Who's the expert?
Name: Dr Pamela Munster
Institution: UCSF
Professor, Department of Medicine (Hematology/Oncology), UCSF; Director, Early Phase Clinical Trials Unit, Co-leader of the Center for BRCA Research, and Leader, Developmental Therapeutics Program.
Clinical research interests are first-in-human early phase clinical trials of novel compounds and alternative strategies for the treatment and prevention of cancer.
Has been involved in clinical and translational research in early phase clinical trials since 1998 with a focus on translating preclinical findings into early-stage clinical trials. Dr. Munster's basic research interest is centered on the role of epigenetic modification in therapy resistance in breast cancer and epigenetic priming.
*****************************************
Call Leader: Hello?
Doctor: Hi.
Call Leader: Hi, Doctor Munster.
Doctor: Can you hear me?
Call Leader: Yeah, hi. Hold on one second. Hey, can you hold on one second? Okay.
Sorry. Dr. Munster, Thank you very much for taking the time for this call
today. We're looking forward to hearing your thoughts on the space. For
compliance purposes, I'd like to confirm a few points, which I'll read through
and then you can grant your verbal consent at the end.
First, this call is being recorded and a transcript of the call will be available
to members of the Slingshot community. Second, you, the expert, attests
that you will not disclose any confidential or material, non public
information. And third, you're attested if you're a physician participating in a
clinical trial, you will not discuss information not yet in the public domain. If
you're a member of a scientific advisory board, you will not discuss ongoing
clinical trials. If you're a member of a clinical trial steering committee,
and/or data safety monitoring board, you will not discuss the drug that is
the subject of the trial or the active trial. Do you agree to these terms?
Doctor: Yup.
Call Leader: Great. I'll serve as the call leader today. I, too, am required to keep any
material, nonpublic information confidential. I attest that I will not disclose
any material, nonpublic information or information that would break any
confidentially agreements by which I am bound.
Then additionally, I'd like to note that this call is intended for informational
purposes only, not investment advice. The contents of this call, including any
and all information provided regarding individual securities or industries do
not constitute financial, legal, or tax advice.
All participants are on mute on this call with the exception of you as the
expert and myself, who's prepared questions with some input from other
people that have joined the call.
Finally, this call is sponsored by PharmaMar, PharmaMar is a company
focused on oncology and committed to research and development, which
takes inspiration from the sea to discover molecules of antitumor activity.
So, with that out of the way, we can get started. Answer the questions that
we've got going here. So first of all, good morning. I really appreciate you
making time early in the day to speak with me. I've been following
Lurbinectedin and the different developments for a while and getting into
the BRCA2 information and some of the details of the mechanism that we're
going to talk about today is something I've really been trying to get my head
around. I'm interested in that. Obviously I've ready your background and I’m
aware of some of your lab research, but do you want to give me a little bit of
a sense of your clinical background and the work that you're doing in terms
of different genetic mutations at the BRCA research lab? To get started.
Doctor: Okay. I'm a medical oncologist by training, and I have been working in,
mainly focused on breast cancer for many years. In that I have an active
research lab that's focused on developing novel targeted strategies for
people with advanced breast cancer. In the last 10 years, I have worked a
little bit more on more general cancers, not just breast cancers. I lead the
phaseon program at UCSF. In pretty much most solid tumors the heme
malignancies are also overseen by my group, but I am not a hematologist.
With this in mind, there's two things that are relevant about two years ago. I
cofounded with Alan Ashworth the Center for BRCA Research. Now, just a
heads up, there are two heads.. I’m the Phase 1 chief at UCSF. Of course, I
have a lot of proprietary information. There will be some instances where I
will say I can't answer that.
Call Leader: Yeah, no problem. No one on the line would like if that if you did.
Doctor: I think you understand that.
Call Leader: Certainly. I think one of the things ... I sent over to you some slides on
Lurbinectedin's mechanism action and some of the data in the metastatic
breast cancer population. I think that's where we want to focus anyway, and
not on any confidential trial information. Maybe to start the conversation,
the company talks about transcription and the importance that
Lurbinectedin has in that process. Could you maybe talk to me a little bit on
the high level about your understanding of the mechanism, and what it is
about Lurbinectedin that has you excited in these patients? Is it just the
data, or is there a scientific and mechanistic rationale for the drug that looks
particularly interesting to you?
Doctor: I think it's a combination of both.
Call Leader: In terms of the mechanism, could you talk a little bit about what it is on that
level that makes Lurbinectedin look unique and interesting to you?
Doctor: Yes, there's two of ways. I mean, I think it's very clear that people with germ
line mutation or symatic mutation, meaning the tumor has the mutation
only, not the germ line in the DNA repair pathway are much more sensitive
to DNA damaging agents. Now, this is evident by sensitivity to carboplatin
and in the breast cancer space, looking more and more backwards what
we've done over the last 20 years. It become more and more clear that
people who respond well to drugs like doxorubicin are those with DNA
vulnerability having a BRCA1 or 2 mutation. It was like DNA damage agent
sensitivity is very clear.
The problem we always had is the therapeutic window is fairly narrow.
Nowadays, time and having drugs that cause significant nausea vomiting for
days, and hair loss and longterm regrowth of leukemia and toxicity is going
to be increasingly challenging. Then I think we don't have...the PARP
inhibitors are really good in ovarian cancer. I think the recent data with
Olaparib just shows that that efficacy is just not there for breast cancer and
it's certainly not there for BRCA2 mutated breast cancer. Which is the ER
positive patients. And right now it looks like we have a lot more triple
negative BRCA1 positive patients. I don't think that's really the case, I think
what happens is because the BRCA1 mutated breast cancers happen a little
bit later in life, patients have not been as readily tested. With more global
genetic testing you will see many more patients that are BRCA2 mutated
and ER positive come out and this is going to be the group of people who
really need treatment.
Call Leader: There's a lot of things there that you just hit on that I want to dig into a little
bit more deeply, but in terms of thinking about how Lurbinectedin as an
approach impacts DNA damage and how scientists are trying to understand
why Lurbinectedin might be successful in these BRCA patients, particularly
BRCA2 patients. How well understood do you think that is and could you try
and explain to me a little bit. I don't have a full science background even
though I've been looking at oncology companies for a long time. I'm trying
to get a sense of how well understood that mechanism is and I think the
company has talked to DNA transcription ...
Doctor: So, I think more simply put, I don’t think we know the full details. We know
that the drugs like doxorubicin which cause double strand breaks are
probably among the most successful drugs in the BRCA mutation. That with
doxorubicin, Lurbinectedin also cause DNA double strand breaks and that's
an important part of breast cancer. Now, I worked for many years in
epigenetics showing that if you inhibit the repair of DNA double strand
breaks, you get synergy with doxorubicin and [inaudible 00:08:48] inhibit
you do exactly that. So I feel very confident that the induction of DNA strand
breaks and the maintenance of them the BRCA mutated tumors cannot
repair will actually determine efficacy.
I've been working in the DNA double strand breaks for more than a decade.
This is a drug that has a fairly decent side effect profile. It looks pretty
active, so hence my excitement.
Call Leader: Excellent. Understood. You had mentioned, when we were having some
preconversations, about working with Yondelis. Had you looked at that? I
want to talk a little bit about how the profile of Lurbinectedin looks relative
to Yondelis, but had you seen some impact or efficacy in the BRCA2 and 1
patient with the Yondelis or was that investigated years ago before the
Epigenetic testing was really understood and used in these populations?
Doctor: Given the fact that ...
Call Leader: [crosstalk 00:09:53]
Doctor: Given the fact that I don't see that many sarcomas and this been a drug that
has been around for that, as I told you before I saw Yondelis in its infancy
when a lot of the side effects were not worked out. I think this one has a
much cleaner profile. I'm looking at what PharmaMar shared with me in
terms of the toxicity it looks very good. And you know, the question what
bothers patients is, neutropenia is not what bothers patients. Neutropenia
bothers doctors. Diarrhea bothers patients, hair loss bothers patients, so I
think one has to be very clear, you can have 80% grade 3 neutropenia and
no one would be bothered by that. But you have 80% leukocytes or diarrhea
that is grade 3, you won't be able to give this drug. [inaudible 00:10:48]
Call Leader: Sorry, I think you broke up there for a little bit. In looking at the profile ...
Doctor: [inaudible 00:11:00]
Call Leader: I think your line ...
Doctor: [inaudible 00:11:03]
Call Leader: Go ahead. Your line broke up just for a second there. You were saying
neutropenia and to keep in mind ...
Doctor: I said, keep in mind that it's not the global harmony grade 3 and 4 toxicity
the drug has. It's like what type of grade 3 and 4 toxicity a drug has. A grade
2 nausea, vomiting, and diarrhea can make a drug very unenticing and I
think, keep in mind, where I sit it's one thing to get the drug to approved it's
another thing to sell it. I think it's really important early on to be mindful
that a drug with a fairly clean side effect profile can really have a lower
efficacy and still be a good drug. Whereas a drug with high efficacy but a lot
toxicity is still going to be a challenge.
Call Leader: Got it. Understood. I wanted to talk a little about BRCA2 patients in
particular. Are those patients currently being identified generally and
especially in metastatic breast cancer what’s their prognosis relative to
other patients? Could you maybe talk to me about what it looks like for a
patient who has that type of mutation? Right now, with current therapy.
Doctor: In ovarian cancer, pretty much every patient with ovarian cancer gets
genetic testing. In breast cancer, depending where you are, a lot of patients
get genetic testing, so clearly everyone is on the 50th family history gets
genetic testing and gets identified except that the onset of BRCA2 mutation
related breast cancer is actually not mostly on the 50. It's actually above 50.
A lot of these patients historically have not been identified. Now, I think this
is going to change with the recognition of this and the recognition that PARP
inhibitors are out there. Patients are more sensitive to carboplatin if they
have a mutation so maybe 2530% of patients with breast cancer get
germline testing, if it's even that high. This number will rapidly increase over
the next few years but the market, or the accepted market, will vastly
increase.
Call Leader: Understood. In terms of how these particularly in breast cancer these BRCA2
patients, like the prognosis and course of the disease for them, are they
better or worse off typically in terms of how treatments go for them and
overall survival rates and things like that?
Doctor: I don't think we have that answer yet.
Call Leader: Okay, I wasn't if that was an area of particular need or not.
Doctor: No, this is an area of particular need. If you look at the olaparib data, these
patients did not respond well to olaparib. Expectancy of survival was very
short on both the chemo arm and the olaparib arm and this was after
wanting two lines of prior therapy which is typically, for a breast cancer, not
a lot.
I think in ovarian cancer BRCA2 is the good prognostic and predictive factor.
In Prostate it’s terrible. People with BRCA2 do very poorly and we don't have
enough PARP inhibitors. We just don't have that answer yet because it has
been this general ... BRCA1 and BRCA2 is always being named in the same
breath and treated in the same breath, but I think they are different
diseases. We would never consider a triple negative mutation [
estrogen/progesterone receptive negative patient with an
estrogen/progesterone receptor positive patient.
It’s unusual that BRCA mutation is put in one basket. That's what has been
done in the last 15 years. Many of these questions are simply not answered.
My personal opinion, looking at the data, I they we don't have a good...I
think they are in dire need of good drugs because I don't think they respond
as well to hormonal therapy and I don't think respond as well to general
chemotherapy. Again, that's my personal opinion. Opinion is one dataset.
Call Leader: Right. When I think about the prevalence of BRCA2, can we talk about that
in ovarian and breast, the company pointed to 7.5 thousand 7,500 new
cases in the United States for breast each year and then 11,000 in the E.U.
Do those numbers seem about right? To your point earlier, how well tested
are these patients and how well identified is that number versus potentially
it could go higher or lower.
Doctor: I think these numbers are, assuming roughly 200,000 patients with a new
breast cancers, of which, depending on which age there is about 37%
prevalence of BRCA1/BRCA2 mutations in that these numbers are probably
about right. About 20,000, would get us about 10%. Yeah, I think these
numbers are right, but I think, looking at lurbinectedin as a DNA damaging
agent, not as a PARP inhibitor. I think there's probably no reason to believe
that someone with a chek2 mutation or a ATP mutation would not respond.
That would double the patient numbers.
Call Leader: Yes, there was two points you just touched on there that I want to make
sure we spoke about before the end of the call. One of them was, you
mentioned multiple times there are PARPs particularly olaparib in BRCA2,
breast but could you talk to me about how you think Lurbinectedin could
exist in a world with PARPs being approved? I think we're probably not too
far away from additional indications for PARPs being approved. I think a lot
of investors I talked to are worried that PARPs are just what's all the rage
right now and that that's going to be the next big wave of cancer treatment
as indications get approved. Thinking about a world where they are broad
approval for PARPs, maybe even multiple options on the market, where
does Lurbinectedin fit? We've identified BRCA2, but how do they compare in
that subgroup? I think that is something that on a high level investors think
about without any granularity, so any granularity you could provide would
be really helpful.
Doctor: I'd like to draw you back on drug development in oncology in general. I've
been working in breast cancer for a long time so there is always this issue
about breast cancer already has eight approved drugs. Our point has always
been, yes, and after the eight drugs patients still need treatment and the
market is still sizeable. In terms of, BRCA1/BRCA2 mutation specific drugs, I
think the more specific drugs and the drugs will all be moved up from
because all you have to show is your drug is not as toxic as chemo and
people will use it.
And that's what olaparib has shown, it was presented at ASCO. The drug is
actually kind of like ... the efficacy is not great ... but looking at the
tolerability, it was so much more tolerable than any of chemo's by patient
reported outcome. So, even if the three month differential over
chemotherapy everyone will give a drug that keeps people out of bed and
out of the house in terms of toxicity. As you see in the duration of treatment
on the PARP inhibitor was very short and a lot of people actually didn't
respond in the first place.
The question is, are these patients responding or have been progressing on
a PARP inhibitor and their responding to Lurbinectedin and the answer is,
we don't know that. If your drug is even a little bit more potent, a little bit
more efficacious, has low toxicity, doesn't cause any longterm leukemia,
your drug will be sold.
Call Leader: Got it. Understood. In terms of Lurbinectedin vs. PARPS in BRCA2 and maybe
even BRCA1
Doctor: [crosstalk 00:20:34]
Doctor: To finish the last sentence ... as a medical oncologist working in this space
am I worried there's going to be too many drugs in this space? No, far from
it. There may be three PARP inhibitors but they are all the same, it's like
once you give them one you're not going to give the two others. You
actually provide a different option which is direly needed. I'm not worried
there is no room for another drug.
Call Leader: Got it. Understood. The last thing you had said before, about DNA repair and
the fact that Lurbinectedin could work in a DNA repair setting, that there's a
way, potentially, for the market to expand ... the addressable market to
expand, could you expand on that and talk a little bit about DNA repair and
if Lurbinectedin is most likely limited to BRCA2 or if there's more genes that
could be impacted this way and a little bit on that?
Doctor: I actually did not say, it is not my opinion, that Lurbinectedin works better
on BRCA2 mutations. My conversation with PharmaMar it was “I would not
dismiss activity against BRCA1 mutations.” I think one has to be very careful
when looking at why the BRCA2 mutation profile looks better whether it's
just a matter of prior treatment or something else, like ... I think the activity
of BRCA2 mutation is very encouraging, the fact that the PARP inhibitors
seems to be less active in the BRCA2 phase further points to that this area of
testing. Intrinsically there is no scientific, there's no reason to believe that
DNA double strand breaks wouldn't work in BRCA1 mutation.
Call Leader: Got it. Is it limited then to BRCA1 and 2 or are there other mutations that
Lurbinectedin could be effective in?
Doctor: Thanks for bringing me back to this. I think ATM and Chek2 are clearly in
that pathway, so is Rad50 and MRE11 and probably a total of about 15
genes ... Clovis in collaboration with Foundation actually put together that
significant gene pool of mutations that could potentially be sensitive to such
drugs. I would really, in terms of mutation carriers in breast cancer,
particularly there's about half of known mutation carriers of BRCA1 and 2
and other quarter is probably ATM and Check. Then there's a smattering of
small things. We know that in populations ATM happens in about 44% of the
population. It's actually fairly common. So I think the market is significantly
expanded.
Call Leader: Are those things tested for currently or would that be something they would
need to develop a test for, as well? Or at least start getting patients to do ...
Doctor: Pretty much over the last 3 or 4 years, everyone who gets genomic testing, a
germline testing, gets a panel and these gene mutations are all on the panel.
Call Leader: Well, those are my main topics ... thinking about different tumor types, they
are looking at ovarian, small cell lung cancer, and breast right now. Are
there other areas and tumor types, solid tumors, that look like it could be
interesting? I'm just trying to think about if I look out five years with the
additional indications that the company could look at. Is it more about
getting granularity in different genetic gene mutations in gene issues in each
of these tumor types, or do you think there are other tumors that could be
addressed by Lurbinectedin?
I'm trying to get a sense of the next five to ten years of development if these
nearterm currently enrolling trials go well. Where do you understand this
with the way it works?
Doctor: I think approval in breast cancer may be more challenging than others
diseases because it's a little more crowded space. Ovarian cancer may also
be somewhat crowded. Not saying that's not the place to go, but that’s a
trial and development question. However, in terms of what other
mutations, what other tumors have BRCA mutations and clearly they are
myosarcomas. The sarcomas are estimated to have at least 1520% BRCA
mutation on the sematic side.
You actually don't need the germline mutation as long as the patient's
tumor has the mutation, we know this is equivalent to whether a tumor has
it or a patient has it, their response rate is the same. Sarcomas is quite
significant, prostate cancer is quite significant and carboplatin is still not
that easy to give. Pancreatic cancer is a fatal disease, bile duct cancer has
quite a significant portion of 24% of patients with the BRCA2 mutation, so
there is a lot of positive patients around with tumors that before we hadn't
thought about it.
Now we know that the approval for MSI and stability for
immunotherapeutics has really, for the first time, created this concept that
you don't need to get approval in setting that is also acceptable. In other
words, you could do a trial of Lurbinectedin in BRCA2 mutated tumor, rather
than BRCA2 mutated breast cancer.
Call Leader: Interesting. Interesting. Are there other questions on Lurbinectedin and the
mechanism that you think I should be thinking about or the side effect
profile that we should be zeroing in on at this point?
Doctor: If memory serves me well, there wasn't any unusual side effects, right? I’m
looking at the profile mainly neutropenia. That’s the main side effect. I think
the important question is how is it different from Yondelis. Because people
... it's probably not a fair comment but you can't undo memory of people.
Yondelis has been in development for so long. Having enough plan that it
isn't going to take another 20 years to get this drug approved in U.S. Its none
of this that's your fault, but everyone who hears Yondelis and Lurbinectedin
thinks, "Oh my gosh, this thing has been around so long." Keep in mind,
medical oncologists are human, and we are ultimately the people who use
this drug.
Call Leader: Do you think that the PK profile and the dosing differences and things like
that and the infusion differences, does separate it in doctors mind and if
these trials go well, the pathway for approval for Lurbinectedin would be
pretty different? Does that, in your mind, make the break for you or no?
Doctor: Yeah, absolutely.
Call Leader: Okay.
Doctor: But, not just saying it's better than Yondelis, but that just forget the Yondelis
part all together ... we wouldn't approve a PARP inhibitor by constantly
saying it's a better doxorubicin. What am I trying to say, don't invoke bad
memories in people when trying show something new. Just say, "This is a
new drug." There's no... you know?
Call Leader: Right. Okay.
Doctor: So in the discussions we have, and I know I'm lecturing here, but that's an
important part is don't ... focus on what's good about this drug and there's
many good things. There's no reason to invoke the past.
Call Leader: Got it. Okay. Well, Dr. Munster, I think we're up on our half hour here but
this was really helpful. I appreciate you taking the time to walk me through
these different aspects of the drug and the role it can play in these different
patient groups.
Doctor: Okay, great. Just followup and let me know.
Call Leader: Yes, I will definitely followup if anyone has anything else or if I have any
other thing come to me. Okay?
Doctor: Okay. Thank you so much!
Call Leader: Have a great day. Take care.
Doctor: Take care. Bye.