
There's a
54:20
tumor there.
54:21
and after
54:22
five months,
54:23
significant
54:23
shrinkage.
54:24
Right.
54:25
And so
54:25
that led
54:26
Anthony
54:26
Joshua,
54:27
to present,
54:29
his trial.
54:30
so this is
54:31
this is
54:32
a small
54:32
kind of single
54:33
seeking trial
54:33
that he did
54:34
in Australia
54:36
called the
54:36
NADOM trial,
54:38
and basically
54:38
what he did
54:39
was he
54:40
he found
54:40
patients who,
54:41
had a tumor
54:42
that would
54:42
require
54:43
an
54:43
enucleation.
54:44
Initially,
54:45
he would
54:45
just treat
54:46
with Daro
54:47
for a month,
54:47
do
54:48
the surgery,
54:48
and then maybe
54:49
give more
54:50
Daro,
54:50
and then once
54:52
he showed
54:53
that was
54:53
feasible
54:53
and safe,
54:54
he, finally
54:55
found patients
54:56
requiring
54:56
enucleation,
54:57
gave up
54:57
to six
54:58
months of
54:58
Daro,
54:59
did definitive
55:00
treatment,
55:00
and then had
55:00
the option
55:01
to do more
55:02
Daro.
55:02
And, so
55:03
this is
55:03
the slide
55:03
that George
55:04
showed
55:04
you already.
55:05
You saw this
55:07
but I would
55:07
just highlight
55:08
that,
55:09
of the
55:09
12 patients
55:11
who were
55:11
treated
55:11
on that
55:11
expansion
55:12
cohort,
55:13
all 12 of
55:13
those had
55:14
a tumor
55:15
that would
55:15
require an
55:16
enucleation.
55:18
After
55:18
the treatment
55:18
course,
55:19
only three
55:20
required
55:20
enucleation,
55:21
which means
55:22
nine patients
55:22
had their
55:23
eye saved,
55:24
which is
55:25
pretty cool
55:26
I think,
55:27
and so
55:27
then that
55:28
led to
55:28
the trial
55:29
that that
55:29
George
55:29
spoke about
55:30
so not
55:30
gonna spend
55:31
anymore
55:31
time here
55:33
and, but
55:33
we are really
55:34
excited
55:34
about this
55:35
one.
55:37
So this
55:37
is just
55:37
the landscape
55:38
of where
55:39
we are
55:39
with, recent
55:40
an ongoing
55:41
adjuvant in
55:42
neoadjuvant
55:42
trials.
55:43
up top
55:44
are the,
55:45
the neoadjuvant
55:46
trials,
55:46
including
55:47
the Anthony
55:47
Joshua trial
55:48
in Australia,
55:49
which, which
55:49
just completed
55:50
accrual,
55:50
the ongoing
55:51
Daro trial,
55:53
and then the
55:53
new adjuvant
55:54
Tebe trial,
55:54
which
55:55
I didn't talk
55:55
too much about,
55:56
but that's
55:56
going to
55:56
be performed
55:57
at Jefferson
55:58
and should
55:58
open up,
55:58
shortly.
56:00
And then
56:00
we have
56:01
the
56:01
preventative
56:01
adjuvant
56:02
trials.
56:02
I spoke
56:03
about the
56:03
IpiNivo trial.
56:04
There's this,
56:05
vaccine trial
56:06
that has
56:06
completed
56:07
accrual.
56:08
So I'm
56:08
looking
56:08
forward
56:08
to seeing
56:09
those results.
56:10
There's
56:10
some more data
56:11
about adjuvant
56:12
Sutent,
56:13
alone
56:14
in combination
56:15
with another
56:15
pill called
56:16
valproic acid.
56:18
The
56:18
first cohort
56:19
results
56:19
was reported.
56:20
There's
56:21
additional
56:21
data that
56:22
should be
56:22
reported
56:22
shortly.
56:24
And then
56:24
we have
56:24
the TebeMRD
56:26
trial, the
56:27
the big
56:27
adjuvant
56:28
European ATOM
56:29
trial,
56:30
and a few
56:31
others
56:31
as well,
56:34
and so,
56:35
where we are,
56:35
overall here
56:36
strategy
56:37
one must take
56:37
what works
56:38
in metastatic
56:38
disease
56:39
treatment
56:39
preventative
56:39
setting.
56:40
I talked
56:40
about Tebe
56:42
and so
56:42
the ATOM trial
56:43
will evaluate
56:44
the idea
56:45
of six months
56:46
of adjuvant
56:46
Tebe in a
56:47
randomized
56:48
trial.
56:48
In terms of
56:49
the signal
56:50
seeking
56:50
adjuvant
56:51
trials,
56:51
we had
56:51
IpiNivo,
56:52
which looked
56:52
really good
56:53
in that
56:53
single arm,
56:54
trial
56:55
compared to
56:55
historical
56:56
controls.
56:57
it's driving
56:57
discussions
56:58
to see
56:59
can
56:59
we actually do
57:00
a randomized
57:01
adjuvant
57:01
IpiNivo trial,
57:02
which is
57:03
the only way
57:03
to really
57:04
tell,
57:04
you know,
57:05
these are
57:05
preliminary
57:06
results.
57:06
Is it real?
57:08
and then
57:08
for Daro,
57:09
we have
57:10
the signal
57:10
seeking
57:10
neoadjuvant
57:11
trial.
57:12
I would love
57:12
to hear
57:13
George's
57:14
thoughts
57:14
about,
57:17
when we
57:17
might expect a
57:18
true adjuvant
57:19
trial,
57:19
not to
57:20
put you on
57:20
the spot,
57:20
George.
57:22
But I think
57:23
that's,
57:24
something that
57:25
should be
57:25
considered
57:26
a high
57:26
priority.
57:29
and lastly,
57:30
I wanted to
57:31
talk
57:31
just really
57:32
briefly about
57:32
the importance
57:33
of real world
57:34
data.
57:34
I showed you
57:35
that IpiNivo
57:36
trial
57:37
and how we use
57:38
historical
57:39
data sets,
57:40
right,
57:41
to get
57:41
a sense of,
57:43
are the
57:43
results
57:43
good or bad?
57:44
And,
57:45
so generating
57:46
that sort
57:47
of data
57:47
is really,
57:48
really
57:48
important.
57:50
as I think
57:51
the prior
57:52
discussion,
57:52
having
57:53
the voice
57:54
of the patient
57:55
and the
57:55
caregiver
57:55
community
57:56
is super,
57:56
super
57:57
important.
57:58
Right?
57:58
And so
57:59
there are
57:59
a number
58:00
of efforts
58:00
that are going
58:02
to rigorously
58:03
collect
58:03
that
58:04
information.
58:06
A Cure
58:06
In Sight,
58:07
has their
58:08
rare registry,
58:08
as you know,
58:09
so it's
58:10
a patient
58:10
powered
58:10
registry
58:11
where patients
58:12
will go online
58:13
consent and
58:14
provide
58:14
their own,
58:15
data.
58:17
the Melanoma
58:18
Research
58:18
Foundation,
58:20
Cure OM Group
58:22
has another
58:23
patient
58:23
powered
58:23
registry,
58:24
which is
58:25
ongoing.
58:28
Bill Harbor
58:28
leads a group
58:29
called the
58:29
Collaborative
58:30
Ocular
58:30
Oncology
58:31
Group, so
58:31
that's a group
58:32
of ocular
58:32
oncologists
58:33
and medical
58:33
oncologist,
58:35
putting data
58:36
in a database
58:37
so that
58:37
we can learn,
58:39
and we also
58:39
have this
58:40
International
58:41
Ocular
58:41
Melanoma
58:41
Natural
58:42
History Study,
58:42
the Omni
58:43
study,
58:43
which is
58:44
a global,
58:46
effort that I
58:47
worked on
58:48
with Anthony
58:48
Joshua
58:49
and Joe Sacco
58:50
where we have
58:51
nearly
58:51
a thousand,
58:52
patients,
58:53
enrolled.
58:54
and I think,
58:56
we need
58:56
other avenues
58:57
to learn
58:57
beyond
58:58
prospective
58:58
clinical trials
58:59
and this is
59:00
a mechanism
59:00
to do that
59:02
and using
59:03
these kind
59:04
of registries,
59:05
I think
59:05
we're going
59:05
to be able
59:05
to answer
59:06
questions
59:07
regarding,
59:08
are we
59:08
actually
59:09
educating
59:10
patients
59:11
caregivers
59:12
right away?
59:13
Are we doing
59:13
the shared
59:13
decision
59:14
making that
59:14
we should be
59:15
doing?
59:16
what are additional
59:16
concerns
59:17
that we
59:17
may not
59:18
be addressing
59:19
right.
59:19
From the
59:19
clinician
59:20
registries?
59:21
We can
59:21
look at,
59:21
you know,
59:22
the various
59:22
correlations
59:23
that,
59:24
are hard
59:25
to do
59:25
with these
59:25
single center
59:26
databases.
59:28
and when
59:29
if we
59:29
ever combine
59:30
these data
59:30
sets,
59:31
combining
59:31
patient
59:32
preference
59:32
with clinical
59:33
outcomes,
59:34
I think
59:34
could be
59:34
really, really
59:35
powerful.
59:37
So, I'll
59:37
leave it
59:37
at that.
59:38
I
59:38
do want to
59:39
again,
59:40
just thank,
59:41
thank
59:41
all of you
59:41
for,
59:42
listening.
59:43
Danet,
59:43
I'd like to
59:44
thank you
59:44
for putting
59:44
this together.
59:45
I think
59:46
this is
59:46
really
59:46
critical
59:47
we're a team,
59:48
and I want to
59:49
work with you,
59:50
to fix
59:50
this problem,
59:52
so I will
59:52
stop there.
59:53
Dr Carvajal,
59:54
thank you
59:54
so, so much.
59:55
This was
59:56
so exciting
59:57
to hear
59:57
and I hope
59:58
that everybody
59:59
who's
59:59
listening
59:59
is hearing
1:00:00
and
1:00:01
understanding
1:00:01
your excitement
1:00:02
just around
1:00:03
the
1:00:03
information
1:00:03
that you guys
1:00:04
are seeing,
1:00:04
the data
1:00:05
that
1:00:05
we're seeing
1:00:06
and just
1:00:06
the potential
1:00:07
that we have
1:00:07
for some
1:00:08
of these newer
1:00:08
treatments,
1:00:09
and some of
1:00:10
the ones
1:00:10
that
1:00:10
we're just
1:00:10
seeing used
1:00:11
in new ways.
1:00:12
let's go ahead
1:00:12
and move
1:00:13
on to, Doctor
1:00:15
Cole again
1:00:16
from Ideaya
1:00:17
Biosciences is
1:00:18
back again
1:00:18
to discuss
1:00:19
the Daro
1:00:20
Crizotinib
1:00:20
combination
1:00:21
trial.
1:00:21
And,
1:00:22
just give us
1:00:23
a little more
1:00:23
of an update
1:00:24
on where
1:00:24
the metastatic
1:00:25
treatment of
1:00:26
the IDE196
1:00:27
is going.
1:00:28
Absolutely.
1:00:29
Let me,
1:00:29
share
1:00:30
my screen here
1:00:31
All right,
1:00:31
everyone,
1:00:32
let me know
1:00:32
if here
1:00:33
if
1:00:34
the screen
1:00:34
here is
1:00:35
blocking
1:00:36
some things.
1:00:36
It
1:00:36
didn't do this
1:00:37
the last time.
1:00:39
and again,
1:00:39
thank you
1:00:40
for that
1:00:40
wonderful
1:00:40
introduction
1:00:41
and my
1:00:42
goodness,
1:00:42
Richard,
1:00:43
thank you
1:00:44
very much.
1:00:44
I hope to be
1:00:45
able to answer
1:00:46
some of
1:00:46
your
1:00:46
questions.
1:00:47
If not,
1:00:47
I will
1:00:48
definitely
1:00:48
be back
1:00:49
in touch
1:00:49
with you.
1:00:50
But let's
1:00:50
take a look
1:00:51
at some of
1:00:51
the things
1:00:51
that, IDEAYA
1:00:52
and
1:00:53
Darovasertib
1:00:54
is doing,
1:00:55
in the
1:00:55
metastatic
1:00:56
uveal
1:00:56
melanoma,
1:00:57
setting.
1:00:58
Again, I'm
1:00:58
going to give
1:00:59
some
1:00:59
information
1:01:00
which,
1:01:00
Richard
1:01:00
already showed
1:01:01
a little
1:01:01
bit of
1:01:02
in terms
1:01:03
of our phase
1:01:03
one two
1:01:04
clinical trial
1:01:05
combination
1:01:05
of
1:01:05
Darovasertib
1:01:07
plus
1:01:07
Crizotinib,
1:01:08
and again,
1:01:09
as was
1:01:10
mentioned
1:01:10
before, it's
1:01:11
very important
1:01:11
to
1:01:11
keep in mind
1:01:12
the one I'm
1:01:12
about to
1:01:13
show you
1:01:14
in some of
1:01:14
the later
1:01:15
slides after,
1:01:15
we look
1:01:16
at some of
1:01:16
this data.
1:01:18
This is
1:01:18
single agent
1:01:19
data, so phase
1:01:20
one,
1:01:20
phase two,
1:01:21
not phase
1:01:22
three.
1:01:22
So when
1:01:23
we look at,
1:01:25
our patient
1:01:25
characteristics
1:01:26
in this trial
1:01:27
and this data
1:01:28
was presented
1:01:29
last year
1:01:30
at ESMO,
1:01:31
important
1:01:32
thing to keep
1:01:32
in mind
1:01:32
in terms
1:01:33
of our phase
1:01:34
two trial
1:01:34
here,
1:01:35
when we look
1:01:35
at the
1:01:35
severity
1:01:36
of disease
1:01:36
in our patients.
1:01:37
So when
1:01:37
we look
1:01:38
at one of our
1:01:38
markers, LDH,
1:01:40
60% of
1:01:41
our patients
1:01:42
in any line
1:01:43
cohort
1:01:43
in patients
1:01:44
who are not
1:01:44
frontline
1:01:46
had a
1:01:46
increased LDH,
1:01:47
you know,
1:01:48
greater than
1:01:48
60% of
1:01:49
those patients
1:01:49
had an
1:01:50
increased,
1:01:50
LDH,
1:01:51
whereas
1:01:51
our patients
1:01:52
in the
1:01:52
frontline
1:01:53
cohort,
1:01:53
50% of
1:01:54
those patients
1:01:55
had
1:01:55
an increase
1:01:56
in LDH.
1:01:57
If we look
1:01:57
at our tumor
1:01:58
sizes
1:01:59
down here,
1:01:59
the largest
1:02:00
metastatic
1:02:00
lesion,
1:02:01
the majority
1:02:01
of the lesions
1:02:02
in both of
1:02:03
our cohorts
1:02:03
were between
1:02:04
3 to 8cm.
1:02:06
And also,
1:02:06
if we look at
1:02:07
the location
1:02:07
of the
1:02:07
metastases,
1:02:08
greater
1:02:09
than 50%
1:02:09
of the
1:02:10
patients in
1:02:10
both of
1:02:11
our arms
1:02:12
had both liver
1:02:13
and extra
1:02:14
hepatic
1:02:15
or outside
1:02:15
liver,
1:02:16
metastatic
1:02:17
disease.
1:02:18
So
1:02:18
these patients
1:02:18
have a
1:02:19
pretty high
1:02:19
severity
1:02:20
of disease,
1:02:20
so we're
1:02:21
in our phase
1:02:21
one two trial
1:02:22
and they're
1:02:22
looking at
1:02:23
our phase two
1:02:23
data
1:02:24
right now.
1:02:25
So again
1:02:26
this is
1:02:27
a, waterfall
1:02:28
plot
1:02:28
that we've seen
1:02:29
before.
1:02:29
But this one
1:02:30
sort of
1:02:30
divided up
1:02:30
into two
1:02:31
different
1:02:32
areas.
1:02:34
and again,
1:02:34
we want to
1:02:35
see bars down,
1:02:36
not bars up
1:02:37
and so by
1:02:38
looking
1:02:38
at these
1:02:39
two things,
1:02:39
we have a lot
1:02:39
of bars down
1:02:40
and that's a
1:02:40
good thing.
1:02:41
The plus signs
1:02:43
talk about
1:02:43
confirmed
1:02:44
response
1:02:45
in a single
1:02:46
arm trial,
1:02:46
we confirm
1:02:47
response with
1:02:48
two Cat scans.
1:02:49
So two cycles,
1:02:51
these patients
1:02:51
had two Cat
1:02:52
scans
1:02:52
confirming
1:02:53
that response.
1:02:55
Top waterfall
1:02:56
plot is front
1:02:57
line, bottom
1:02:58
waterfall plot
1:02:58
any line.
1:02:59
So, patients
1:03:00
this is a
1:03:00
combination of
1:03:01
front line
1:03:01
and patients
1:03:03
who have
1:03:03
more than one
1:03:04
line
1:03:04
of therapy.
1:03:05
The confirmed
1:03:06
overall
1:03:06
response
1:03:07
for our
1:03:07
front line
1:03:08
patients
1:03:08
about 45%
1:03:09
and
1:03:10
importantly
1:03:10
our disease
1:03:11
control rate
1:03:11
was about 90%.
1:03:13
So disease
1:03:14
control rate
1:03:14
is a criteria
1:03:15
that we use
1:03:16
that
1:03:16
encompasses,
1:03:17
stable
1:03:17
disease.
1:03:18
Another thing
1:03:19
that I want
1:03:19
to say
1:03:20
when we
1:03:20
take a look
1:03:21
at tumors
1:03:21
that had,
1:03:22
greater
1:03:22
than 30%
1:03:23
shrinkage
1:03:24
overall,
1:03:24
12 out of 20
1:03:25
and it was
1:03:25
60% of
1:03:26
the patients,
1:03:27
but what's
1:03:28
exciting to me
1:03:29
is our disease
1:03:29
control rate
1:03:30
here in the
1:03:31
single arm
1:03:31
study,
1:03:32
about 90%
1:03:33
stable
1:03:33
disease,
1:03:34
as we've now,
1:03:35
I would say,
1:03:36
modern
1:03:36
oncology
1:03:37
to have
1:03:37
developed
1:03:37
modern
1:03:38
thinking.
1:03:38
Stable
1:03:39
disease is not
1:03:40
a bad thing.
1:03:41
It truly means
1:03:41
that we
1:03:42
still have
1:03:42
that tumor
1:03:43
under control.
1:03:44
When we look
1:03:44
at our 80 line
1:03:45
patients
1:03:46
down here
1:03:46
again,
1:03:46
patients
1:03:47
that are
1:03:47
more heavily,
1:03:48
treated
1:03:49
confirmed
1:03:49
overall
1:03:50
response
1:03:50
rates,
1:03:50
about 30%, but
1:03:52
our disease
1:03:52
control
1:03:53
rate, again
1:03:53
is about
1:03:54
the same
1:03:54
as those
1:03:54
frontline
1:03:55
patients.
1:03:55
About 90%,
1:03:56
again,
1:03:58
very
1:03:58
encouraging
1:03:59
single line
1:04:00
data.
1:04:01
And again
1:04:02
down here
1:04:02
where we're
1:04:03
looking at
1:04:03
this are
1:04:03
heavily
1:04:04
pretreated
1:04:04
patients.
1:04:05
62% of
1:04:06
these patients
1:04:06
in this
1:04:07
waterfall plot
1:04:08
that we're
1:04:08
taking a look
1:04:09
at down here
1:04:10
at two
1:04:10
or greater,
1:04:11
prior lines
1:04:12
of therapy.
1:04:15
So I'm
1:04:16
sorry
1:04:16
about this on
1:04:17
the side here.
1:04:18
I couldn't
1:04:18
get that
1:04:18
to shrink,
1:04:19
but what we're
1:04:20
trying to
1:04:20
show here
1:04:21
is that
1:04:21
even in our
1:04:22
trial,
1:04:23
we are
1:04:23
HLA-A2
1:04:24
agnostics.
1:04:25
So we had both
1:04:27
HLA-A2
1:04:27
Negative
1:04:27
patients
1:04:28
and HLA-A2
1:04:29
Positive
1:04:29
patients
1:04:30
enrolled
1:04:31
in this trial.
1:04:32
And what's
1:04:32
interesting
1:04:33
for us is
1:04:33
when we
1:04:34
take a look
1:04:34
at our
1:04:34
response
1:04:35
rates again,
1:04:36
single arm
1:04:36
data,
1:04:37
the response
1:04:38
rate for
1:04:38
our frontline
1:04:39
patients
1:04:39
about 42%
1:04:41
and when we
1:04:41
take a
1:04:42
look at,
1:04:42
our HLA-A2
1:04:44
positive
1:04:45
patients,
1:04:45
frontline
1:04:46
patients,
1:04:46
there's a 62%
1:04:47
response rate.
1:04:48
Both patients
1:04:49
have 100%
1:04:49
disease
1:04:50
control rate.
1:04:51
When we look
1:04:51
at any line
1:04:52
patients,
1:04:53
HLA2 Negative,
1:04:54
we have
1:04:54
29% or 30%,
1:04:57
response rate
1:04:58
with about
1:04:58
a 94%
1:04:59
control rate.
1:05:01
And when
1:05:01
we look
1:05:01
at any line
1:05:02
in the HLA2
1:05:03
Positive
1:05:03
patients,
1:05:04
but a 32%,
1:05:05
response
1:05:06
rate with an
1:05:06
84% disease
1:05:08
control rate,
1:05:10
when we look
1:05:11
at our, I'll
1:05:12
say molecular
1:05:13
responses
1:05:13
with the
1:05:14
circulating
1:05:15
tumor DNA
1:05:17
again,
1:05:17
when we,
1:05:19
and this
1:05:19
is
1:05:19
regardless of
1:05:20
BAP1 mutation,
1:05:21
you get
1:05:21
another
1:05:22
mutation,
1:05:22
which,
1:05:23
which portends
1:05:24
to more
1:05:25
aggressive
1:05:25
disease
1:05:26
or disease
1:05:27
or bad
1:05:27
tumor markers.
1:05:28
We like
1:05:28
to say,
1:05:29
we're showing
1:05:29
pretty robust
1:05:30
responses
1:05:31
here.
1:05:31
Again,
1:05:32
single agent,
1:05:33
single arm
1:05:33
trial
1:05:34
with patients,
1:05:35
whether
1:05:36
they are
1:05:36
first line
1:05:36
patients
1:05:37
and or
1:05:37
pretreated
1:05:38
patients.
1:05:39
And again,
1:05:40
keep in mind
1:05:41
this is our
1:05:41
combination
1:05:42
Darovasertib
1:05:42
and
1:05:43
Crizotinib.
1:05:44
And
1:05:44
so one thing
1:05:45
that we have
1:05:45
to remember
1:05:45
with our uveal
1:05:46
melanoma
1:05:47
patients,
1:05:48
as Richard
1:05:48
showed,
1:05:48
and as
1:05:49
I showed
1:05:49
a little bit
1:05:50
before,
1:05:50
Darovasertib
1:05:51
is really
1:05:52
shutting down,
1:05:52
signaling
1:05:53
through PKC
1:05:55
another route
1:05:56
of signaling
1:05:57
with a
1:05:57
uveal melanoma
1:05:58
is through
1:05:58
MET and
1:06:00
most of
1:06:00
our patients
1:06:01
another
1:06:01
oncogene.
1:06:02
Most of
1:06:03
our patients
1:06:03
are showing
1:06:04
increased
1:06:04
signaling
1:06:05
through MET
1:06:06
and Crizotinib
1:06:07
stops
1:06:07
signaling
1:06:08
through MET,
1:06:10
and in
1:06:10
Richard’s
1:06:10
slide, he
1:06:11
showed
1:06:11
that aspect
1:06:12
of the MET
1:06:12
signaling in.
1:06:13
So what
1:06:14
we like
1:06:14
to think
1:06:14
in terms
1:06:15
of this
1:06:15
combination,
1:06:16
we’re
1:06:16
shutting down
1:06:17
all signaling
1:06:18
that is
1:06:18
driving
1:06:19
this tumor.
1:06:21
So when we
1:06:22
look at,
1:06:23
progression
1:06:23
free survival,
1:06:24
in these
1:06:25
patients
1:06:26
and again,
1:06:26
it's
1:06:27
any line,
1:06:28
when we
1:06:28
look at
1:06:28
front line
1:06:29
patients
1:06:29
and or
1:06:30
any line
1:06:30
patients
1:06:31
about the
1:06:31
same amount
1:06:32
of progression
1:06:32
free survival,
1:06:33
about
1:06:33
seven months
1:06:34
frontline,
1:06:35
7.11
1:06:36
specifically,
1:06:37
any line,
1:06:37
6.8 months
1:06:39
for patients
1:06:39
who only have,
1:06:40
liver
1:06:41
disease, it's
1:06:41
about
1:06:42
11 months.
1:06:43
the treatment
1:06:44
duration
1:06:44
for this,
1:06:45
50% of
1:06:46
the patients
1:06:46
had treatment
1:06:47
greater
1:06:47
than six
1:06:48
months,
1:06:48
and about
1:06:48
30% of
1:06:49
the patients
1:06:49
had treatment
1:06:50
for greater
1:06:50
than one year.
1:06:54
When we
1:06:54
look at our,
1:06:55
Kaplan-Meier
1:06:55
curves
1:06:56
and again,
1:06:56
we have to
1:06:57
take this
1:06:57
slide
1:06:58
a little
1:06:58
bit of
1:06:58
grain of salt
1:06:59
because the,
1:07:01
Darovasertib/Crizotinib
1:07:03
data is
1:07:03
not phase
1:07:04
three data,
1:07:05
but we're
1:07:05
trying to see
1:07:06
where
1:07:06
this falls
1:07:07
into place
1:07:07
with some
1:07:08
other phase
1:07:08
three data.
1:07:09
And I
1:07:09
would say
1:07:10
when we look
1:07:11
at this,
1:07:11
Kaplan-Meier
1:07:12
curve
1:07:13
compared to
1:07:13
some other
1:07:13
curves,
1:07:14
this gave us
1:07:15
the confidence
1:07:16
and the
1:07:16
wherewithal
1:07:17
to conduct
1:07:18
our phase
1:07:18
three trial.
1:07:20
But we do
1:07:20
see, the
1:07:21
PFS curve
1:07:22
and I think
1:07:23
the most
1:07:23
important
1:07:23
thing to
1:07:24
keep in mind
1:07:25
from
1:07:25
this slide,
1:07:25
if we look at
1:07:26
that control
1:07:27
arm where
1:07:27
the Daro in
1:07:28
the arm is.
1:07:31
So again,
1:07:32
when we
1:07:33
look at this
1:07:33
line again,
1:07:34
we're not
1:07:34
comparing
1:07:35
cross,
1:07:35
but we're just
1:07:36
taking a look
1:07:36
at
1:07:36
some numbers,
1:07:37
and we see
1:07:38
this slide
1:07:38
along
1:07:39
with the,
1:07:39
curve that
1:07:39
I just showed
1:07:40
you gave us
1:07:41
that
1:07:41
confidence
1:07:43
to move
1:07:43
forward
1:07:43
with our phase
1:07:44
three trial.
1:07:45
So when we
1:07:46
look at our,
1:07:46
potential,
1:07:47
tolerability,
1:07:48
safety,
1:07:48
something
1:07:49
that was
1:07:49
mentioned
1:07:49
before,
1:07:50
when we look
1:07:51
at our
1:07:51
grade greater
1:07:51
than or equal
1:07:53
to three,
1:07:53
AEs that we're
1:07:54
drug related.
1:07:55
About a third
1:07:55
of the
1:07:55
patients
1:07:56
in our
1:07:57
phase, one,
1:07:58
two trial,
1:07:59
when we
1:07:59
look at
1:07:59
tumor
1:08:00
shrinkage
1:08:00
with a
1:08:01
robust
1:08:01
amount of
1:08:02
tumor
1:08:02
shrinkage
1:08:03
when we
1:08:03
look at
1:08:04
ORR again,
1:08:05
frontline
1:08:05
about 45%
1:08:06
patients,
1:08:07
and some
1:08:08
had a
1:08:08
confirmed,
1:08:09
overall
1:08:09
response rate,
1:08:10
about 30%
1:08:12
had a
1:08:13
confirmed
1:08:13
overall
1:08:13
response rate.
1:08:14
Again,
1:08:14
this is by
1:08:15
our RECIST
1:08:15
1.1.
1:08:16
And when we
1:08:17
look
1:08:17
at our PFS,
1:08:18
we know about
1:08:18
seven months.
1:08:22
So what is our
1:08:23
phase
1:08:23
two three
1:08:23
trial
1:08:24
look like.
1:08:24
This trial is
1:08:25
currently
1:08:25
open,
1:08:25
currently
1:08:26
running
1:08:27
and I can say
1:08:28
we are
1:08:28
HLA restricted
1:08:30
to HLA
1:08:30
to negative
1:08:31
patients only,
1:08:32
and that's
1:08:33
because,
1:08:33
you know,
1:08:33
having good
1:08:34
therapy
1:08:35
is already
1:08:35
approved
1:08:36
for HLA2
1:08:36
positive
1:08:37
patients.
1:08:38
So this is
1:08:42
the schema
1:08:43
of our phase
1:08:44
two three
1:08:44
trial.
1:08:45
We are currently
1:08:46
in the phase
1:08:47
two portion
1:08:48
right now.
1:08:49
what we're
1:08:49
doing now
1:08:50
and because of
1:08:51
some, guidance
1:08:51
or recent
1:08:52
guidance
1:08:53
from the FDA,
1:08:54
the phase
1:08:55
two portion
1:08:55
of this trial
1:08:56
is sort
1:08:56
of divided
1:08:56
into two
1:08:57
parts, phase
1:08:57
two A
1:08:58
and phase
1:08:58
two B.
1:09:00
We're having
1:09:00
a dose
1:09:01
optimization
1:09:02
part of
1:09:02
this trial.
1:09:03
At first,
1:09:03
figure out
1:09:04
the
1:09:04
appropriate
1:09:04
dose for
1:09:05
Darovasertib
1:09:05
in combination
1:09:07
with
1:09:07
Crizotinib
1:09:07
I think
1:09:08
we have
1:09:08
an idea
1:09:08
what that dose
1:09:09
should be,
1:09:10
but in order
1:09:10
to make sure
1:09:11
that we tested
1:09:11
appropriately,
1:09:12
we're testing
1:09:13
two doses.
1:09:13
We plan
1:09:14
on having
1:09:15
a meeting
1:09:15
with our
1:09:16
independent
1:09:16
data review
1:09:17
committee
1:09:18
and that
1:09:18
meeting, in
1:09:19
a blinded
1:09:20
fashion,
1:09:20
will help
1:09:20
us determine
1:09:21
what is the
1:09:22
best dose.
1:09:23
We're looking
1:09:23
at both
1:09:23
efficacy
1:09:24
and safety
1:09:24
to do that,
1:09:25
once
1:09:26
we have confirmed
1:09:27
what our dose
1:09:28
is going
1:09:28
to be,
1:09:29
we're going
1:09:29
to continue
1:09:30
to enroll
1:09:31
patients at
1:09:31
that next
1:09:32
level
1:09:34
to
1:09:34
complete the
1:09:34
phase two
1:09:35
portion,
1:09:35
patients
1:09:36
that were at
1:09:37
a different
1:09:37
dose level
1:09:38
and will
1:09:38
then be
1:09:39
allowed to
1:09:39
move up
1:09:40
to, that
1:09:41
other dose
1:09:41
level,
1:09:42
or down,
1:09:43
and as
1:09:44
that dose
1:09:44
level
1:09:44
was chosen,
1:09:46
our goal is
1:09:47
to have
1:09:47
accelerated
1:09:48
approval
1:09:49
and rapid
1:09:49
phase
1:09:50
two portion,
1:09:50
that's
1:09:51
going to
1:09:51
be a PFS.
1:09:51
After that,
1:09:52
we are
1:09:52
simultaneously
1:09:53
enrolling
1:09:53
patients
1:09:54
in the phase
1:09:55
three portion,
1:09:56
where the
1:09:57
primary
1:09:58
endpoint
1:09:58
is going to be
1:09:59
overall
1:09:59
survival
1:10:00
and similar
1:10:01
to, Dr.
1:10:02
Correa,
1:10:03
I mentioned
1:10:03
before,
1:10:04
we do have
1:10:04
fast track
1:10:05
designation
1:10:06
for, our,
1:10:06
combination
1:10:07
with the
1:10:07
Darovasertib
1:10:08
plus
1:10:08
Crizotinib
1:10:08
in metastatic
1:10:09
uveal
1:10:09
melanoma.
1:10:12
And so this is
1:10:12
our overall,
1:10:14
clinical
1:10:14
development
1:10:14
strategy.
1:10:16
our plan
1:10:16
is to, yes,
1:10:17
move forward
1:10:18
in the
1:10:18
neoadjuvant
1:10:19
setting
1:10:20
with both,
1:10:20
HLA2 Positive
1:10:21
and HLA2
1:10:22
Negative
1:10:22
patients.
1:10:24
Yes, we
1:10:24
do have a,
1:10:25
adjuvant plan.
1:10:27
I could say,
1:10:28
Richard with
1:10:28
a big smile
1:10:29
and I'm
1:10:29
sure
1:10:29
I'll be on
1:10:30
to talk
1:10:30
with you
1:10:30
the next couple
1:10:31
of weeks.
1:10:31
But, since
1:10:32
ASCO, myself
1:10:34
and my,
1:10:34
lead
1:10:35
statistician
1:10:36
have been,
1:10:36
vigorously
1:10:37
designing,
1:10:39
a adjuvant
1:10:40
trial,
1:10:41
and over here,
1:10:41
we see what
1:10:42
we're doing
1:10:43
right now
1:10:44
in terms
1:10:44
of metastatic
1:10:46
melanoma.
1:10:46
The trial
1:10:47
that I just
1:10:47
presented,
1:10:48
data for
1:10:48
and spoke
1:10:49
about,
1:10:50
we've just
1:10:50
amended that
1:10:51
clinical
1:10:51
trial,
1:10:52
actually
1:10:52
to enroll
1:10:53
an arm
1:10:54
with an HLA2
1:10:55
Positive
1:10:56
patients.
1:10:59
And that ends
1:11:00
this portion
1:11:00
of my
1:11:00
presentation
1:11:01
We
1:11:01
are going to
1:11:02
bring on Dr.
1:11:03
Vukovic
1:11:03
from the
1:11:04
Delcath
1:11:04
Systems
1:11:05
company,
1:11:05
and they're
1:11:06
going to talk
1:11:06
a little
1:11:06
about the FDA
1:11:07
approval of
1:11:08
Hepzato kit.
1:11:08
So thank
1:11:09
you, Doctor
1:11:09
Vukovic, for
1:11:10
being here.
1:11:11
I thank you
1:11:12
very much
1:11:12
for
1:11:13
inviting me,
1:11:13
and happy
1:11:14
to be here
1:11:14
to have
1:11:15
the
1:11:15
opportunity
1:11:16
to, tell
1:11:16
a couple
1:11:17
of things
1:11:17
about,
1:11:18
Hepzato and,
1:11:19
focus trial
1:11:20
and what's
1:11:21
next.
1:11:21
So I'll start
1:11:22
by sharing
1:11:23
my screen.
1:11:24
So, again,
1:11:25
I'm going
1:11:26
to tell
1:11:26
a couple
1:11:27
of things
1:11:27
about
1:11:27
Hepzato kit,
1:11:29
and my name
1:11:30
is Voji
1:11:30
Vukovic
1:11:31
and I’m chief
1:11:31
medical
1:11:31
officer
1:11:32
at Delcath
1:11:33
Systems.
1:11:34
Doctor
1:11:35
Carlisle has
1:11:35
already kindly
1:11:36
introduced,
1:11:37
so I'm
1:11:37
going to go
1:11:38
relatively
1:11:38
quickly
1:11:39
to the
1:11:39
first couple
1:11:40
of slides.
1:11:41
The Hepzato
1:11:42
kit is
1:11:43
basically
1:11:43
a drug device
1:11:44
combination
1:11:44
and the
1:11:45
relatively
1:11:46
complex schema
1:11:47
shown here
1:11:48
on the right
1:11:49
shows
1:11:49
it's really
1:11:49
essentially
1:11:50
a system
1:11:51
of catheters
1:11:52
that's
1:11:52
inserted into
1:11:53
the patient's
1:11:53
blood vessels
1:11:54
to isolate
1:11:56
the
1:11:56
circulation
1:11:57
and deliver
1:11:58
and, to allow
1:12:00
for high dose
1:12:01
chemotherapy
1:12:01
to be
1:12:02
administered
1:12:03
just
1:12:04
to the liver.
1:12:05
And then
1:12:06
the blood
1:12:06
that flows
1:12:07
out of the
1:12:07
liver
1:12:08
is isolated
1:12:10
and, taken
1:12:11
to
1:12:11
extracorporeal
1:12:12
circuit
1:12:13
to filters,
1:12:14
which remove
1:12:15
close to 90%
1:12:16
of the chemo
1:12:17
that was
1:12:17
given, meaning
1:12:19
we are
1:12:19
achieving,
1:12:20
regional
1:12:21
focused
1:12:22
high dose
1:12:23
chemotherapy
1:12:23
of the liver,
1:12:24
which of
1:12:25
course,
1:12:25
in patients
1:12:26
with
1:12:26
metastatic
1:12:27
melanoma is of
1:12:28
extreme
1:12:28
importance
1:12:29
because 90%
1:12:30
of patients
1:12:31
with
1:12:31
metastatic
1:12:31
disease
1:12:32
will have
1:12:32
liver lesions
1:12:34
and actually
1:12:34
half of,
1:12:36
but
1:12:36
essentially
1:12:37
all melanoma
1:12:37
patients
1:12:38
have liver
1:12:38
lesions only.
1:12:40
And,
1:12:40
unfortunately,
1:12:41
most of
1:12:42
the patients
1:12:42
will succumb
1:12:43
to
1:12:43
the disease,
1:12:44
do so
1:12:45
because of
1:12:45
progression
1:12:46
to liver
1:12:46
that cannot
1:12:47
be controlled
1:12:47
with
1:12:47
systemic therapy
1:12:49
and that is
1:12:49
the reason why
1:12:50
local regional
1:12:51
therapies,
1:12:52
such as
1:12:53
percutaneous
1:12:54
hepatic
1:12:54
perfusion,
1:12:56
which is
1:12:57
basically
1:12:57
enabled
1:12:58
with the
1:12:58
Hepzato kit,
1:12:59
the other
1:13:00
component of
1:13:00
the kit
1:13:01
is the drug
1:13:01
Melphalan.
1:13:02
It's an
1:13:02
old drug.
1:13:03
It's actually
1:13:04
older by
1:13:05
about
1:13:05
two years,
1:13:06
and that's
1:13:06
something.
1:13:07
but old
1:13:07
doesn't
1:13:08
mean bad.
1:13:08
The reason
1:13:09
why all drugs,
1:13:11
chemotherapy
1:13:11
is banned
1:13:12
in favor of,
1:13:13
modern drugs
1:13:14
and new
1:13:14
therapies,
1:13:14
is that
1:13:15
not the
1:13:16
lack of
1:13:16
efficacy.
1:13:17
Chemotherapy
1:13:18
is a very
1:13:18
efficacious
1:13:20
problem,
1:13:20
is toxicity
1:13:21
and toxicity
1:13:22
means
1:13:23
that you're
1:13:23
not only
1:13:23
hitting
1:13:24
the tumor,
1:13:24
which is the
1:13:25
desired
1:13:25
effect,
1:13:26
but
1:13:26
unfortunately,
1:13:27
chemotherapy
1:13:28
being given
1:13:28
systemically
1:13:29
will also,
1:13:31
hit, targets
1:13:33
such as
1:13:33
our organs,
1:13:35
blood vessels
1:13:36
and the
1:13:36
whole body.
1:13:37
Basically,
1:13:37
it's
1:13:37
making the
1:13:37
patients sick.
1:13:39
So if you
1:13:39
had a
1:13:40
means of
1:13:40
delivering
1:13:41
high dose
1:13:41
chemotherapy
1:13:42
specifically
1:13:43
to the
1:13:43
tumor site
1:13:44
without
1:13:44
damaging
1:13:45
too much,
1:13:45
the rest
1:13:46
of the body,
1:13:46
chemotherapy
1:13:47
could really
1:13:48
be quite
1:13:48
effective
1:13:49
and that's
1:13:50
what I'm going
1:13:50
to show
1:13:51
you in
1:13:52
the next
1:13:52
slides.
1:13:53
So
1:13:55
the,
1:13:56
Hepzato kit
1:13:57
is utilized
1:13:58
with a team
1:13:58
of specialists
1:13:59
on the left.
1:14:00
You see,
1:14:01
the team
1:14:01
of specialists
1:14:02
is conducting
1:14:02
the procedure,
1:14:04
PHP or Hepatic
1:14:05
Perfusion
1:14:05
Procedure,
1:14:06
which is
1:14:07
led by
1:14:07
an
1:14:07
interventional
1:14:08
radiologist,
1:14:09
the
1:14:09
anesthesiologist,
1:14:10
and
1:14:10
perfusionist,
1:14:11
and in
1:14:12
addition
1:14:12
to that,
1:14:13
of course,
1:14:13
is the
1:14:13
treatment team
1:14:15
led by
1:14:15
the oncologist
1:14:16
and other
1:14:16
people
1:14:17
who help,
1:14:19
prepare, treat
1:14:20
and manage
1:14:21
to the patient
1:14:22
and then
1:14:22
also manage,
1:14:23
the patient
1:14:24
between
1:14:24
treatments
1:14:25
with Hepzato
1:14:26
kit.
1:14:28
The three
1:14:28
steps of
1:14:29
the procedure
1:14:29
are the
1:14:30
isolation,
1:14:31
followed
1:14:32
by a local
1:14:32
administration
1:14:33
of the high
1:14:34
dose chemo
1:14:35
and then
1:14:35
finally
1:14:36
filtration
1:14:36
to remove,
1:14:38
the vast
1:14:39
majority
1:14:39
of the chemo
1:14:41
so that the
1:14:41
systemic
1:14:42
circulation
1:14:43
receives
1:14:43
only ten, 15%
1:14:45
of the
1:14:45
administered
1:14:46
dose.
1:14:49
The product
1:14:50
was approved
1:14:51
by the FDA
1:14:52
in August 23,
1:14:54
as mentioned
1:14:55
earlier,
1:14:55
by Dr.
1:14:56
Carvajal
1:14:57
And the
1:14:58
rationale,
1:14:59
the basis for
1:15:00
the approval
1:15:01
was the
1:15:01
pivotal
1:15:01
focus trial,
1:15:03
which was
1:15:03
published,
1:15:04
and you see
1:15:04
the reference,
1:15:05
publication
1:15:06
below.
1:15:08
And,
1:15:10
the history
1:15:11
of the trial,
1:15:12
it was
1:15:12
designed
1:15:12
originally
1:15:13
as a phase
1:15:13
three,
1:15:14
randomized,
1:15:15
multicenter,
1:15:15
prospective,
1:15:16
trial,
1:15:17
where patients
1:15:18
would be
1:15:18
randomized
1:15:19
to receive
1:15:19
treatment
1:15:20
with,
1:15:20
the
1:15:21
Melphalan/HDS
1:15:22
or Hepzato kit
1:15:23
or the best
1:15:24
available care
1:15:25
investigator
1:15:26
choice,
1:15:26
which included
1:15:27
another
1:15:28
regional
1:15:28
therapy called
1:15:29
TACE/Pembrolizumab,
1:15:29
Ipilimumab, or
1:15:31
Dacarbazine.
1:15:33
About 85
1:15:34
patients
1:15:35
into the trial,
1:15:36
we noticed
1:15:36
a significant
1:15:37
slowdown
1:15:38
in the
1:15:38
treatment,
1:15:39
because,
1:15:40
patients
1:15:40
who were
1:15:41
randomized
1:15:41
to the
1:15:42
control arm
1:15:42
started,
1:15:44
withdrawing
1:15:45
consent
1:15:46
to that level
1:15:47
that
1:15:47
jeopardized
1:15:48
the
1:15:48
randomization
1:15:49
and the
1:15:49
statistical
1:15:50
design.
1:15:50
So we met
1:15:51
with the FDA,
1:15:51
discussed
1:15:52
with them
1:15:52
the problem,
1:15:53
and the
1:15:53
FDA proposed
1:15:54
that we amend
1:15:55
the protocol
1:15:55
to make it
1:15:56
a one
1:15:57
arm trial,
1:15:58
single
1:15:58
on trial
1:15:58
to drop the
1:15:59
control arm,
1:16:00
because
1:16:00
otherwise
1:16:01
the integrity
1:16:01
of the
1:16:01
trial couldn’t
1:16:02
be preserved.
1:16:02
So that,
1:16:03
happened
1:16:03
with
1:16:04
amendment,
1:16:05
and the study
1:16:05
has been
1:16:06
completed
1:16:06
as a
1:16:06
single arm
1:16:07
study
1:16:08
where all
1:16:09
enrolled
1:16:09
patients
1:16:10
with the
1:16:10
receive
1:16:10
the treatment
1:16:11
with
1:16:11
Melphalan/HDS
1:16:13
and the
1:16:14
treatment
1:16:14
cycles are
1:16:15
administered
1:16:15
typically 6
1:16:16
to 8 weeks
1:16:17
apart.
1:16:20
Inclusion
1:16:21
criteria,
1:16:22
basically,
1:16:24
as for
1:16:25
the extent
1:16:25
of disease,
1:16:26
both patients
1:16:27
with liver
1:16:28
only and
1:16:28
extrahepatic
1:16:29
disease
1:16:29
as well.
1:16:30
The eligible
1:16:31
is support
1:16:32
when 50%
1:16:32
or less of
1:16:33
the liver
1:16:34
be occupied
1:16:34
by the tumors
1:16:35
to be
1:16:36
measurable,
1:16:37
and patients
1:16:37
have to be,
1:16:38
in good
1:16:38
perform
1:16:39
status.
1:16:40
If the liver,
1:16:41
was
1:16:41
compromised
1:16:42
by cirrhosis
1:16:43
or portal
1:16:44
hypertension,
1:16:44
that was the
1:16:45
exclusion
1:16:46
criteria,
1:16:47
and because
1:16:47
the procedure
1:16:48
is conducted
1:16:49
under general
1:16:49
anesthesia,
1:16:50
the patients
1:16:50
have to be
1:16:51
fit enough
1:16:51
to be able
1:16:52
to, undergo
1:16:53
general
1:16:54
anesthesia
1:16:54
procedure,
1:16:56
and patients
1:16:56
will,
1:16:57
on
1:16:58
immunosuppressant
1:16:58
drugs
1:16:58
for infections
1:16:59
were not
1:17:00
eligible
1:17:00
because
1:17:01
Melphalan
1:17:02
would suppress
1:17:03
the bone
1:17:03
marrow
1:17:03
and make
1:17:04
patients
1:17:04
more likely to
1:17:05
experience
1:17:05
infections.
1:17:09
So, the
1:17:09
primary
1:17:10
endpoint of
1:17:11
the study was,
1:17:12
response
1:17:12
rate
1:17:12
confirmed,
1:17:13
independently
1:17:14
reviewed,
1:17:15
a
1:17:15
response rate
1:17:16
and a
1:17:17
historical
1:17:17
control,
1:17:18
requested by
1:17:19
the FDA.
1:17:20
was a meta
1:17:21
analysis
1:17:22
of
1:17:22
contemporary,
1:17:23
trials
1:17:24
where
1:17:24
immunotherapy,
1:17:25
ipilimumab,
1:17:26
nivolumab
1:17:27
or the
1:17:27
combination
1:17:27
thereof, was,
1:17:29
used to treat
1:17:30
patients with
1:17:30
metastatic
1:17:31
disease
1:17:32
based on the
1:17:32
meta analysis
1:17:33
results,
1:17:34
the response
1:17:35
rate in the
1:17:35
historical
1:17:36
control was 5%
1:17:37
approximately.
1:17:39
And response
1:17:39
rate in
1:17:40
the focused
1:17:40
trial was 36,
1:17:41
which was,
1:17:42
highly
1:17:42
statistically
1:17:43
significant.
1:17:44
Equally
1:17:45
important
1:17:45
is not just
1:17:46
the large
1:17:47
number
1:17:47
of patients
1:17:47
who responded
1:17:48
to the
1:17:48
treatment.
1:17:49
It's actually
1:17:50
the duration
1:17:50
of response.
1:17:52
The median
1:17:52
duration was
1:17:53
14 months,
1:17:54
which is,
1:17:55
depending on
1:17:55
which trial
1:17:56
you look at
1:17:56
between 3
1:17:57
and 5
1:17:57
times longer
1:17:58
than what
1:17:59
you typically
1:18:00
see acceptable
1:18:00
long term
1:18:01
survivors, in
1:18:02
the therapy.
1:18:05
Here's the
1:18:06
complete
1:18:07
data set.
1:18:08
What is
1:18:08
probably,
1:18:09
very
1:18:10
interesting
1:18:10
for this
1:18:10
group,
1:18:11
all these
1:18:12
patients,
1:18:12
both treatment
1:18:13
naive and,
1:18:14
treated
1:18:15
patients,
1:18:16
we saw
1:18:17
some
1:18:17
responders,
1:18:19
patients
1:18:19
who had
1:18:20
complete
1:18:20
response,
1:18:21
and I'll
1:18:22
show you
1:18:22
in graph
1:18:22
in a moment
1:18:24
that,
1:18:24
and actually,
1:18:24
whether what
1:18:25
I call
1:18:25
the right away
1:18:27
on the
1:18:27
vertical plot,
1:18:28
you see that
1:18:29
the majority
1:18:30
of the
1:18:30
patients
1:18:30
respond
1:18:31
with the tumor
1:18:31
shrinkage,
1:18:33
but when you
1:18:33
look to
1:18:34
the far right,
1:18:35
you see that,
1:18:36
total patients
1:18:36
have a
1:18:37
complete
1:18:37
disappearance
1:18:37
of the
1:18:38
target
1:18:38
lesions,
1:18:39
seven of
1:18:39
which
1:18:40
were
1:18:40
classified
1:18:40
as CR,
1:18:41
that means
1:18:41
there was
1:18:41
no tumor
1:18:42
left in
1:18:42
the body,
1:18:43
and five were
1:18:44
not classified
1:18:44
as CR, meaning
1:18:46
it was
1:18:46
still extra
1:18:47
disease
1:18:47
leftover.
1:18:48
That really
1:18:49
says a lot
1:18:51
about
1:18:51
the efficacy
1:18:52
of the
1:18:52
treatment in
1:18:52
the liver.
1:18:54
but what's
1:18:55
really also
1:18:55
very important
1:18:56
is on the
1:18:56
previous
1:18:57
slide,
1:18:57
I will just
1:18:57
go back to
1:18:58
for a moment,
1:18:59
is the disease
1:19:00
control rate
1:19:00
so close
1:19:01
to 74%
1:19:03
of patients
1:19:04
achieved
1:19:05
disease
1:19:05
control,
1:19:07
which is,
1:19:07
as Dr.
1:19:08
Cole mentioned
1:19:08
previously, is
1:19:09
really
1:19:10
important.
1:19:10
The
1:19:11
controlling
1:19:12
the disease,
1:19:13
having
1:19:13
a potential
1:19:14
prolonged
1:19:14
life is really
1:19:15
what you're
1:19:15
trying
1:19:16
to accomplish
1:19:17
in this,
1:19:17
setting,
1:19:18
in the
1:19:18
setting of
1:19:18
metastatic
1:19:19
disease.
1:19:21
So that's the
1:19:22
efficacy data.
1:19:24
In addition
1:19:24
to that,
1:19:24
I'm showing
1:19:25
you also
1:19:25
progression
1:19:26
free survival,
1:19:27
which is
1:19:27
nine months,
1:19:28
which is
1:19:29
I think,
1:19:30
very,
1:19:31
very good.
1:19:31
I don't know
1:19:32
of any
1:19:32
published data
1:19:33
that shows
1:19:34
longer PFS
1:19:35
in metastatic
1:19:36
uveal
1:19:36
melanoma.
1:19:37
The overall
1:19:38
survival is
1:19:39
also,
1:19:40
very
1:19:40
encouraging,
1:19:40
more than
1:19:41
20 months.
1:19:42
Obviously,
1:19:42
the limitations
1:19:43
are that
1:19:44
this is not a
1:19:44
randomized trial.
1:19:45
So
1:19:46
we cannot make
1:19:46
definitive
1:19:47
statements,
1:19:47
but it's
1:19:48
encouraging
1:19:49
to see,
1:19:50
both
1:19:50
progression
1:19:51
free survival
1:19:51
and overall
1:19:52
survival,
1:19:53
trending in
1:19:54
the right
1:19:54
direction.
1:19:58
Here's
1:19:59
a safety
1:19:59
summary, and
1:20:00
I'll show you
1:20:00
a more
1:20:01
detailed slide
1:20:02
as well.
1:20:03
In the focus
1:20:04
trial,
1:20:05
the median
1:20:05
number of
1:20:06
treatment
1:20:06
cycles
1:20:07
was four.
1:20:08
We planned
1:20:08
up to six
1:20:09
treatment
1:20:09
cycles,
1:20:10
And about
1:20:10
37% of
1:20:11
patients
1:20:12
completed
1:20:13
all six
1:20:13
treatment
1:20:13
cycles.
1:20:15
We didn't
1:20:15
record
1:20:15
any deaths
1:20:16
related to
1:20:17
study
1:20:17
treatments,
1:20:18
which is
1:20:18
very
1:20:18
important,
1:20:19
because,
1:20:20
the previous
1:20:21
method used
1:20:21
to deliver
1:20:22
high dose
1:20:23
chemotherapy
1:20:23
for the liver,
1:20:24
called IHP
1:20:26
or isolated
1:20:26
hepatic
1:20:27
perfusion,
1:20:28
had a
1:20:28
mortality rate
1:20:29
about
1:20:29
5%
1:20:30
historically.
1:20:31
Obviously,
1:20:32
PHP is
1:20:32
a less
1:20:33
invasive,
1:20:33
repeatable
1:20:34
procedure,
1:20:35
and it's
1:20:36
better
1:20:36
tolerated.
1:20:37
Approximately
1:20:38
41% of
1:20:39
patients
1:20:39
had serious
1:20:40
adverse
1:20:40
events,
1:20:40
which is,
1:20:41
very typical
1:20:42
for pivotal
1:20:43
studies
1:20:44
in advanced
1:20:45
metastatic
1:20:45
disease.
1:20:46
Typically,
1:20:47
patients,
1:20:48
we put around
1:20:50
40 to 50% SAE,
1:20:51
so
1:20:51
this is in
1:20:52
line with
1:20:54
other phase
1:20:54
two trials.
1:20:56
The
1:20:56
predominant
1:20:56
toxicity
1:20:57
experienced
1:20:58
by patients
1:20:58
with transient
1:20:59
non-cumulative
1:21:00
hematological
1:21:01
toxicities.
1:21:01
Melphalan,
1:21:03
is a drug
1:21:03
that will
1:21:04
suppress the
1:21:04
bone marrow.
1:21:05
And although
1:21:05
we are able
1:21:06
to filter out,
1:21:07
more than 80%
1:21:08
to 90% of
1:21:09
the
1:21:09
administered
1:21:10
Melphalan,
1:21:10
there's
1:21:10
still some
1:21:11
residual
1:21:11
Melphalan
1:21:12
which is
1:21:12
causing this
1:21:13
transient,
1:21:14
non-cumulative
1:21:15
hematological
1:21:15
toxicity.
1:21:16
However,
1:21:17
hematological
1:21:17
toxicity
1:21:18
is something
1:21:18
that, doctors
1:21:20
are very
1:21:20
experienced
1:21:21
with managing
1:21:22
and it
1:21:23
responds
1:21:23
well to
1:21:23
standard,
1:21:24
supportive
1:21:24
care therapy.
1:21:26
80% of
1:21:27
patients had
1:21:27
AE that led
1:21:28
to treatment
1:21:28
discontinuation,
1:21:31
but this
1:21:31
is again,
1:21:32
it's very
1:21:32
strict
1:21:33
definition,
1:21:33
so all
1:21:34
the patients
1:21:35
who
1:21:35
discontinue
1:21:35
due to AE,
1:21:37
were planned
1:21:38
to receive
1:21:39
six treatment.
1:21:40
So that's
1:21:40
why the rate
1:21:41
is a
1:21:41
little bit
1:21:41
higher
1:21:42
than what
1:21:42
you would
1:21:42
normally
1:21:42
expect.
1:21:44
And, what's
1:21:45
important,
1:21:46
although
1:21:46
we give
1:21:47
the treatment
1:21:47
directly
1:21:47
to the liver,
1:21:48
people
1:21:48
ask, well,
1:21:49
is this
1:21:49
high dose
1:21:50
chemotherapy
1:21:50
toxic
1:21:51
to the liver?
1:21:51
And the answer
1:21:52
is no
1:21:53
because less
1:21:53
than 10%
1:21:54
of patients
1:21:54
experienced
1:21:55
transient
1:21:55
Grade 3/4
1:21:56
liver AEs,
1:21:57
which were
1:21:57
predominantly,
1:21:59
increases in
1:22:00
liver
1:22:00
transformations,
1:22:01
enzymes that,
1:22:03
indicate
1:22:03
potential
1:22:04
damage
1:22:04
to the liver.
1:22:08
In terms
1:22:08
of specific,
1:22:11
treatment,
1:22:11
emergent
1:22:12
serious
1:22:12
adverse events
1:22:13
and events,
1:22:14
related
1:22:15
and unrelated
1:22:16
to the
1:22:17
treatment,
1:22:18
you can see
1:22:19
here on
1:22:19
the left,
1:22:20
the table,
1:22:21
Thrombocytopenia,
1:22:22
Neutropenia,
1:22:23
Leukopenia,
1:22:24
are events
1:22:25
that happened,
1:22:26
most
1:22:26
frequently,
1:22:27
we had
1:22:27
three patients
1:22:28
with cardiac
1:22:29
arrest,
1:22:30
none of them
1:22:30
fatal and none
1:22:31
of them
1:22:32
related
1:22:32
treatment.
1:22:34
Some of
1:22:34
the side
1:22:35
effects
1:22:36
happened
1:22:36
during the
1:22:36
treatment.
1:22:37
For example,
1:22:38
Hypoxia,
1:22:38
Pulmonary
1:22:39
Edema,
1:22:40
because
1:22:40
you have
1:22:40
to remember,
1:22:41
these are
1:22:41
patients
1:22:42
who are,
1:22:42
in general
1:22:43
anesthesia,
1:22:43
and hypoxia,
1:22:44
pulmonary
1:22:45
edema happens
1:22:46
in a small
1:22:46
percent of
1:22:47
patients,
1:22:48
and it's
1:22:48
related to the
1:22:49
anesthesia
1:22:50
procedure.
1:22:51
And, then
1:22:52
after the
1:22:52
procedure at
1:22:53
the bottom
1:22:54
right table,
1:22:54
you see again,
1:22:56
the mostly
1:22:57
hematological
1:22:58
toxicity,
1:22:59
as previously
1:22:59
mentioned.
1:23:02
So that's
1:23:03
the focus
1:23:03
trial
1:23:04
and people ask
1:23:05
the question,
1:23:06
okay,
1:23:06
what's next?
1:23:07
What's next
1:23:08
for Hepzato
1:23:08
kit patients
1:23:09
with uveal
1:23:10
melanoma
1:23:11
and, we,
1:23:12
do have plans.
1:23:13
I think,
1:23:15
the
1:23:15
most imminent,
1:23:16
projects
1:23:17
that we're
1:23:17
currently
1:23:17
working on
1:23:18
are
1:23:18
combinations
1:23:19
with
1:23:19
immunotherapies
1:23:21
in patients
1:23:21
with
1:23:21
metastatic
1:23:22
disease.
1:23:23
combining
1:23:24
chemo with,
1:23:25
immunotherapy
1:23:26
has proven
1:23:27
very
1:23:27
successful
1:23:28
in many
1:23:29
solid tumors.
1:23:30
So,
1:23:30
we were hoping
1:23:32
to see,
1:23:33
similar effect
1:23:34
in patients
1:23:35
with
1:23:35
metastatic
1:23:36
melanoma
1:23:36
and I'll
1:23:36
show you
1:23:37
1 or 2 slides,
1:23:38
how this is,
1:23:39
shaping up.
1:23:41
And then,
1:23:41
again,
1:23:42
as mentioned
1:23:42
by Doctor
1:23:43
Carvajal
1:23:43
earlier,
1:23:44
we're also
1:23:45
interested in
1:23:46
looking at
1:23:46
the efficacy
1:23:47
of the
1:23:47
treatment
1:23:48
in patients
1:23:49
with high risk
1:23:50
metastatic
1:23:51
disease
1:23:51
profile,
1:23:51
meaning
1:23:52
patients
1:23:53
were
1:23:53
successfully
1:23:54
treated
1:23:54
for the
1:23:55
primary tumor
1:23:56
but
1:23:56
unfortunately
1:23:57
have a high
1:23:57
risk of
1:23:58
metastatic
1:23:58
disease.
1:24:00
There's lots
1:24:00
of trials
1:24:00
underway,
1:24:01
and we believe
1:24:02
that treatment
1:24:04
with Hepzato
1:24:04
kit,
1:24:05
has a really
1:24:07
high potential
1:24:08
to mitigate
1:24:10
the risk of
1:24:10
metastasis.
1:24:12
And,
1:24:13
we are
1:24:13
discussing
1:24:14
some
1:24:14
proposals,
1:24:15
about
1:24:15
launching
1:24:16
such studies,
1:24:16
but that's
1:24:16
something
1:24:17
we'll probably
1:24:17
discuss
1:24:18
next time
1:24:19
in a forum
1:24:19
like this.
1:24:20
But
1:24:21
in the meantime,
1:24:21
for
1:24:22
conclusion,
1:24:22
let me show
1:24:23
you how
1:24:24
the
1:24:24
combination
1:24:24
therapies,
1:24:25
may look
1:24:26
like,
1:24:27
in patients
1:24:27
with
1:24:27
metastatic
1:24:28
disease.
1:24:29
Study called
1:24:30
the CHOPIN
1:24:31
Trial
1:24:32
was initiated
1:24:32
in the
1:24:33
Netherlands
1:24:33
about
1:24:34
four years ago
1:24:35
as a phase 1b
1:24:37
phase
1:24:37
two study.
1:24:38
Currently,
1:24:39
the phase two
1:24:39
is completing
1:24:40
enrollment,
1:24:41
and we
1:24:41
expect
1:24:41
the results
1:24:42
from the phase
1:24:43
two randomized
1:24:43
trial
1:24:44
to be
1:24:44
available
1:24:45
sometime
1:24:45
next year.
1:24:47
But,
1:24:47
what was
1:24:48
published
1:24:48
about
1:24:48
two years
1:24:49
ago,
1:24:49
are results
1:24:49
from the
1:24:50
phase 1b,
1:24:51
the dose
1:24:52
finding part
1:24:52
because PHP
1:24:54
or Hepzato
1:24:55
kit
1:24:55
was combined
1:24:57
with
1:24:57
ipilimumab
1:24:58
and nivolumab,
1:24:59
the two
1:25:00
most effective
1:25:01
checkpoint
1:25:01
inhibitors
1:25:02
thus far.
1:25:04
And you
1:25:05
see here
1:25:06
the spider
1:25:06
plot basically
1:25:07
how the
1:25:07
tumor size
1:25:09
changes
1:25:09
following
1:25:10
the treatment.
1:25:11
It's very
1:25:11
encouraging
1:25:12
to see that
1:25:14
the vast
1:25:14
majority,
1:25:15
although it's
1:25:15
a small number
1:25:15
of patients.
1:25:16
So with
1:25:16
some patients,
1:25:17
we see
1:25:18
definitely,
1:25:19
very
1:25:19
encouraging
1:25:20
signs of
1:25:20
tumor
1:25:20
shrinkage.
1:25:22
And on
1:25:22
the next
1:25:23
slide,
1:25:25
we see
1:25:26
a very
1:25:27
interesting,
1:25:27
intriguing
1:25:28
signal of
1:25:28
efficacy
1:25:29
and response
1:25:30
rates.
1:25:30
You know,
1:25:31
very high,
1:25:32
as shown here.
1:25:33
Again,
1:25:33
a caution,
1:25:34
this is a
1:25:34
small number
1:25:34
of patients,
1:25:35
only seven
1:25:35
patients
1:25:36
and the
1:25:36
larger trial
1:25:37
that is
1:25:37
currently
1:25:37
completing
1:25:38
enrollment,
1:25:39
will hopefully
1:25:39
provide
1:25:40
a much
1:25:40
more
1:25:40
conclusive
1:25:41
data set.
1:25:42
What is also
1:25:43
very
1:25:43
intriguing,
1:25:44
it's shown
1:25:44
in the table
1:25:45
on the right.
1:25:45
And that's
1:25:46
the
1:25:46
progression
1:25:46
free survival.
1:25:48
If you recall,
1:25:48
if you use
1:25:49
systemic
1:25:49
treatments,
1:25:50
typically
1:25:50
you'll see
1:25:51
three months
1:25:51
progression
1:25:51
free survival
1:25:53
or maybe
1:25:53
with some
1:25:53
of the
1:25:54
novel drugs
1:25:54
like the
1:25:55
IDEAYA drug,
1:25:56
maybe
1:25:56
seven months.
1:25:57
Here
1:25:57
we have seen,
1:25:58
in this
1:25:59
very small
1:26:00
initial trial,
1:26:00
29 months,
1:26:02
again,
1:26:02
this is
1:26:03
just something
1:26:04
to, intrigue
1:26:07
our curiosity
1:26:08
and then
1:26:09
really
1:26:09
make us,
1:26:12
wait for the
1:26:13
randomized
1:26:14
system data,
1:26:14
which will be
1:26:15
available
1:26:15
next year.
1:26:16
So that's,
1:26:17
all the,
1:26:19
technical sets
1:26:20
that I had
1:26:20
here,
1:26:21
then I
1:26:21
thank you
1:26:21
very much.
1:26:22
thanks to
1:26:23
the audience.
1:26:23
Thank you, Dr.
1:26:24
Vukovic!
1:26:25
So you guys
1:26:25
have
1:26:25
questions,
1:26:25
please drop
1:26:26
them in
1:26:26
the Q&A
1:26:26
and we'll
1:26:27
get to them
1:26:27
after
1:26:27
our final
1:26:28
presenter.
1:26:29
I'm going
1:26:29
to go ahead
1:26:29
and bring on
1:26:30
our next
1:26:30
speaker
1:26:30
from Replimune
1:26:31
to talk about
1:26:32
their, data
1:26:33
that was
1:26:33
presented
1:26:34
at ASCO
1:26:34
this year.
1:26:35
Dr.
1:26:36
Olsson-Brown,
1:26:36
thank you
1:26:36
so much
1:26:37
for being
1:26:37
with us.
1:26:39
Thank you
1:26:39
so much
1:26:39
for
1:26:39
the invite.
1:26:40
I'll just
1:26:40
share
1:26:40
my screen.
1:26:45
So, as I said
1:26:46
thank you
1:26:46
so much
1:26:46
for the invite
1:26:47
time there.
1:26:48
I’m Anna
1:26:49
Olsson-Brown,
1:26:49
I'm
1:26:49
a oncologist,
1:26:50
medical
1:26:50
oncologist
1:26:50
based in
1:26:51
the UK.
1:26:52
I'm working
1:26:52
directly on
1:26:54
a number
1:26:54
of that,
1:26:55
that oncolytic
1:26:55
virus therapy.
1:26:56
So I'm just
1:26:56
going to give
1:26:56
a little bit
1:26:57
of background
1:26:57
around
1:26:58
oncolytic
1:26:58
viruses
1:26:59
in general,
1:27:00
and then,
1:27:00
talk about
1:27:01
a study
1:27:02
that was
1:27:02
presented at
1:27:03
ASCO this
1:27:03
year.
1:27:11
Here’s my
1:27:11
disclosures.
1:27:13
So obviously,
1:27:14
throughout
1:27:14
this entire
1:27:15
and really,
1:27:15
frankly
1:27:16
amazing,
1:27:17
webinar,
1:27:17
we've heard
1:27:17
about all
1:27:18
different
1:27:18
types
1:27:18
of therapeutic
1:27:19
approaches
1:27:20
to managing
1:27:20
ocular
1:27:21
uveal
1:27:21
melanoma,
1:27:23
and I think
1:27:23
one of
1:27:23
the things
1:27:24
that's one
1:27:24
was really
1:27:24
important
1:27:25
is that
1:27:25
we understand
1:27:26
and have this
1:27:27
sort of
1:27:27
moment
1:27:28
of reflection
1:27:28
on how quickly
1:27:29
this field
1:27:30
has expanded,
1:27:30
particularly
1:27:31
thinking about
1:27:32
how we sort
1:27:32
of diversify
1:27:33
and, harness
1:27:34
the power of
1:27:34
the immune
1:27:35
system
1:27:36
to try
1:27:36
and treat
1:27:37
in the,
1:27:37
as we've
1:27:38
heard,
1:27:38
the
1:27:38
neoadjuvant,
1:27:39
adjuvant,
1:27:39
and metastatic
1:27:40
setting
1:27:41
and oncology
1:27:41
viruses
1:27:42
are one of
1:27:42
those
1:27:42
subgroups
1:27:43
of therapies
1:27:44
that we
1:27:44
are working
1:27:44
very heavily
1:27:45
on to try
1:27:46
and understand
1:27:47
where
1:27:47
they might
1:27:47
have a role
1:27:48
in the
1:27:49
management of,
1:27:50
multiple
1:27:50
different
1:27:50
malignancies.
1:27:51
That actually
1:27:52
includes uveal
1:27:53
melanoma
1:27:54
and when we
1:27:55
think about
1:27:55
how all kinds
1:27:56
of viruses
1:27:57
work,
1:27:58
essentially
1:27:58
they
1:27:58
actually do
1:27:59
a number
1:27:59
of things.
1:28:00
So, the virus
1:28:02
I'm going to
1:28:02
talk about
1:28:03
is called
1:28:03
the virus.
1:28:05
but it's
1:28:05
based on
1:28:06
the principle
1:28:06
that,
1:28:07
oncology
1:28:07
viruses
1:28:08
can infect,
1:28:10
malignant
1:28:10
cells
1:28:10
and cause
1:28:11
direct,
1:28:12
cellular
1:28:12
destruction.
1:28:13
But also that
1:28:14
leads to a
1:28:15
series of,
1:28:16
of the
1:28:17
downstream
1:28:17
events,
1:28:18
which
1:28:18
essentially
1:28:19
leads
1:28:19
to recruitment
1:28:20
and efficacy
1:28:21
of, T cells,
1:28:23
probably
1:28:24
amongst
1:28:25
the
1:28:25
immune cells
1:28:26
that we can
1:28:26
also cause,
1:28:27
at optimal
1:28:29
recruitment
1:28:29
by the,
1:28:30
by the
1:28:30
introduction
1:28:31
of, of an
1:28:32
all kinds
1:28:32
of virus
1:28:33
generally
1:28:33
speaking,
1:28:34
at the moment
1:28:34
and certainly
1:28:34
the virus I'm
1:28:35
going to talk
1:28:35
about
1:28:35
is directed
1:28:36
that is directly
1:28:37
injected into
1:28:38
a area
1:28:39
of tumor.
1:28:40
and it causes
1:28:41
these
1:28:41
localized
1:28:42
effects
1:28:43
and certainly
1:28:44
the,
1:28:44
the viruses
1:28:45
that we've
1:28:45
been working
1:28:46
on have
1:28:46
been used
1:28:47
in combination
1:28:48
with
1:28:48
checkpoint
1:28:48
inhibitors
1:28:49
in the aim
1:28:50
to optimize
1:28:50
our immune
1:28:51
response.
1:28:51
So, the virus
1:28:52
sort of allows
1:28:53
direct effects
1:28:54
on the
1:28:54
tumor cells,
1:28:55
but also
1:28:55
T-cell
1:28:56
recruitment
1:28:57
with the
1:28:57
principle
1:28:57
that if we add
1:28:58
a checkpoint
1:28:58
inhibitor,
1:28:59
we actually
1:28:59
have an
1:29:00
upregulated,
1:29:02
a much less,
1:29:02
inhibited,
1:29:04
t cell that
1:29:05
that arrives
1:29:06
and is much
1:29:07
more able
1:29:07
to be
1:29:08
efficacious
1:29:09
in the,
1:29:09
in the
1:29:09
tumor
1:29:09
microenvironment.
1:29:11
So there are
1:29:11
multiple
1:29:12
different,
1:29:13
downstream
1:29:13
effects
1:29:14
of the
1:29:14
oncolytic
1:29:14
virus
1:29:15
as well as the
1:29:16
sort of
1:29:16
the viral,
1:29:17
the viral
1:29:17
effect
1:29:18
itself,
1:29:19
which is
1:29:19
quite,
1:29:20
quite amazing.
1:29:20
And,
1:29:21
this has
1:29:21
been trialed
1:29:22
in a number
1:29:22
of different,
1:29:23
settings
1:29:24
so far
1:29:24
in this
1:29:24
direction.
1:29:25
Recognition
1:29:25
looking at
1:29:26
using the Aki
1:29:26
one virus,
1:29:27
which
1:29:27
showed that
1:29:28
it was
1:29:28
very,
1:29:28
very, useful
1:29:30
in the
1:29:30
setting of
1:29:32
Pt one failed
1:29:33
treated
1:29:34
cutaneous
1:29:34
rendering
1:29:35
when we saw
1:29:36
so many
1:29:36
promising
1:29:37
signs
1:29:37
of efficacy.
1:29:39
and so
1:29:39
the question
1:29:39
was, could we,
1:29:40
could we
1:29:41
put that
1:29:41
some
1:29:41
introduced
1:29:42
into,
1:29:42
you know,
1:29:42
melanoma.
1:29:43
So as we've
1:29:44
talked about,
1:29:45
throughout
1:29:45
the day,
1:29:46
the kind
1:29:46
of the
1:29:46
complexities
1:29:47
of the
1:29:47
melanoma
1:29:48
and
1:29:48
malignancy,
1:29:49
particularly
1:29:50
in the
1:29:50
metastatic
1:29:50
setting,
1:29:51
we know that
1:29:51
it's a
1:29:52
very
1:29:52
challenging
1:29:53
to treat,
1:29:53
and it doesn't
1:29:54
respond in
1:29:54
quite the
1:29:55
same way
1:29:55
as it's
1:29:55
cutaneous
1:29:56
and
1:29:56
counterpart.
1:29:58
But also
1:29:58
there were
1:29:58
there were
1:29:59
different
1:29:59
immunological,
1:30:01
issues with
1:30:02
uveal
1:30:02
melanoma.
1:30:03
metastatic
1:30:03
setting
1:30:04
is going to
1:30:05
cold.
1:30:05
Tumor is
1:30:06
quite
1:30:06
difficult
1:30:06
to get.
1:30:07
2000
1:30:08
other immune
1:30:08
cells
1:30:08
into the
1:30:09
microenvironment.
1:30:10
and also
1:30:11
understanding
1:30:11
whether
1:30:11
these T-cells
1:30:12
are
1:30:12
efficacious
1:30:13
once they get
1:30:13
there is
1:30:14
also a
1:30:15
challenge.
1:30:15
So to try
1:30:16
and to sort
1:30:17
of address
1:30:17
some of those
1:30:18
issues,
1:30:19
has led
1:30:19
to the
1:30:19
development
1:30:20
of a series
1:30:20
of oncolytic
1:30:21
viruses,
1:30:21
but this one
1:30:22
is called
1:30:22
the RB
1:30:23
T virus.
1:30:24
It's a,
1:30:24
genetically
1:30:25
modified HSV
1:30:26
one virus,
1:30:28
that has got
1:30:29
a number
1:30:29
of different
1:30:29
mechanisms
1:30:30
by which
1:30:31
you can
1:30:31
sort of
1:30:32
and optimize
1:30:32
it.
1:30:33
It is
1:30:33
a minimal
1:30:34
modulation,
1:30:35
and that
1:30:35
includes with
1:30:35
the RBt
1:30:36
two virus.
1:30:37
this sort
1:30:38
of anti
1:30:39
for antibody
1:30:40
like molecule
1:30:40
which allows
1:30:41
some
1:30:42
initial
1:30:43
checkpoint,
1:30:44
antagonism
1:30:46
as part
1:30:47
of the viral
1:30:47
at the
1:30:47
viral cascade.
1:30:49
so the hope
1:30:49
is that
1:30:50
this would,
1:30:50
this would
1:30:51
should be seen
1:30:52
to show
1:30:52
some efficacy
1:30:54
in the
1:30:54
metastatic
1:30:54
setting
1:30:55
to thinking
1:30:55
about
1:30:55
patients,
1:30:56
with,
1:30:57
with their
1:30:58
metastatic
1:30:58
disease.
1:30:59
this is,
1:31:00
going on
1:31:01
to form
1:31:02
part of a
1:31:02
bigger,
1:31:03
body of work,
1:31:04
the vaccine,
1:31:04
and taking
1:31:05
a different,
1:31:07
virus is
1:31:07
different,
1:31:07
different
1:31:08
versions of it
1:31:09
at the same
1:31:09
base.
1:31:10
looking in
1:31:11
various
1:31:11
different,
1:31:12
different
1:31:12
settings.
1:31:13
And there is,
1:31:14
a planning
1:31:14
underway to do
1:31:15
a bigger
1:31:16
for melanoma,
1:31:17
study.
1:31:18
But this is,
1:31:18
this is this
1:31:19
is this
1:31:19
of the data
1:31:20
from the phase
1:31:20
one trial,
1:31:21
which was a
1:31:22
solid tumor,
1:31:23
trial,
1:31:24
but looking
1:31:25
we were going
1:31:25
to look
1:31:26
specifically
1:31:26
at the,
1:31:27
uveal
1:31:27
melanoma
1:31:27
cohort,
1:31:29
within
1:31:29
that trial.
1:31:29
And this
1:31:30
was presented
1:31:30
to asked
1:31:30
for this year
1:31:31
by my
1:31:31
colleague, Dr.
1:31:32
Saket.
1:31:33
So if we think
1:31:34
about
1:31:34
the design
1:31:34
of this today
1:31:35
and there were
1:31:36
two parts
1:31:36
to the study,
1:31:37
one was
1:31:38
a monotherapy,
1:31:39
dose
1:31:39
escalation
1:31:40
and so
1:31:41
selection,
1:31:42
part.
1:31:43
And then that
1:31:43
went on to
1:31:44
a second
1:31:45
this year,
1:31:45
which divided
1:31:46
into two
1:31:46
cohorts A
1:31:48
and B,
1:31:49
and really
1:31:50
the difference
1:31:50
between the
1:31:51
two parts
1:31:52
of the,
1:31:52
of the second
1:31:52
part of
1:31:53
the city
1:31:53
was when
1:31:54
you would
1:31:54
introduce the,
1:31:55
the checkpoint
1:31:56
inhibitor, did
1:31:57
you need
1:31:57
that upfront
1:31:58
or or do you,
1:31:59
do you,
1:32:00
can you,
1:32:00
can you
1:32:01
introduce it
1:32:01
later on
1:32:01
with the same,
1:32:02
the same outcome.
1:32:03
And we're
1:32:03
still
1:32:03
answering
1:32:04
that question.
1:32:04
The city's
1:32:05
an ongoing
1:32:06
so our P
1:32:07
two, as I
1:32:07
said, is
1:32:08
an oncology
1:32:08
virus.
1:32:08
It's directly
1:32:09
administered
1:32:10
into
1:32:10
the tumor,
1:32:11
and can be
1:32:12
and
1:32:13
administered
1:32:13
either
1:32:13
subcutaneous
1:32:14
or superficial
1:32:15
lesions
1:32:15
or to deep
1:32:16
and visceral
1:32:16
lesions
1:32:17
using image
1:32:18
guidance.
1:32:18
And
1:32:18
that was IDed
1:32:19
by, CT guided
1:32:21
injection
1:32:22
into the liver
1:32:23
predominantly
1:32:23
or ultrasound
1:32:24
guided
1:32:25
injection
1:32:25
to into
1:32:26
any lesions
1:32:27
in the liver.
1:32:28
Patients
1:32:28
were included
1:32:29
if
1:32:29
they were over
1:32:30
18, if
1:32:30
they had
1:32:31
advanced
1:32:31
or metastatic
1:32:32
non
1:32:32
neurological
1:32:33
solid tumors
1:32:33
including the
1:32:34
melanoma
1:32:35
cohort.
1:32:36
and that they
1:32:37
had progressed
1:32:37
or couldn't
1:32:38
tolerate
1:32:38
standard
1:32:39
therapy.
1:32:40
They had to
1:32:40
have at
1:32:40
least one
1:32:41
measurable
1:32:41
and injectable
1:32:42
tumor of more
1:32:43
than or equal
1:32:43
to one
1:32:44
centimeter.
1:32:44
And they had
1:32:45
to have
1:32:45
an equal
1:32:46
performance
1:32:46
data set equal
1:32:47
to one.
1:32:48
Patients
1:32:48
were excluded
1:32:49
if they had
1:32:49
prior
1:32:50
treatment
1:32:50
with oncolytic
1:32:51
viruses,
1:32:52
if they had a
1:32:52
history of
1:32:53
hepatitis
1:32:55
B C or
1:32:56
HIV infection,
1:32:57
or if they had
1:32:58
any active
1:32:58
significant
1:33:00
infections
1:33:00
or prior
1:33:01
complications
1:33:01
with HSV one,
1:33:03
if they had
1:33:03
active brain
1:33:04
metastases
1:33:05
or,
1:33:06
meningitis
1:33:06
from a
1:33:07
secondary
1:33:07
to malignancy,
1:33:08
or if they had
1:33:09
major surgery
1:33:10
in less
1:33:11
than two weeks
1:33:11
prior
1:33:11
to starting
1:33:12
institutions
1:33:13
and the
1:33:13
endpoints.
1:33:14
The primary
1:33:14
endpoint was
1:33:15
the safety
1:33:15
and
1:33:15
tolerability
1:33:16
of the
1:33:16
virus, plus
1:33:17
or minus
1:33:17
the checkpoint
1:33:18
inhibitor,
1:33:18
in this case
1:33:19
nivolumab.
1:33:19
that was
1:33:20
tracked as a
1:33:22
standard in
1:33:22
the case.
1:33:24
And the
1:33:24
overall
1:33:24
response to
1:33:25
the virus
1:33:26
plus or minus
1:33:26
the nivolumab
1:33:27
secondary
1:33:28
endpoints
1:33:28
were duration
1:33:29
of response,
1:33:29
complete
1:33:30
response rate,
1:33:31
disease
1:33:31
control rate
1:33:32
and
1:33:32
progression
1:33:32
free survival,
1:33:33
and the one
1:33:34
and two rate
1:33:34
for survival.
1:33:35
And then we
1:33:36
as part
1:33:37
of the trial,
1:33:37
we wanted
1:33:37
to understand
1:33:38
the biomarker,
1:33:39
elements
1:33:40
of this
1:33:40
is that
1:33:41
there was
1:33:41
a large
1:33:41
translational
1:33:42
component
1:33:42
to this
1:33:43
with multiple
1:33:44
biopsies
1:33:45
taken as part
1:33:45
of
1:33:46
the process.
1:33:46
And there were
1:33:46
optional
1:33:47
biopsies
1:33:47
as well
1:33:48
to try
1:33:48
and understand
1:33:49
what what
1:33:49
changes that
1:33:50
the treatment
1:33:51
was affecting
1:33:52
in
1:33:52
to
1:33:52
microenvironment.
1:33:53
And I'll talk
1:33:54
a little bit
1:33:54
more
1:33:54
about that
1:33:54
towards
1:33:55
the end.
1:33:56
So in terms
1:33:57
of the
1:33:57
at the
1:33:58
demographics,
1:33:58
I think that,
1:33:59
you know, they
1:33:59
were they were
1:34:01
the IBT
1:34:02
monotherapy
1:34:02
in those
1:34:03
three patients
1:34:03
with uveal
1:34:04
melanoma
1:34:05
and then
1:34:05
the RPt
1:34:05
2% volume up.
1:34:06
second phase
1:34:08
that was that
1:34:08
14 patients,
1:34:10
essentially
1:34:11
the the
1:34:12
monotherapy
1:34:13
to, to, to
1:34:14
phase two,
1:34:15
there weren't
1:34:15
any really
1:34:16
notable
1:34:17
differences.
1:34:17
But it's
1:34:18
really
1:34:18
I think
1:34:18
the thing
1:34:19
that's
1:34:19
really key
1:34:20
is the fact
1:34:20
that most
1:34:21
patients
1:34:21
had had
1:34:22
prior
1:34:23
anti-PD-1 and
1:34:25
TLR four
1:34:26
in their,
1:34:26
in their
1:34:27
treatment
1:34:28
prior
1:34:28
to being given
1:34:29
this
1:34:30
treatment
1:34:30
incumbent
1:34:30
in the
1:34:31
volume up
1:34:31
in combination
1:34:32
with the
1:34:33
the RBP to
1:34:35
an overall
1:34:36
17.6%
1:34:37
the patients
1:34:38
had received
1:34:39
were more
1:34:39
or equal
1:34:40
to three lines
1:34:41
of therapy.
1:34:42
So these were
1:34:42
heavily
1:34:43
pretreated
1:34:43
patients.
1:34:45
and
1:34:45
the majority
1:34:46
had also
1:34:46
received
1:34:47
this
1:34:47
combination of
1:34:48
PD1 and TCT.
1:34:49
And I thought
1:34:51
if we
1:34:52
look at the
1:34:52
clinical
1:34:52
activity,
1:34:53
which is
1:34:53
essentially
1:34:53
we were
1:34:53
looking for
1:34:54
early,
1:34:55
early markers
1:34:55
of clinical
1:34:56
activity
1:34:56
in this
1:34:57
patient group,
1:34:58
what did we see
1:34:59
any was really
1:35:00
the
1:35:00
fundamental
1:35:00
question.
1:35:01
and
1:35:02
interestingly,
1:35:03
we saw an
1:35:03
overall
1:35:03
response rate
1:35:04
at 29.4%
1:35:06
or partial
1:35:07
responses,
1:35:08
and a disease
1:35:09
control rate
1:35:09
of 58.8%
1:35:11
at the median
1:35:12
duration
1:35:12
of response
1:35:13
was 11.5
1:35:14
months,
1:35:15
with a
1:35:15
range of 2.8
1:35:16
to 21.2
1:35:17
months.
1:35:18
And
1:35:18
you can see
1:35:19
you can
1:35:19
see that
1:35:19
written
1:35:20
down here
1:35:20
in the table.
1:35:21
the responses
1:35:22
were and
1:35:23
interestingly,
1:35:24
we found
1:35:25
we observed
1:35:26
both HLA
1:35:26
to positive
1:35:28
and negative
1:35:29
patients
1:35:29
and obviously
1:35:30
quite a lot
1:35:30
of the work
1:35:31
that we're
1:35:31
doing
1:35:31
in the
1:35:32
immune space
1:35:32
in the
1:35:33
and leave
1:35:34
your melanoma
1:35:35
is focused
1:35:35
on the HLA
1:35:36
to positive
1:35:37
group.
1:35:37
So
1:35:38
so we wanted
1:35:39
to see
1:35:39
whether
1:35:40
actually
1:35:40
you can
1:35:40
see activity
1:35:41
in both of
1:35:41
these groups.
1:35:41
there
1:35:42
was in fact
1:35:42
activity seen.
1:35:44
And this
1:35:46
just breaks it
1:35:46
down in
1:35:46
terms of
1:35:47
visuals
1:35:47
for you.
1:35:47
So you can see
1:35:48
that there
1:35:48
were,
1:35:49
five patients
1:35:50
that showed
1:35:50
a partial
1:35:51
response,
1:35:52
and a
1:35:53
further five
1:35:53
that showed,
1:35:54
stable
1:35:54
disease,
1:35:55
over time.
1:35:58
And actually
1:35:58
what we're
1:35:58
really
1:35:59
looking for
1:35:59
is whether
1:35:59
we see
1:36:00
a response
1:36:01
in the
1:36:01
injected,
1:36:02
the,
1:36:02
an injected,
1:36:03
lesions.
1:36:04
And this is
1:36:04
a really
1:36:05
this is a
1:36:05
really key
1:36:06
question
1:36:06
for us
1:36:07
with, virus
1:36:08
therapy.
1:36:08
Can we
1:36:09
essentially
1:36:10
show,
1:36:10
antigen
1:36:11
presentation.
1:36:12
that leads
1:36:13
to further
1:36:14
T-cell
1:36:14
recognition
1:36:15
of other
1:36:15
areas, that,
1:36:18
that will
1:36:18
lead to
1:36:18
response, in,
1:36:20
in the non
1:36:20
injected
1:36:21
lesions.
1:36:21
And you can
1:36:21
see in these
1:36:22
and in this,
1:36:23
in this
1:36:23
patient here
1:36:24
who had a
1:36:25
partial
1:36:25
response,
1:36:26
you can see
1:36:26
responses
1:36:27
in both
1:36:27
both T
1:36:28
and injected.
1:36:28
the injected
1:36:29
lesions
1:36:30
which is
1:36:30
important to,
1:36:32
to notice
1:36:32
that we do
1:36:33
see this
1:36:33
sort of
1:36:34
more upscale
1:36:35
effect.
1:36:36
and
1:36:38
and again,
1:36:39
you can
1:36:40
see that
1:36:40
as well.
1:36:43
So what are
1:36:43
we thinking
1:36:43
about?
1:36:44
the clinical
1:36:45
responses.
1:36:46
We also
1:36:46
want to see
1:36:46
what's
1:36:47
happening
1:36:47
at a more,
1:36:48
more baseline,
1:36:48
translational
1:36:49
level,
1:36:50
because
1:36:50
that will help
1:36:50
us understand
1:36:51
how we can
1:36:51
then
1:36:52
essentially
1:36:53
coordinate
1:36:53
and, and,
1:36:54
build on
1:36:55
these results.
1:36:56
So what we did
1:36:56
here is
1:36:57
we took
1:36:57
biopsies,
1:36:58
at baseline
1:36:59
screening
1:37:00
and at day 43
1:37:01
and we
1:37:02
stained
1:37:02
for CD8,
1:37:03
which is
1:37:04
a marker
1:37:04
of T-cell
1:37:05
presence,
1:37:06
and a
1:37:07
marker of
1:37:07
immune
1:37:07
activity.
1:37:09
and you can
1:37:09
see that
1:37:09
these change
1:37:10
over time
1:37:10
that
1:37:11
the tumors
1:37:11
become
1:37:12
more
1:37:12
infiltrate it,
1:37:14
in response
1:37:14
to the
1:37:15
injections.
1:37:15
And also
1:37:16
there's a
1:37:16
higher, higher
1:37:17
expression of
1:37:17
PD one,
1:37:18
which would
1:37:18
suggest that
1:37:19
there is a,
1:37:21
a more sort
1:37:21
of a need
1:37:22
and immune
1:37:23
environment,
1:37:24
interestingly,
1:37:24
new selected
1:37:25
T cell
1:37:26
receptor
1:37:27
sequencing
1:37:28
and within
1:37:28
pbmcs
1:37:29
within the
1:37:29
with skin
1:37:30
and peripheral
1:37:30
blood
1:37:31
looking to see
1:37:31
if we
1:37:32
could see
1:37:32
a response.
1:37:33
in the sort
1:37:34
of the
1:37:34
circulating
1:37:35
immune
1:37:37
so
1:37:38
repertoire,
1:37:39
as a, as a
1:37:40
response
1:37:40
to treatment.
1:37:41
And we can see
1:37:41
that there are
1:37:42
significant
1:37:43
expansion
1:37:43
and new
1:37:44
clones.
1:37:45
there was very
1:37:46
there was
1:37:46
some claims
1:37:47
that got
1:37:47
smaller,
1:37:48
but actually
1:37:49
there are,
1:37:49
as you
1:37:49
can see,
1:37:49
a lot of blue
1:37:50
blobs on that.
1:37:51
On
1:37:51
these curves,
1:37:52
it showed that
1:37:52
numerous
1:37:53
clones
1:37:53
exhibited
1:37:54
expansion,
1:37:55
that were
1:37:56
first
1:37:56
identified on
1:37:57
day 43.
1:37:58
So after the,
1:37:59
the sort
1:38:00
of the
1:38:00
implementation
1:38:01
of treatment.
1:38:02
So
1:38:02
we can see
1:38:03
that these,
1:38:03
this
1:38:04
therapeutic,
1:38:05
combination
1:38:06
is leading to
1:38:06
mean
1:38:07
activation.
1:38:07
and and
1:38:09
actually
1:38:09
seeing
1:38:09
benefit.
1:38:10
One of the
1:38:10
things that
1:38:12
was
1:38:12
interesting is
1:38:13
we didn't
1:38:13
necessarily
1:38:14
see that
1:38:14
this clonal
1:38:14
expansion
1:38:15
correlates to
1:38:16
clinical
1:38:16
response.
1:38:17
So that
1:38:17
that means
1:38:18
that there's
1:38:18
probably
1:38:19
more work
1:38:19
that we
1:38:19
could do
1:38:20
with
1:38:20
additional
1:38:21
agents
1:38:21
or
1:38:22
a different,
1:38:22
trial design
1:38:23
to actually
1:38:24
understand
1:38:24
how that will,
1:38:25
that will
1:38:25
lead itself
1:38:26
to, to,
1:38:27
to leading
1:38:27
to clinical
1:38:28
clinical
1:38:28
response,
1:38:29
you know,
1:38:29
but actually
1:38:30
just seeing
1:38:30
the fact
1:38:30
that we see
1:38:31
those changes
1:38:31
means
1:38:32
that these,
1:38:32
these
1:38:32
therapies,
1:38:33
therapies are
1:38:34
made immune,
1:38:35
generally
1:38:35
active,
1:38:36
which is
1:38:36
really
1:38:36
reassuring
1:38:37
in this phase,
1:38:37
in this
1:38:38
setting phase
1:38:39
on trial,
1:38:40
the safety
1:38:41
profile
1:38:41
is also
1:38:41
quite
1:38:42
interesting.
1:38:42
So as you can
1:38:43
see here,
1:38:43
there were
1:38:44
there were
1:38:44
some patients
1:38:45
who who got
1:38:46
toxicity.
1:38:46
the most were
1:38:48
common
1:38:48
were grade
1:38:49
one away
1:38:49
two in
1:38:51
in groups
1:38:52
were directed
1:38:52
towards
1:38:53
fatigue
1:38:53
and
1:38:53
hypertension.
1:38:54
And some
1:38:54
people
1:38:55
also got it.
1:38:56
But process.
1:38:57
there were
1:38:58
two cases
1:38:59
of grade
1:39:00
three
1:39:00
hypertension,
1:39:01
but both
1:39:01
were transient
1:39:02
and mostly
1:39:02
managed
1:39:03
with fluid
1:39:03
therapy alone.
1:39:04
And there were
1:39:05
no grade
1:39:05
4 or 5,
1:39:07
a which
1:39:08
again,
1:39:08
is quite,
1:39:08
quite
1:39:09
relevant.
1:39:09
Interestingly,
1:39:10
given the fact
1:39:11
that the
1:39:11
majority
1:39:12
of the eight
1:39:12
of the
1:39:12
patients
1:39:13
in the RPE,
1:39:14
I'll be
1:39:14
treated
1:39:15
as nivolumab
1:39:15
trial
1:39:16
also didn't
1:39:17
experience,
1:39:18
any particular
1:39:20
I mean, when
1:39:20
I set
1:39:21
this event
1:39:21
toxicities
1:39:22
is really
1:39:23
quite
1:39:23
noticeable.
1:39:24
and and
1:39:25
and suggesting
1:39:27
a lower rate
1:39:27
than
1:39:27
we would do
1:39:28
with
1:39:28
the volume of,
1:39:29
therapy,
1:39:30
is a single
1:39:30
agent,
1:39:30
which is
1:39:31
quite
1:39:31
interesting
1:39:31
at this point.
1:39:33
So in
1:39:33
conclusion,
1:39:34
we see
1:39:34
the optimal
1:39:35
therapy
1:39:36
in P2.
1:39:36
Plasma volume
1:39:37
therapy
1:39:38
resulted in
1:39:39
an overall
1:39:39
response
1:39:39
rate of 29.4%,
1:39:42
and
1:39:42
the disease
1:39:42
control rate
1:39:43
at 58.8%.
1:39:44
In a cohort
1:39:45
of patients
1:39:46
with
1:39:46
metastatic
1:39:47
melanoma,
1:39:48
who have
1:39:48
been heavily
1:39:49
pretreated,
1:39:50
and
1:39:51
they showed
1:39:51
durable
1:39:51
responses
1:39:52
and a
1:39:52
favorable
1:39:53
safety
1:39:53
profile.
1:39:55
We saw
1:39:55
this activity,
1:39:56
regardless of
1:39:56
HLA status,
1:39:58
I think is
1:39:58
very
1:39:58
reassuring
1:39:59
for those
1:39:59
for that
1:39:59
patient group
1:40:00
that don't
1:40:00
have a
1:40:01
need to
1:40:01
positivity.
1:40:03
and
1:40:03
it doesn't
1:40:03
seem to
1:40:03
be specific
1:40:04
to a priori
1:40:05
PSI regime.
1:40:06
Essentially,
1:40:06
patients
1:40:07
could have had
1:40:07
already
1:40:08
been treated
1:40:08
with
1:40:08
an anti-PD-1,
1:40:09
and we would
1:40:10
still CMT,
1:40:11
associate the
1:40:12
benefit
1:40:12
in this
1:40:13
in this
1:40:13
setting.
1:40:14
And we saw,
1:40:15
responses in
1:40:16
both
1:40:16
the hepatic
1:40:17
and that
1:40:17
to testes
1:40:18
and injected
1:40:19
in yet
1:40:19
to
1:40:19
the lesions.
1:40:20
So we're
1:40:21
seeing quite
1:40:21
a lot
1:40:21
of activity
1:40:22
across
1:40:22
the
1:40:22
metastatic,
1:40:24
repertoire in
1:40:25
even in
1:40:26
those patients
1:40:26
who've
1:40:26
had only
1:40:27
a small number
1:40:28
of lesions
1:40:28
injected,
1:40:29
we do see an
1:40:30
increase in
1:40:31
the infiltration
1:40:32
and we see
1:40:32
increased
1:40:33
Pd-l1
1:40:33
expression
1:40:34
in tumors.
1:40:35
and we see
1:40:35
also there's
1:40:36
changes
1:40:36
in the
1:40:36
peripheral
1:40:37
T-cell
1:40:37
repertoire,
1:40:38
which is
1:40:38
useful
1:40:38
in
1:40:39
understanding
1:40:39
the fact
1:40:39
that we see
1:40:40
different
1:40:40
T cells
1:40:41
being,
1:40:41
the expressed
1:40:42
and expanded,
1:40:43
but also
1:40:43
we can
1:40:44
we have a
1:40:44
peripheral
1:40:45
marker of
1:40:45
potential,
1:40:46
I mean
1:40:47
activation,
1:40:48
which is,
1:40:48
which is
1:40:48
useful in
1:40:49
the patient
1:40:49
group
1:40:50
in patients
1:40:50
generally.
1:40:51
I might
1:40:52
possibly have
1:40:52
some clinical
1:40:53
translate
1:40:53
ability
1:40:54
further down
1:40:54
the line.
1:40:55
This suggests
1:40:56
that, this,
1:40:57
intramural
1:40:58
gated
1:40:58
community
1:40:58
therapy,
1:40:59
within
1:41:00
in this
1:41:00
expression
1:41:01
of this
1:41:01
antigenic
1:41:02
four molecule
1:41:03
as part of
1:41:03
its genetic
1:41:03
modification,
1:41:04
in combination
1:41:05
with this
1:41:05
checkpoint
1:41:06
inhibitor,
1:41:06
has a
1:41:07
potential for
1:41:07
clinically
1:41:08
meaningful
1:41:08
benefit
1:41:09
and a
1:41:09
favorable
1:41:09
toxicity
1:41:10
profile.
1:41:11
And therefore,
1:41:12
we're going
1:41:12
to directly,
1:41:13
you know,
1:41:13
taking these
1:41:14
forward
1:41:14
and developing
1:41:15
a more
1:41:16
advanced phase
1:41:17
two trial.
1:41:18
so essentially
1:41:19
we see
1:41:20
we see
1:41:20
really notable
1:41:21
objective
1:41:22
response rates
1:41:22
and disease
1:41:23
control rates
1:41:24
and patients,
1:41:25
and don't
1:41:25
appear to
1:41:26
exhibit,
1:41:26
particularly
1:41:27
concerning
1:41:28
safety
1:41:29
profiles.
1:41:30
and obviously,
1:41:31
we will be
1:41:32
more than
1:41:32
happy to
1:41:33
take any,
1:41:34
any for
1:41:35
information
1:41:35
and that,
1:41:36
that emails
1:41:36
at the bottom
1:41:37
of this slide,
1:41:38
I'm
1:41:38
going to stop.
1:41:41
Thank you
1:41:41
so much.
1:41:42
this
1:41:43
was amazing.