Ovarian Cancer Online Symposium: Platinum-Sensitive & Platinum-Resistant Recurrence

hello and welcome to the next session of

the ovarian cancer online Symposium I'm

Dr Kathleen Moore associate director of

JuJu partners and a gynecologic

oncologist from the Stevenson Cancer

Center in Oklahoma City I'm thrilled to

be joined today by my colleague and

friend Dr David O'Malley for today's

discussion on Platinum sensitive and

platinum resistant recurrent ovarian

cancer Dr O'Malley wanted to introduce

yourself

thanks Katie uh Dave O'Malley from the

Ohio State University where I lead the

division of gynecological oncology and

in geog Foundation I help with the

ovarian cancer portfolio is clinical

trial advisor

the ovarian cancer online Symposium

Series has been developed through a

partnership between the clarity

foundation and the Gog Foundation to

provide patience character givers and

other Advocates with impactful

information and support that is

personalized for their ovarian cancer

Journey

during today's discussion Dr Moore and I

are going to use case studies to help

walk you through and understand the

current available treatment options for

platinum sensitive and platinum

resistant recurrent ovarian cancers Dr

Moore

great so let's get started we're going

to kind of use some slides just as

visual aids for this uh discussion today

so we're just going to start with some

cases

um so we kind of made up to frame the

discussion

we'll start with a patient of mine 67 uh

currently she was diagnosed so back in

2018 with Advanced stage high grade

steros ovarian cancer she had a primary

site reductive surgery which means

surgery was done at first and she had a

very successful surgery with no evidence

of disease at the end of that surgery

she was then treated with very much the

standard of care

paclitaxal and carboplatin chemotherapy

with severicizumab and our listeners may

know that as a fasten but we'll call it

that this is a map to be compliant and

Then followed by 15 Cycles or about a

year of that this is enough maintenance

after that and she was without evidence

of disease at the conclusion of that

treatment in 2019 October of 19 was

doing really well and so kind of

relatively recently and came in

we'll see a little bit of symptoms uh

and our ca125 had jumped from very

normal

um six months before to now uh 457 that

you can see it's a very healthy

individual

um no relevant kind of medical personal

history uh and so this looks like

recurrent disease so Dr O'Malley she's

sitting in front of you

um you know has been doing great really

seeing my advanced practice providers

for a few years because she's just been

in maintenance doing great living her

life now it looks like she's recurred

what's your sort of initial workup plan

for her would you order any other

molecular testing like what are you

thinking about for her

well first hand jumps out is how our

world has changed in five years right so

she didn't have molecular testing now

every patient uh gets somatic and

germline testing

um you could argue somatic and then

triage into germline but really every

single patient so in this scenario I'm

checking germline and somatic

am I going to send an hrd test off maybe

but I'm definitely going to get full

Next Generation sequencing because this

patient's now recurred she's in the

primary setting I would have done

germline and hrd and then upon

recurrence Next Generation sequencing

this is a beautiful slide to show about

about one half of our patients will be

hrd positive but another half just less

than half uh will be hrd test negative

here referred to as HR proficient so the

molecular testing in The Upfront setting

is so important when the recurrent

setting

though important the the clinical

features so this is four years out she's

almost like a new diagnosis so I'm going

to talk to her about surgery I'm going

to talk to her about molecular testing

now talk to her about parp Inhibitors

and retreat with Bev all of those things

how about you I mean was is this a

patient you would you would have surgery

on or or is what would you do for her

yeah I mean I think we agree and I did

make simple with that I had actually

germline tests or vacancies

um

um but I made it up so I would if she

had not had germline testing I

definitely would send germline testing

uh which just to Define for our

listeners that is testing for mutations

that you're born with that predispose

you to developing breast and ovarian

cancer and actually prostate in men and

pancreatic cancer in both and genders

um

that's what germline means and so that

has implications for family members so

it's really critically important that we

test that not just for the patient but

also to identify hopefully

um unaffected family members so we can

prevent cancers moving forward and then

you mentioned somatic testing is where

that what that means is we test the

tumor

to see if it has veraca or other

mutations and I'll bump back to this

slide there's other mutations that we

look for particularly rad 51c that have

no implication for family if we find

them in the tumor and not in your blood

or saliva

but they do have implications for how

well patients who impart and then we

test for this thing called hrd which you

alluded to which is homologous

recombination deficiency and basically

what that means is it's a marker of a

tumor that struggles to fix its DNA and

so if you challenge it with a drug that

targets its DNA

um it does we're more likely for that

and so that's why we look for that so I

would actually send

um germline first and if the germline is

negative then I would send tumor and

we'll talk about this a little bit more

there's a lot of other things we look

for in those tumor tests that may help

for clinical trials

um so I would that's how I would test

her

and that really is the current set of

recommendations I'm just showing you the

European recommendations but they are

the same in the United States where we

really want germline first and if that's

negative then we move on to tumor pet

things as a standard of care so catching

people up who kind of were diagnosed

before all this came into play is an

important part of our job now so we can

best assess them

um when they progress now you asked a

good question is would I consider a

surgery

and that's called secondary cyto

reduction

um and the short answers as you'll see

in the case yes I would consider surgery

um it is controversial though patients

always ask when they recur

I mean almost every time can't you

operate please operate please take it

out

um

does that make sense and and the short

answer is that it's not clear what do

you kind of what why don't you take us

through dark formally kind of what the

this is an air we call clinical

equipoids where you could argue of both

ways like you should do it or you

shouldn't do it so it's not an easy

assessment

so the first thing I look up when

talking about secondary exercise

reduction is am I going to be able to

get all the disease I can see or feel at

the time of second secondary side of

reduction meaning leave that we can't

see or feel anything in in throughout

the entire body okay so that's one of

the number one criteria even to consider

if I don't think that we can get her

down what we call an R zero resection

which means remove all clinically

evidence disease then that's not even

consideration

the other though the data is not as

strong is the time or the Platinum free

interval or time from diagnosis this

patient had four years from her Platinum

for her Platinum free interval which

means four and a half years really

almost that since Her diagnosis so

you're starting getting that five-year

window it's almost like a new diagnosis

and we can't quite say that but you know

that's another consideration what else

uh and we'll get into this a little bit

later in the discussion but can I remove

all uh excuse me was at the primary

surgery was all the disease removed and

did they not require Neo agile we'll

talk a little bit more about that but

you see here on these curves and we're

not going to go into the details but Gog

213 was the U.S trial and everybody in

that trial received um

uh not everybody but uh patients receive

Bev and so we looked at surgery versus

no surgery actually amazingly so those

that received did not have surgery did

better but the ago desktop which is uh

are one of our European colleagues or

German colleagues

but there was a survival advantage and

then we have the sock one which showed

there was no difference but a slight

Trend towards Improvement so this

question across the world is not

answered

um and I you know if we're looking at is

this an option I think really where this

is shared decision comes up but those

three criteria there are some others

that we'll talk about clearly need to be

considered and you potentially would you

harm to a patient by delaying

chemotherapy if you took them to the to

the operating room and you didn't think

you could remove all the disease now

sometimes you think you can and you

can't and that happens and we we're

willing to take that chance but you see

here this is a uh Dr Coleman our good

friend overlaid all the survival curves

and you can see that those that had a

Bev

um in in no surgery really did did the

best and so it's it really is again

shared decision and are you gonna be

able to get all the disease out but also

looking back how are they treated in the

first line and how the surgery go in the

first line

um you made the decision to do surgery

here again four years out you got all

the disease out which we see here uh the

the goal no residual disease and now she

has a complete response CR means

complete response no clinical evidence

of disease or no evidence of disease

with utilizing the chemotherapy for the

for the bad so you know we talked about

surgery

um

now you know I'm really curious to see

what was the doublet you used you know

we have three doublets we can use here

so how did you treat her yeah so I did

operate

um and it's just as you say it's so much

shared decision making and making sure

patients understand but also patient

selection is really key like really

going into the surgery with a pretty

firm belief that you're going to get it

all out starting with laparoscopy not

opening somebody if you're not going to

get it all out because you do I think

with the even though the data you talked

about Dave is while the results were a

little bit all controversial in terms of

benefit they were very consistent in

harm in all the cases where patients

were received surgery that was

incomplete they all were harmed over the

patient who didn't get surgery so doing

the surgery and not getting it all out

harms patients as compared to no surgery

so that's very clear and I believe that

the question is does if you get it all

out does it help

I think there's some equipoise there but

I operate on her and we got it all out

and then um then the question is right

what because that's not enough you still

gotta get chemo again I'm sorry to tell

you all and then maintenance is really

important like I really don't plan just

for six cycles and stop it's six cycles

and then I'm going to try and maintain

the benefit we achieved

um so there's two questions here

um what am I going to use and what

maintenance am I going to use and this

is complicated

um because it's really based on so many

things

the Baseline of which is what did the

patient already receive well of course

they receive tackle facts on carboplatin

did they get by this is a map did they

already get a part did they get both

because that's a thing now in front line

um and then what would I use how does

that impact what I'm going to use in

this in the first recurrent setting you

know if they had a prior part but not

Bevis is enough I would use Bevis map if

they had prior bed is this patient dead

and not a part I would use a part if

they had both well there's data for

repeat and we'll talk about that but

this is really where clinical trials

become important so these are the three

kind of backbones that we use

um and they're all based on carbocation

because that's our key drug until it

stops working we use carboplatin so

carbon platin and Gem cyta bean

carboplatin and paclotaxal or

carboplatin and what we call peglin

liposomal doctorubicin which you

probably have heard as doxyl

those are the three backbones

two which you can add beds bevacism and

bevisismab maintenance and these are

just the studies that um really gave us

those as standards of care

and the Improvement in time to

recurrence and more importantly the

Improvement in overall survival and so

you can see a little bit of a bump in

overall survival when we use tackle

attack so carboplasmicism app over Paco

attacks on carbo platin alone

as well as a little bump in overall

survival when we use carboplatin doxyl

bevacismab versus carboplatin gym

cytopenevacism

and so because of that

um

I tend to use carboplatin

and doxyl with bevisismab when patients

have not had it or even if they have

we'll talk about this in a little bit

there is data that you can reuse

bevisismab and some countries you can't

do that in the U.S we can so even if she

has had bevacism abs I might reconsider

it

um the other option is to not use

bevisismab with the chemo just give

chemo especially in this patient had a

surgery I'm not trying to shrink any of

her tumor I'm just trying to get rid of

whatever microscopic diseases left and

then transition to a parp inhibitor for

maintenance post

and this is all of the data for the

studies of olaparib and the rapid and

Route apparib in this setting all of

which show an improvement in the time to

next recurrence because unfortunately it

will come back

but more importantly also an improvement

in overall survival with use of carb

Inhibitors in patients with braca

particularly actually only is where you

see the overall survival advantage and

that patient is as I think we forgot to

point out we did molecularly test her

and she is germline braca

um and so for her

um even though I could reuse that

decision map all the things I told you

because of this overall survival

Advantage with park for me it's sort of

a no-brainer that she would have gotten

um part for maintenance I don't know

what you want if you have something to

add to that you made this very easy for

me right she's germline Bracco or

somatic BRAC in that scenario if they

have not received parp absolutely 100 I

I don't believe there's any debate I

have to be honest there's no debate if

they haven't received a part and they're

Platinum sensitive you have to get you

have to have a part

um I do think there's a debate uh in the

FDA has said this

um they've reduced the indications or

eliminated the indications for for uh or

or

recaparib and naraparib and non-bracca

patients

um we continue to have indication in a

lapariv for non-braca patients to

platinum sensitive so we just studied we

just published a paper from the aerial

three which is the recaper of data and

looking at predictors of extreme

responders in this case in a good way

right people who had years of Disease

Control in the Platinum sense of space

and what we found was the clinical

features what do I mean by clinical

features so

did the patient get a complete response

to their platinum-based therapy do they

have normalization of ca125 do they have

no disease on CAT scan those three

things really predicted as well as that

hrd testing that we did now the best by

far is bracca around 51c or D so if you

have one of those mutations or your

tumor has one of those mutations hands

down you need a purp if you haven't had

one okay but those other patients if

they have a complete response and they

haven't had a part before I'm really

having a conversation

about utilizing parp in that scenario so

this case you made it easy for me thank

you Dr Moore I appreciate that uh we're

gonna give our Platinum doublet we could

debate that all day there's three

Platinum dub it's I do there's a lot

more Platinum gems are kind of modified

the schedule which we've published a

couple papers from here on but um the

maintenance with the Barb inhibitor

absolutely let's move on to our next

case so this is different patient she's

55 now she the history of stage four

high grade endometrioid ovarian cancer

and that was diagnosed in 2020 so right

when covert is starting

um she knows she got new adjuvant

chemotherapy

um Taco packs on carboplatinum for three

cycles and then went to surgery

um and she had a very good response and

a very nice surgery uh to no gross

residual and they got three more cycles

of Paco Paxil and carboplasts she is

Barack a wild type she did have German

testing but she responded really well to

chemo and so went on to receive

maintenance with naraparib which was for

a planned three years that's what the

indication for a neuroparib is and she

tolerated this really well she did need

a dose reduction because of platelets as

many do but it was tolerating it fine

but about two and a half years in

um the c125 starts to go up

and so we get a CT scan which shows um

sort of

um peritoneal metastases she had some

lymph nodes in the chest that were kind

of you know suspicious but not

measurable but kind of clearly her

disease was more active and again this

is someone that's germline wild type so

this is another kind of question she has

always held it and she's young 55.

so is this someone you would consider a

second surgery on Dr O'Malley

and have to think about her

yeah I I think in this scenario you

really touched on a couple of really

important points number one is what's

going on today she has disease outside

of the abdominal cavity so you're not

gonna be able to get rid of all of that

she had peritoneal disease would you

have to again make sure you alluded to

putting a laparoscope in making sure

that you could

um get uh that you can completely resect

her what else is in this the ago model

which is actually you know the model I

really utilize which is at the time of

their primary surgery they were not they

did not have any disease left at their

primary surgery what else uh if that

neoadjet they weren't eligible if they

present with a cities that at the

current time they would not be eligible

so I think as you look at these group of

patients really seen in the past how

they presented will

modify you if you offer them surgery in

this case again you made it easy for me

right which is she's disease in her

chest

and I'm not going to get all of it out

we talked about the harm we're doing so

I would not pursue surgery even this

young healthy patient because you're

going to delay chemotherapy and clearly

not benefit the patient and as you

alluded to potentially even harm the

patient uh if you take her to the

operating room

and I will just say I know a lot of

patients and family members are

listening this is really one of

there's several hard discussions we have

this oncologist but this is one of the

harder ones because I just can tell you

almost every patient in this setting

in the recurrent setting wants me to

operate again

um and take it out and that's really an

understandable sort of Desire

um but we do have

pretty good prospective data that if we

are willing to consider that there are

real real patient selection criteria and

Dr O'Malley just went through them that

have to be met to even consider that

otherwise you are almost guaranteeing

harm

um in the way of a shortened lifespan uh

and so

um so it's a hard discussion to have but

it's really important to emphasize that

the decisions that we make are often

Based on data and it's in it

can be frustrating but um

but science is important and that's why

we do trials so I agree I would not

operate here and it did not operate here

how about um you know she didn't get

bracket testing at the time

um

you know sometimes you do any ads and

you ads but you don't have enough tissue

to send for all the molecular testing

we'd want to do and if they had a really

good response it's surgery sometimes

it's hard to send

so she doesn't have somatic testing

tumor testing is there anything else you

would want to send now at the time of

recurrence Darker O'Malley and and why

would you be sending that

yeah and I think you and I really we do

a lot of clinical trials for the two of

the biggest institutions in the country

for clinical trials for GYN cancers

right and

we're always looking for opportunities

to help our patients to Target mutations

in the tumor

with our new agents that can help kill

those cancer cells right so what do I do

I I I said that everybody gets tumor

testing at the at the when they're

diagnosed when we can't you alluded to

potentially some challenges

and I'd test just something called the

hrd I also said next Generation

sequencing what do I mean by that we're

doing the same testing we do on the

genes we do on the tumor and we're

looking at mutations which are

potentially actionable

what do I mean we have drugs which can

Target those mutations on clinical

trials sometimes off clinical trial

there there is there's rare mutations

and track infusion I'm still looking for

one my partner just found one

um not an ovarian cancer but we just

found one so uh you know there are

mutations that have very high response

rates which there are drugs that we can

Target both on clinical trial and off

clinical trial yeah I agree I and we'll

we're going to show some example

say just to look at kind of show the

audience how we think about finding

these do sometimes you're looking for a

needle in the haystack but when you find

it it's meaningful for that patient and

so we do look

um and let me just interject there

before we go on this you know needle in

a haystack you say well that's only one

to two percent of the time but if you

have four or five one to two percent of

the time now you're five to ten percent

of the time right so I think when we're

looking at these it's not it's it's it's

a number of needles in a haystack which

add up to probably

you know with bracca somatic testing

which would be 10 to 15 of patients

you're looking at as many as a quarter

of a patients maybe even a third which

will be actionable mutations if you send

this type of testing on the tumor

so it is Meaningful to sense

um so

shipping it's going to take the number

of weeks to come back you got to get her

going so kind of same question is before

what would be your chemotherapy how are

you going to think about her

chemotherapy backbone and are you going

to use the vicism apps for this patient

yeah so this is the data really looking

above a city map which unbelievably is

consistent with with changes

improvements in the progression-free

survival at three to four months if you

add Bev and platinum sensitive disease

now the only trial that showed survival

Advantage

was the grg 213 we alluded to that

earlier which was uh utilizing Bev in in

U.S like population so in those patients

this patient who hasn't had bed before

who has disease outside or abdominal

cavity again very straightforward in my

mind I'm going to try to utilize Bev if

she doesn't have a contraindication to

it what are the contraindications

there's a lot of disease on the bowel

uncontrolled hypertension

um there are some other relative

contraindications uh with regards to

vascular disease and cardiac but um

those those those contraindications if

the if she doesn't have one present I'm

really going to try to get Bev to

increase the progression free survival

potentially impacting uh her overall

survival I mean how about you are you

gonna are you gonna add Bev to her

yeah I'm definitely

gonna well it would be thinking

this is a map here and I think I said

before and the first recurrent setting I

do tend to favor

carboplatin and doxyl

um with or without the vicismab but you

know my expectation for this patients

and every patient until proven otherwise

is that what I'm going to do is going to

work and that when they do occur again

they'll still be sensitive to platinum

so I'm going to come back to carvo gem

at some point and I may come back to

carbo taxol at some point or cover

Platinum alone we use carboplatin until

carboplatinum stops working or what can

happen is that your body develops an

allergy to the carboplastin which is

really frustrating

um and then we have to be a little bit

more creative about how we treat the

cancer that's still sensitive to

platinum so it's not one of these and

we're done like a lot of times patients

will see several of these doublets

um across their trajectory is we're

really kind of quilting together these

increasingly long periods of time

between recurrences that cumulatively is

keeping our patients alive longer fun

treatments a lot of the time which I

would prefer we could cure but we are

doing better in terms of lengthening

that time of survival

but this patients we talked about

secondary side reductions not indicated

because she did not meet the agio

criteria she does have

um as we said peritoneal metastases but

when you review the CT scan it's like

all up kind of just tracking up the

rectus sigmoid thicken looks a little

inflamed you're worried maybe that

there's some Invasion there and so

bevacism has kind of contraindicated for

her and so

uh gave her carboplatin and doctoral

alone for six Cycles

instead of partial response a pretty

good partial response but it didn't all

go away

and I do get her molecular testing back

during this because you have to start

the chemo before you have the testing

back a lot of the time and she as we

knew is Barack a wild type she doesn't

have a somatic bracha

and she's but she is homologous

recombination deficiency test positive

and I'll remind you she's already had an

araparid in the front line for about two

and a half years of Maintenance so Dr

Mali what were six Cycles what's your

maintenance plan for her

yeah this this is a tough one right

because she's progressed on

uh parp inhibitor before so uh in the

Oreo trial which you have up here

um this was re-treatment with

retreatment with parp when they

previously had parp if they had a

response to the platinum-based therapy

so in this scenario

um

I don't believe the patient would be

eligible because she had progressed so a

patient who had progressed on parp I am

not going back to a part unless as part

of a clinical trial because in that

scenario we're adding a second drug

right but if this patient would have

stopped say at two years even though we

know the the rapper of date is three

years she would have stopped at two

years then and then uh progressed six

months later

I would have a conversation about going

back to harp with her

um absolutely have a conversation uh you

could argue that the part was keeping

her disease at Bay and then when you

stopped the parp it started to grow and

you see here that the array of data

really looked at a small group of

patients I guess it wasn't that small it

was a couple hundred but a group of

patients that are wildly sensitive to

platinum therapy a group that you just

referred to

so when they're wildly sensitive to

platinum therapy they haven't progressed

on a prior part I will have a

conversation about going back to a park

part of that conversation has to be AML

and MDS leukemias right because the we

we think we don't know we think the more

exposures we have to part is potentially

increasing our rate of secondary

malignancies so again that's where that

shared decision comes in so in summary

if a patient's progressed on parp

outside of a clinical trial I'm not

going back to a part but if they had

prior part

and then stop therapy then recurred

absolutely having that conversation uh

and we just had some data that came out

of um uh ask one of our big National

meetings showing that those patients are

really different the patient who

progressed on part versus the patient

who had previous part I call those purp

exposed and then they progress so those

two patients are very different in my

mind I mean how how would you how would

you go back to harp on on this patient

who progressed I do consider

um re-treatment if I don't have a

clinical trial available

um which we'll talk about in a moment

um but I I agree with

um kind of the the theme that you

brought up that this study this is the

array of study was a very

um unique population of patients when

you make the statement about extreme

Platinum sensitivity just so our

listeners understand and it's in the box

here

this group of patients isn't the patient

we were just talking about in my case

who's at her first recurrence if you can

see here in the upper box you know

almost actually over 50 or right at 50

percent had had four or more platinums

when they came onto this study and we're

still responding to platinum so Platinum

Platinum Platinum

Platinum again responded come on the

study or even another Platinum so that's

a very unique phenotype and we don't

often see that and so so these patients

had gotten apart before and progressed

on it they had to stay on it for at

least six months or at least 12 months

depending if they're a breath or not but

there's their tumors are so exquisitely

sensitive to platinum that when they got

a park again you did see a benefit but

not much and I think that's the thing to

say you I think our audience even if you

don't know how to read a kaplan-meyer

curve can see that the majority of

patients these are patients that bracha

mutations and these are the patients

without bracket mutations

that the majority whether or not they

got a park or Placebo for maintenance at

that first CT scan like half of them had

already progressed

and so there is a small group who

benefits from partagan and that's real

and so I do consider it

but I really think about kind of who I'm

giving that to

um and I probably wouldn't be someone

who progressed on Frontline Park to your

point start from alley

um but that's not who was in this study

so this study does show us we can reuse

parp but it should be selective

um and

and we and I think the bottom line is we

need better drugs and maintenance rather

than just repeating things like let's

just develop some new things but you can

consider that just like we already

mentioned that

um you can repeat bevacismab as well now

the data actually for repeat by the

suzumab is a little bit stronger than

for parp it actually works just as well

and this is the study that proved that

if patients got bevis's met with their

first chemotherapy and you gave it with

their second chemotherapy they still did

just as well and their response rates

were higher so there's probably stronger

data for repeat use of bevacismab then

repeat use of carp inhibitor

um so I think I would emphasize that

doesn't really apply to this patient but

just to make the point that sometimes we

do reuse things

and they can work pretty well

and that's a great point which is the

you know your your difference again

progression free survival very

consistent three to four months and this

is here again looking at about a 10

increase in your overall response rate

you know with much more uh complete

responses and we talked about the impact

that halves on our decision making but

that was a great segue into clinical

trials and better ways of uh of of

Maintenance therapy so if this patient

would have been eligible for Bev

um

this is a trial that that I'm leading in

it's it comes from a long uh history of

combining Merv which you've led the

trials that have uh will will have led

to the indication with Merv the

antibiotic drug conjugate folate

receptor Alpha

um and so we have a clinical trial right

now Merv is indicated in Platinum

resistant we'll talk about that in a

second so Murph I'm sorry I referred to

as Merv from toximav or the trade name

for that is Ella here

it is we're trying to find ways to

utilize the drug earlier and so a

clinical trial is look at patients who

are on Bev for platinum sensitive

recurrence first first Platinum sense of

recurrence and then the randomizing

patients to continue Bev which is what

we normally would do continue Bev give

about six cycles of the Platinum doublet

and then drop the Platinum doublet

continue bath and now we're adding uh

merbe and comparing it to what we've

always done which is Bev and so this

this clinical trial is up and enrolling

very very important to screen early on

for platinum sense of disease to see if

you're in that 35 to 40 percent of

patients that will have high folate

receptor Alpha expression so something

to ask your providers have you been

screened for this trial if you have a

platinum sense of recurrence and if not

is there a a center close that you could

potentially that you could potentially

go to if your phone to be screened uh

excuse me if you're found to be folate

receptor Alpha High

yeah so just

um can you just reiterate a little bit

what's the biomarker and how do patients

know if they have the biomarker oh great

question so so fully receptor Alpha is

looking at its PS2 plus we don't have to

get into that but it's looking at how

much of the folate receptor Alpha is on

the cancer cells okay and so you can

screen a couple of different ways there

are commercial uh uh vendors commercial

companies which we send tissue off and

part of their normal results is to say

if we have high folate receptor Alpha so

we can utilize that as screen now in the

protocols just uh but also if you're at

a center that has this trial open you

can sign a consent form where that

tissue is sent off to be tested to see

if you're eligible and that's paid for

by the clinical trial so there's two

different ways you can do you can have

it tested by the commercial vendor

there's many different ones that have

the fully receptor alpha or is part of

the clinical trial and the screening

consent while you're on therapy for

platinum sensitive to see if you're

eligible to go on to maintenance portion

which is the clinical trial

yeah so I think what um is important for

listeners to know is that

you know many of you have had testing

done in the past there's a variety of

molecular tests they have various names

Terrace Tempest Foundation

neogenomics there's a bunch

um

but before November of last year they

did not have fully receptor Alpha

included on them and so you may have had

testing scent but that wasn't known so

this is something that can be tested now

in you know just to know for the future

or if you are receiving chemotherapy in

the Platinum sensitive setting you can

request it to be sent so it will get you

access either to this trial as a

maintenance or

um for just use of Ella here or more of

a toximab in later lines of therapy so

it's um something that just gets added

on you have to kind of catch people up

who were tested before last year we're

kind of catching them up now so we know

who our whole receptor Alpha expressing

tumors are so we can get them the right

drug at the right time so just something

to think about we're always having to

retest as new tests emerge

um so we know what is on our patient's

menu of options

so let's move on to the last case which

is probably our most complicated setting

is this is a patient with um with

Platinum resistant a platinum resistant

tumor so this is a 75 year old patient

she's a history of stage four uh ovarian

cancer she was treated with neoaded

chemotherapy got an interval surgery

that was actually successful and they

got three more cycles of

papotaxocarboplastin followed by the

wraparib here for just which is a parp

inhibitor here for just a year and then

she progressed so 12 months is her

Platinum free interval

um she was still considered sensitive to

platinum so that carboplatin and doxyl

with the vicismab for three cycles and

on her first CT scan is noted to have

progression with fortunately no ascites

or bowel obstruction but does have

disease in the chest in the mediastinum

and some nodules in her for abdomen

otherwise feeling okay and good

performance status so you know can be

treated with what we think is best

bathroom alley this patient's been sent

to you for a consult now she has disease

considered resistant to platinum in

general how do you think about treatment

options for a tumor that's considered

Platinum resistant

well you know I think as we look at this

I step back particularly when these

patients come to to me for a second

opinion right which is okay what's her

histology is she serious is she mucinous

clear cell is she high grade serious or

low-grade serious so obviously the

difference treatments for low grade

serious versus high grade serious

everything we've really talked about up

to this point has been serious cancers

these other rare tumors we'll talk about

low grade in a second but the high grade

series I want to confirm I want to go

back and even have the pathology

reviewed making sure I have that those

what we talked about the Next Generation

sequencing but a really important aspect

of this is this particular patient

progressed on the Platinum doublet with

pld and carboplatin but if she would

have gotten a complete response and then

recurred within say four or five months

the classic historical definitions would

have been well she's primary Platinum

excuse me she's Platinum resistant but

really Platinum resistance applies to

the first line therapy so the nccn

guidelines got updated this year and

they now utilize platinum and platinum

doublets and you see here on the screen

and we've highlighted some of the

changes in the nccn guidelines

so they're they're they are now saying

continue to utilize Platinum until

they have progressed on Platinum or they

have a hypersensitivity they're not and

or they can't tolerate and there's

people with hematologic toxicity

what are some other options I really go

through this list and unfortunately

they're somewhat limited outside of

clinical trial there's probably about

three to four options

um you see on the left side

cyclophosphamide doxorubicin gems gem

CIS which is part of the Platinum uh

combination I fost mine I can't tell you

the last time I use iphosamide for for

uh ovarian cancer but it is Irene and

tcan same thing

exabethalone bath based on a phase two

trial very interesting our colleagues at

uh Yale uh targeted uh utilized and ran

this clinical trial really interesting

data when you combine it with Bev this

is a drug that's approved in uh breast

cancer and some others which are listed

the most common ones we use are

paclitaxel and we've talked about pld

dopo tcan so but these are some other

recommended regimens Beyond those usuals

that we will utilize now

when I have a low grade completely

different right I I don't I will use

some of these but really I'm looking at

other therapies I know Katie this is one

of your passions how do you look at with

a low-grade serous cancer patient

yeah so just like you said and I see a

lot of content

to diagnose but if I'm sure I have a

patient presenting with a recurrent

low-grade tumor

chemotherapy is still in play like it's

not entirely inactive and that's

important to say it's just not as active

as it is in high grade Cirrus so it's

still there but we tend to go to

endocrine therapy before we kind of one

of our colleagues calls it the breast

cancer of the pelvis we tend to use our

breast cancer regimens with endocrine

therapies letrozole

um Sylvester and combinations with cdk46

Inhibitors kind of routinely and in

emerging you see it here on the under

targeted therapy on the um right hand

side of the slide

um you'll see at the very bottom

tremendous these are Mech inhibitors so

these are listed on the nccn they are

not FDA approved but these are targeted

therapies that really Target

um uh tumors that have alterations

in that particular pathway and they have

a reasonable response rate it's about 15

to 20 percent

um and they can kind of hold disease

stable for a while but they do have some

toxicities that are somewhat limiting um

we have to watch cardiac function very

closely and they cause rash

so one of the clinical trials that is

has been enrolling and is about to

launch in a big phase three is taking

the next generation of Mech Inhibitors

these are Mech there's a combination Mac

Wrap inhibitor called a glutametamin a

Ruto which is hard to say

Plus what's called a fat inhibitor so

it's two drugs but basically three

targets

that use meth and then outsmart the

mechanisms of resistance

and that has been shown you'll see some

data in an upcoming meeting I wish I

could tell you that that's playing it

right now but it's embargoed where we

actually see high response rates which

we don't ever see in low grade we

stabilize low-grade tumors so you don't

see them shrinking a lot you just see

them not growing here we see them

shrinking

um and not growing for a long period of

time so this is led by a company called

veristem a glutamateinib and defaxanib

it's about to launch its big phase three

so keep your eyes peeled for that if you

do have a low-grade tumor

um it's not without toxicities

but they do appear to be less less rash

less cardiac toxicity than Mecca alone

but the phase three really adjudicate

that but we do think this is one of our

more exciting opportunities for low

grade right now like when you and I look

at a test like this what do you what do

you see here when you're trying to plan

options for your patient

um Dr O'Malley like what things stand

out to you as targetable yeah so I think

anything targetable you've brought up a

really really good point of mine

emphasize for the audience right which

is if you would have sent this tissue

testing six months ago no no a year ago

it would not have given you the folate

receptor Alpha so if this patient recurs

in Platinum resistant I need to make

sure she has folate receptor Alpha

tested because it wouldn't have been

sent for example when she's Platinum

sensitive a year ago which is what I

said right so it's very important that

it you haven't had that testing that

it'd be resent now what am I looking for

Action view mutations right starting in

the bottom right folate receptor Alpha

urby2 hertenew we have antibi drug

conjugates targeting her2 at this point

um you have the big you know red arrows

CCNA amplification we have uh trials we

want Inhibitors uh ATR Inhibitors which

are targeting this Machinery obviously

Brack a Rad 51c or d uh so this patient

had had a part so it's a bit of a moot

point but we have we have a trial open

right now targeting Aaron 1A mutated

tumors and what else you can't forget

about that rare but actionable uh uh

n-track infusion that every referred to

and the reason I laugh is Dr Moore and I

continue to look for these are

unbelievably rare but um but you know

what else we see rarely is tumor

mutational burden high or MSI so we

really have these opportunities though

it's only about one to two percent of

patients that if you have that that

immune therapy is shown to work very

very well so you know it is it is a a

small chance but as we said earlier in

this conversation a one to two percent

chance you have enough of those and now

you have a real opportunity

uh there's just so much here Katie I we

could talk all day

um what what else what else do we need

the audience to know about you know the

way when we look at these but this is

just your point I I just want our our

patients to sort of understand what

we're we're kind of scheming in the

background of what things make the most

sense for you while you're on standard

of care medicines for for platinum

resistance or maybe another trial so

every single one of these that I and I

should have I'll get Baraka one every

single one of these are like we look at

every single one of these so some of

them this patient doesn't have she

doesn't have bracha one or bracket two

um so check those out I make I'm always

double checking that I didn't miss

something MSI is microsatellite

instability

um two rotation burden those are markers

for immunotherapy which are rare it's

like two percent will have abnormalities

there this patient does not

but if they do I want to get them an

immunotherapy even though that's not

common arid 1A there are clinical trials

for Aaron 1A there are clinical trials

for ATMs there which she doesn't have

those two

um CC need one amplification does she

have that have trials she doesn't have

that but she does have that fully

receptor Alpha expression

it says negative though so you might say

well why are you talking about that

but she actually is two plus 40 which is

a medium expressor so this is something

that Dr O'Malley and I are trying to

make sure our providers understand is

that it's not black and white it's not

like positive negative

the FDA indication is for high but we

have data for medium where it works

really well which I'll show you in a

moment

this is just um the next page I pulled

another sheet of um

there we go

for sure

sorry

there we go

failed Advanced Zoom today here we go I

just pulled another sheet off another

um

uh

uh

well my circles are there I really did

fail advancing but we'll get over it

um I pulled another sheet up just

another patient so you could see kind of

the other things we're looking for

um you know there's there's clinical

trials open for ovarian cancers that

have KRS mutations right now this

patient doesn't have one but I'm looking

I have a checklist does she have a k-ras

does she have a rad 51d that shift tp53

those things all matter

um in terms of how we're thinking about

patients and trying to making sure that

they have options to access the trials

that are most relevant for their tumor

it's getting very individualized

um finally

um which is what you want

so um so this patient

um just to come back to her uh Dr

O'Malley so she you know she had

severicism ad and progressed on bevacism

um and her third line treatment I think

you alluded to is sort of monotherapy

chemotherapy weekly packed with tax

cells probably our most relevant option

and so when Platinum is not an option

you said that virusesumab is kind of off

the table for her but why don't you take

us through sort of how you think about

in general standard of care for platinum

resistance we really look at in in the

use of of of avocado map has really been

shown to not only improve uh upfront in

Platinum sensitive but really Platinum

resistant and this is really uh where we

see

um impact on symptoms control we have

not seen impact on overall survival but

we have seen impact on patients with

ascites whose tumors are whose tumors

are causing them symptoms abdominal pain

distension uh pressure and when we have

those symptoms it is uh is pretty clear

that the utilization of a civil map with

chemotherapy helps and now we see that

we've alluded to this weekly path of

taxol being one of is is is a higher

level of response but yet it also has

the highest inconvenience not highest

but it's inconvenient It's weekly side

effects neuropathy hair loss neuropathy

damage to the nerves and hair loss so

though it has one of the better response

rates it's more difficult to tolerate

um for multiple reasons so and I would

argue that the Merv now is giving us the

same type of response uh without some of

those safety now on fortunately our

response rates in single agent

chemotherapy are modest are modest

really thirty five to thirteen percent

are the response rate now this is

clinical trial response rate so those

are disease which shrinks at least 30

percent we have many of these of these

uh agents that the disease will be

maintained or just shrink a little but

not hit that 30 percent so these are

underestimating the clinical benefit

underestimating the clinical benefit but

these are the response rates which we

talk about in clinical research and you

see again modest or modest I think the

next slide Dr Moore we have the uh so

this is really the opportunity when we

talk about clinical trials and we talk

about having more options for our

patients I love this diagram and this is

really looking at the number of Agents

out there that are being developed in

Platinum resistant ovarian cancer

and we have so many more options than

what's what's available to us through

FDA approved agents or commonly used

agents

through clinical research

Katie I know that this is one of your

passions and you're involved in so many

of these jobs well we both are but I

think this is it was beyond the scope of

this this presentation really take you

through all of the trials that are open

but really just to highlight a few that

are really interesting you know I

mentioned to you we look at the few

patients who might be eligible for

immune therapy meaning immune checkpoint

Inhibitors like pembrolizmab which you

know is ketruda they don't work very

well and ovarian cancer except in a few

but there are studies ongoing a very

novel immunotherapies this is one of

them is called nemvelucin which is

interleukin-2 it's run by a companies

called alchemers they have a study a

very interesting study going with

combination of

of a checkpoint inhibitor Plus il-2

versus chemo and that's open and

accruing right now and it's not

biomarker link but it's really taking a

very novel strategy

um towards uh ovarian cancer that I

think is exciting and I'm excited to see

kind of the results of that that play

out and then we talked about more of a

Texoma we're going to show that in the

next slide that's how we're going to end

this talk that's here this one is FDA

approved now so it actually met made it

into the bullseye here but there's

others out here this is

um a drug called rdxd that's entering a

clinical trial soon it's another

antibody drug conjugate like

mervitaximab but it targets a different

protein and it has a different chemo so

it's another targeted chemo that will

open up hopefully

uh eligibility for these anti-drug

conjugates Beyond fully receptor Alpha

so we're excited about that are there

any others on here you wanted to call

out Dr O'Malley that I didn't well I

think yeah I want to talk kind of more

you know what what are and you broke it

down here from so overall immuno

oncology we believe this next generation

of immune therapies by specific

antibodies the next generation of il2

um you know is one group okay then we

have a further agents being developed

anti-angiogenic also these bi-specific

antibodies okay now we're trying then we

go to the left side of it and we're

trying to manipulate the the cell how

the cell communicates how the cell

repairs itself okay and so you know the

we one Inhibitors a zentalis has two

really cool trials out there okay and

then antibiotic drug conjugates I I mean

we have the the world of antibiotic drug

conscious continues to get the targets

get better the the the the payload the

the cytotoxic what kills the cells are

getting better how those are linked are

getting better and we're going to

continue to develop drugs like they have

in breast cancer that really targets the

right drug the right patient at the

right time I love you said that earlier

I think I added one more part to that

but you know that is that's really the

four making sure and you know what we're

going to take you know you have the

opportunity as a patient to get each one

of those sections and maybe a couple

within the same texture because

antibiotic drug conjugates with

different targets in different uh

payloads are going to allow you to get

more access to those agents

exactly

exactly and so we're you can tell we're

kind of the most excited about insulated

drug conjugates

because they work

um so I am a little biased so uh and so

we are just gonna

um kind of end for this particular

patient that I showed you

um who I showed you the the Keras

testing and she's fully receptor Alpha

medium and so she doesn't need

eligibility for by the FDA approval uh

that came from the Soraya study and

student miracle for full receptor Alpha

High so

um do we have to say that however

Dr O'Malley can tell you about his trial

called forward two and why this may be

an option for her yeah so what we did is

on that trial we enrolled

um uh patients across all Expressions

okay

um they've decided to do construction

right above me so if you hear background

noise I apologize but um you know what

we've done here is we we publish our

experience across all folate receptor

Alpha expression and we show that the

response rate was right about 40 percent

when we combine Merv plus Bev okay and

really consistent across all levels of

folate receptor Alpha expression that we

hit a 40 response rate remember that's

the clinical trial definition of

response rate the the the the schema on

the upper right excuse me the the

diagram on the upper right you see that

almost all patients had some clinical

benefit okay and so what the nccn did

when they listed out the guidelines for

Merv beb they just said folate receptor

Alpha expression they didn't say hi

medium or low they just said expression

so this has become an option for our

patients

um even those that don't have high

expression now

Dr Moore said this is not the FDA

approval this is an off-label discussion

that we're having but it is nccn

guidelines listed it's called a category

2B and this is an option for patients

how low a folate receptor Alpha

expression

um is something that we would use it

well anything less than 25 percent

without debate I shouldn't say without

debate we would not use because that

would be considered uh uh

essentially negative but you know when

we're really looking at those levels at

25 to 50 50 to 75 and greater than 75

those are considerations that you'll

that you should have a conversation

how about you what how how low my

especially pharmacist uh Dr Moore asked

me how low is too low the other day on

folate receptor Alpha expression I mean

I I it's hard for me to say because you

know it's I am biased because I've

participated in this development of this

drug for a long time so I think our

listeners should know that that but it

is a biasing mind uh and I've seen it

work in low so I you know I I feel like

it's uh it should be available

um to people to try if they're well

counseled but I tend to use the two plus

as a general marker because because we

still as you mentioned this is NCC

enlisted is not FDA approved and so some

insurances will not allow this uh and so

I have to emphasize that but but many

will because this is published and you

can show the benefit and I do think it's

worth a try and I've been able to get it

from my patients the one thing I wanted

to point out to our because there's a

lot of patients and and I on that are

listening and I actually draw these

waterfall plots for my patients when I'm

explaining response rate to them

um because response rate often sounds

terrible but we're sponsoring on a

clinical trial is Dr O'Malley alluded to

means that we we add up all of your

tumors on the CT scan at the beginning

of the trial and then we add them all up

again at some number of CTS later a

response rate means you've decreased by

30 or more that's what this dotted line

is showing you here and so it is true

that all of these patients who

participated had a 30 reduction and they

will disresponders that's your 40

percent

but these patients here their tumors

didn't grow and many of them shrink some

so this is clinical benefit and this is

what we care about as Physicians I mean

I care about response rate as a childist

but as a physician in front of a patient

I care about their tumor not growing and

shrinking as much as it possibly can but

I'm fine with 20 as long as it doesn't

grow right back so this is really what's

missing when we talk to you guys about

response rate response rates below this

dotted line but this is still the

patients who benefit these patients

unfortunately it didn't work

but there's not many of them which is

why I'm kind of pro using things so just

so you understand where the definitions

come from

um

any final words Dr O'Malley on on

Platinum resistant or recurrence or what

you'd want patients to know

you know I think

um making sure you're being seen in a

site that has a large volume of ovarian

cancer uh patients uh expertise within

ovarian cancer is very very important

making sure that you have access to

clinical trials to the best of your

abilities some some patients live in

areas that they just have trouble

getting access there's a lot more

resources available today than there was

a few years ago with regards to

supporting patients so they can

participate in clinical research and

that's really how we're going to get

access to these exciting drugs before

they're approved

and so you know is there an option for a

second opinion to a site that's a high

volume or to a site that has a lot of

clinical trials it's it's a possibility

Clarity has done a wonderful job of

trying to match patients to sites that

have these options for you and we're

there and we want to help you and thank

you for taking the time today Dr Moore

and bring us home thank you thank you

for taking time to join us for this

ovarian cancer online Symposium the

clarity foundation and the juji

foundation Incorporated would also like

to thank our commercial supporters for

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thank you so much for joining us and

have a great day

thank you