The Evolution of Antibody-Drug Conjugates in Oncology: Have we found our “Magic Bullet”?

Transcript

• 00:01It's really pretty often that
• 00:03we have experts
• 00:04from our own faculty who
• 00:06go around the world and
• 00:07give talks, and we never
• 00:09ask them to give talks
• 00:10here.
• 00:11So we're trying to fix
• 00:13that problem.
• 00:15And so our speaker today
• 00:17is Ian Cropp.
• 00:19I think many of you
• 00:20know Ian.
• 00:22Ian came here,
• 00:24a month after I did,
• 00:26three years ago from Dana
• 00:28Farber.
• 00:30He
• 00:31spent most of his life,
• 00:34up until about age,
• 00:35I don't know, somewhere in
• 00:37his
• 00:38mid thirties at, Hopkins where
• 00:40he went to college and
• 00:41medical school and got his
• 00:43PhD and trained,
• 00:44and then came to Dana
• 00:45Farber where he was a
• 00:46fellow
• 00:47and stayed on the faculty
• 00:49for quite a number of
• 00:50years.
• 00:51He he is a breast
• 00:53cancer expert,
• 00:55of,
• 00:57known around the world.
• 01:00And for the purposes of
• 01:01today's talk,
• 01:02he's also,
• 01:04an expert in antibody drug
• 01:06conjugates.
• 01:08In fact,
• 01:09he ran,
• 01:11the first phase one trial
• 01:14of the first antibody drug
• 01:16conjugate that was approved in
• 01:18solid tumors, and that was,
• 01:20TDM one now back,
• 01:23a number of years ago.
• 01:25So,
• 01:26I'll also mention that Ayan
• 01:28is the chief,
• 01:30chief scientific officer for the
• 01:31translational breast cancer research consortium.
• 01:34Here at Yale,
• 01:35he's our,
• 01:37chief clinical research officer
• 01:40and runs the the clinical
• 01:42trials office.
• 01:43So, Ian,
• 01:45please.
• 01:51Good afternoon.
• 01:53Thank you for that kind
• 01:54introduction.
• 01:59So,
• 02:00we're gonna be talking about
• 02:02antibody drug conjugates, which, you
• 02:03know, I think is a
• 02:04this is a particularly opportune
• 02:06time to have that discussion.
• 02:07This is an area that's
• 02:08moving very quickly. There's actually,
• 02:11been two FDA approvals of
• 02:13ADCs just in the last,
• 02:15like, eight or nine days,
• 02:16and that's just within breast
• 02:18cancer.
• 02:19So there's a lot going
• 02:19on.
• 02:21And
• 02:24what I thought I would
• 02:25do would be to talk
• 02:26about ADCs using
• 02:28HER2 positive breast cancer as
• 02:29kind of an example, and
• 02:31and the reasons for that,
• 02:33selection is because,
• 02:35HER2 positive disease is,
• 02:38an area where we've had
• 02:39the biggest clinical impact of
• 02:41of targeted therapy in general
• 02:42and ADCs specifically.
• 02:45There's interestingly, there's a we
• 02:47see a benefit of ADCs
• 02:48across a very wide range
• 02:49of target expression in in
• 02:51this, subtype of breast cancer,
• 02:53which I I think is
• 02:54worth talking about.
• 02:55And,
• 02:57it's a there's a examples
• 02:59of basically all the key
• 03:00features of of ADCs are
• 03:02kind of manifest in HER2
• 03:03positive disease. And lastly,
• 03:06this is what I study,
• 03:07so I have most of
• 03:08the slides. So it was
• 03:09easier.
• 03:10So,
• 03:12just for those of you
• 03:12who don't treat breast cancer,
• 03:15HER2 positive disease makes up
• 03:17about fifteen to twenty percent
• 03:18of breast cancers, and these
• 03:19cancers have dramatic overexpression
• 03:22of of this cell surface
• 03:24protein
• 03:25tyrosine kinase called HER2.
• 03:27There's typically a million or
• 03:29even two million copies of
• 03:30HER2 protein on each cancer
• 03:32cell.
• 03:33These cancers are typically high
• 03:35grade, and they present with
• 03:36more advanced stage. They recur
• 03:38more frequently, and they have
• 03:40resistance,
• 03:41to,
• 03:42standard therapy. So these patients,
• 03:45had very poor prognosis
• 03:48prior to the realization
• 03:49that the reason these cancers
• 03:51were behaving so badly was
• 03:52because of this dramatic overexpression
• 03:54of HER2 and all the
• 03:55downstream signaling,
• 03:57that was happening because of
• 03:58that.
• 04:00So that led to the
• 04:01development of drugs targeting HER2,
• 04:03the first of which was
• 04:04an antibody
• 04:05called trastuzumab,
• 04:07and it was shown back
• 04:08in, I think, nineteen ninety
• 04:09eight or nineteen ninety nine,
• 04:11that the addition of paztuzumab
• 04:14to chemotherapy
• 04:15led to substantial improvements in
• 04:17in outcomes, progression free overall
• 04:19survival.
• 04:20And,
• 04:22if you use it in
• 04:22early stage disease, it increased
• 04:25the cure rate by about
• 04:26fifty percent. So it was
• 04:27a clear breakthrough,
• 04:30with the with this HER2
• 04:30targeted therapy introduction.
• 04:33And it really, in many
• 04:34ways, met this met the
• 04:36criteria of,
• 04:38the Nobel laureate Paul Ehrlich's,
• 04:41idea of a of a
• 04:42magic
• 04:43bullet, a a a drug
• 04:44that specifically
• 04:45targets,
• 04:47a pathogen by while sparing
• 04:49normal tissues. And, actually, doctor
• 04:51Ehrlich was thinking,
• 04:54about chemicals and chemical dyes,
• 04:56originally, but but we use
• 04:57it in terms of, thinking
• 04:59about antibody antibiotics and and
• 05:01antibodies,
• 05:02as well. So this feels
• 05:04like it it met those
• 05:05criteria.
• 05:07But the problem,
• 05:08particularly in HER2 positive disease,
• 05:11was that
• 05:13for trastuzumab really to work,
• 05:14you need to have chemotherapy
• 05:16around. You need to have
• 05:17some type of cytotoxic agent,
• 05:18and that's because one of
• 05:20the things trastuzumab does is
• 05:21helps encourage,
• 05:23apoptosis when you need something
• 05:25to,
• 05:25produce that apoptosis, and that's
• 05:27where chemotherapy comes in. But,
• 05:30you know, you have this
• 05:31very targeted
• 05:32antibody,
• 05:33the magic bullet, and then
• 05:34you throw in non targeted
• 05:36chemotherapy. So you lose some
• 05:37of your magicness,
• 05:39when you have to have
• 05:40chemotherapy around. So this was
• 05:41a perfect opportunity to take
• 05:43advantage of this then very
• 05:45new type of technology called
• 05:47an antibody drug conjugate,
• 05:49and,
• 05:50you know, this is a
• 05:51very simplified diagram,
• 05:52obviously,
• 05:54but the idea of an
• 05:55ADC is you have an
• 05:56antibody targeting some cell surface
• 05:58protein,
• 05:59and you have a very
• 06:00cytotoxic,
• 06:02moiety, typically a potent chemotherapy,
• 06:04and you attach them,
• 06:06with a linker that's typically
• 06:08cleaved once or the idea
• 06:10is that it's cleaved once
• 06:11the
• 06:13the conjugate gets inside of
• 06:14a cell.
• 06:15With the overall goal that
• 06:16you're gonna increase the efficacy,
• 06:19of of the of the
• 06:20cytotoxic drug while decreasing the
• 06:22toxicity
• 06:23by selectively delivering this to,
• 06:26the cancer cells. So these
• 06:27are the conjugates you talk
• 06:29about,
• 06:30guided missiles, smart bombs,
• 06:33whatever warmongering,
• 06:35terminology you wanna use, but
• 06:36that's the general idea.
• 06:39And so
• 06:40the first of these, as
• 06:41Eric had mentioned, to really,
• 06:44become clinically useful in solid
• 06:46cancers was this one called
• 06:47trastuzumab emtansine,
• 06:49and the idea of ADCs
• 06:51actually had been around for
• 06:52decades. The problem is none
• 06:53of them really worked, and
• 06:54the main problem they were
• 06:56having in the past,
• 06:57was that was toxicity because
• 07:00the linker tended to break,
• 07:02in,
• 07:03in in blood. So you
• 07:05had disassociation,
• 07:06showed you had lots of
• 07:07free cytotoxic,
• 07:09drug floating around, and that
• 07:10was causing nonspecific toxicity.
• 07:13And so,
• 07:15what was different about TDM
• 07:16one, was that it it
• 07:18started with this trastuzumab
• 07:20monoclonal.
• 07:24Oh, it's a touch screen.
• 07:25It starts with this trastuzumab
• 07:27monoclonal,
• 07:29targeting HER2 that we talked
• 07:30about. It had a,
• 07:33microtubule inhibitor payload, and the
• 07:36linker in this case was
• 07:37actually not not cleavable. So
• 07:38I talked about the idea
• 07:39of general user cleavable. This
• 07:41one was not.
• 07:43And
• 07:44the story is kind of
• 07:45interesting how that came about,
• 07:47and I promise this is
• 07:48the only chemistry I will
• 07:49be talking about today.
• 07:51So when Genentech was trying
• 07:52to develop this drug,
• 07:54they were really trying to
• 07:55make for a more stable,
• 07:57linker. Because, again, the problem
• 07:59in the past would be
• 08:00the linkers weren't stable, and
• 08:01so you were getting toxicity.
• 08:02So they said, okay. Well,
• 08:03let's try to make this
• 08:04super stable. And so they
• 08:05were testing a number of
• 08:07different,
• 08:08chemical structures, looking different,
• 08:11link different,
• 08:13cleavable
• 08:14linker,
• 08:15chemistries and and distances between
• 08:17the antibody and the and
• 08:18the payload.
• 08:19And they threw in at
• 08:20the bottom of their experiments
• 08:22this, MCC
• 08:23linker, which is basically non
• 08:25cleavable. And they put that
• 08:26there as a negative control
• 08:27because, of course, this wasn't
• 08:28gonna work,
• 08:29because if you don't have
• 08:30a cleavable linker, then you
• 08:32can't release the drug to
• 08:33kill the cancer cell. So
• 08:34they throw that they threw
• 08:35that in there just as
• 08:36a control.
• 08:38And what they found was,
• 08:39as expected, that the the
• 08:42non cleavable linker, the MCC
• 08:44in blue there at the
• 08:45top, was very stable in
• 08:47plasma, the most stable, and
• 08:48it was, stable different ways
• 08:50looking at it.
• 08:53And it actually was pretty
• 08:54well tolerated because,
• 08:56you know, the there you
• 08:57weren't having this, disassociation
• 09:00in blood, but the surprise
• 09:02was is also was the
• 09:03most effective.
• 09:04And so the blue line
• 09:05at the bottom there is
• 09:06the is the TDM one,
• 09:07essentially.
• 09:14Conjugate, the TDM one binds
• 09:15to the cell surface,
• 09:17on the HERT the HERT
• 09:18two. It gets internalized
• 09:20into lysosomes where the proteases
• 09:22actually were
• 09:24would dissolve the antibody essentially,
• 09:27and so you you didn't
• 09:29break the linker.
• 09:30It's just the the amino
• 09:31acid, the lysine from the
• 09:33antibody where it's connected would
• 09:34just leave,
• 09:35with the with the with
• 09:37the drug attached to it.
• 09:38And so that's how this
• 09:40drug was working, and that's
• 09:41how you got this selective
• 09:42delivery of the DM one,
• 09:45was because the antibody was
• 09:46getting just,
• 09:48proteolyzed.
• 09:49So, as Eric mentioned, we
• 09:51were involved in this phase
• 09:53one trial,
• 09:54the phase first in human
• 09:55study of TDM one. We
• 09:57enrolled patients who had had
• 09:59already progressed on multiple, HER2
• 10:01directed therapies,
• 10:03and despite that and despite
• 10:05this being just the phase
• 10:06one, there was a lot
• 10:07of efficacy seen. So the
• 10:09forty four percent response rate,
• 10:12these were durable responses, the
• 10:13progression free survival is about
• 10:14ten months, and seventy three
• 10:16percent of patients had some
• 10:17benefit.
• 10:19And at the same time,
• 10:20not only was it efficacious,
• 10:23but it was very well
• 10:24tolerated. So we didn't see
• 10:26the usual chemotherapy side effects,
• 10:28people generally didn't get nauseous
• 10:29or,
• 10:30have neutropenia or neuropathy or
• 10:32hair loss,
• 10:34And so it
• 10:35it probably and and the
• 10:37reason why
• 10:38was because the amount of
• 10:39the free payload, which is
• 10:41in black here, was very
• 10:42low. It was negligible. So
• 10:44it really wasn't releasing that
• 10:45payload,
• 10:46very quickly as
• 10:48the hope, as as was
• 10:49hoped.
• 10:51We then moved to a
• 10:52phase two trial again in
• 10:53very heavily pretreated patients, and
• 10:55I'm just showing this because
• 10:57it's probably the first trial
• 10:58that that Eric,
• 11:00and Pat Larusso and I
• 11:01did together,
• 11:03back in the day.
• 11:05And we saw the same
• 11:06thing heavily pretreated patients, response
• 11:08rate was
• 11:09was was reasonable, and and
• 11:11and, it was effective.
• 11:13And then we moved on
• 11:14to do a a registrational
• 11:15phase three,
• 11:17two phase three studies. This
• 11:18one, in patients who had
• 11:20already progressed on all standard
• 11:22therapies,
• 11:23showing that TDM one was
• 11:25better than the standard of
• 11:26care in terms of survival
• 11:28and PFS and was less
• 11:30toxic.
• 11:31And similarly,
• 11:32this is a earlier line
• 11:34trial again,
• 11:36showing better,
• 11:37efficacy and less toxicity compared
• 11:40to the standard of care.
• 11:41So these trials led to
• 11:42the approval of of PDM
• 11:44one as you heard, I
• 11:45think, in two thousand twelve,
• 11:47as the first ADC,
• 11:48in solid cancers,
• 11:52and really,
• 11:54kind of it did a
• 11:55couple of things. It validated
• 11:56HER2 as a as a
• 11:57target for an antibody drug
• 11:59conjugate,
• 12:00but most importantly,
• 12:02as being the first success
• 12:03in a common cancer,
• 12:05it led to the widespread
• 12:07development of ADCs across,
• 12:09tumor types.
• 12:10So, at last check, there
• 12:12were three hundred and seventy
• 12:13ADCs in clinical development,
• 12:16again, spurred on by, by
• 12:18the success of of this
• 12:19drug.
• 12:21And it also inspired people
• 12:22to start looking at better
• 12:24technologies for for linkers and
• 12:25payloads,
• 12:26and that's probably been best
• 12:28exemplified by this next generation,
• 12:31drug targeting HER2, which is
• 12:33called trastuzumabdoroxican,
• 12:35which differs in a few
• 12:36ways. It's no longer it
• 12:38has a different class of
• 12:39payload. It's not a microtubule
• 12:40inhibitor. It's a topoisomerase
• 12:42inhibitor.
• 12:43But perhaps the most unique
• 12:44feature,
• 12:45was it it evidence this
• 12:47thing called bystander effect.
• 12:49And it had and the
• 12:50reason it did this is
• 12:51because it had a different
• 12:52linker that that was cleavable,
• 12:54by, proteases,
• 12:57inside the cell and that
• 12:58led to this bystander effect,
• 13:00which,
• 13:01I'll try to depict,
• 13:03here. So if you the
• 13:04conjugate now binds, again, binds
• 13:07to the surface of cell,
• 13:08gets internalized, the payload's released,
• 13:10and if you'll excuse my,
• 13:12grade school animation,
• 13:15that once that payload is
• 13:17in the cytoplasm,
• 13:18unlike TDM one, in this
• 13:20case there's no lysine attached
• 13:22to it, it's thus membrane
• 13:24permeable, and so it can
• 13:25diffuse outside the cell and
• 13:27kill neighboring cells, even if
• 13:29those neighboring cells don't have
• 13:30HER2 on their surface.
• 13:33Why is this important? Again,
• 13:34we're targeting a HER2 positive
• 13:36cancer. Why is it matter
• 13:37that this drug could work
• 13:39in cancers cells that don't
• 13:40have HER2 on them?
• 13:42Well,
• 13:43and I'm sorry. This and
• 13:44this just shows that this
• 13:45bystander effect really seems to
• 13:47work.
• 13:48So this is a xenograft,
• 13:50on the left of a
• 13:51combination of a HER2 positive
• 13:53cell line and HER2 negative
• 13:54cell line, HER2 positive stains
• 13:56brown,
• 13:57and by IHC.
• 13:59And if you treat with
• 14:00t d m one as
• 14:01shown in the middle,
• 14:02diagram, you kill off the
• 14:03HER2 positive cells, but you
• 14:05leave behind the HER2 negative
• 14:06cells. Again, because HER2 TDM
• 14:08one doesn't have this bystander
• 14:09effect. But on the right,
• 14:10you use TDXD
• 14:12with bystander effect, you kill
• 14:13off both cell lines. Okay.
• 14:14Again, why does that matter?
• 14:16This is a xenograph where
• 14:17you mix two cancers together.
• 14:19Obviously, people have one cancer,
• 14:22and it's HER2 positive, so
• 14:24there should be lots of
• 14:25HER2 on all the cells.
• 14:26Well, let's just for the
• 14:28sake of argument say that's
• 14:29not the case and that
• 14:30there are heterogeneous,
• 14:32expression of HER2 in some
• 14:34cancers. The concern would be
• 14:36that if you have this
• 14:37heterogeneous cancer shown
• 14:40here where the blue cells
• 14:41are the HER2 positive and
• 14:43the red ones are not,
• 14:44you treat with a very
• 14:45targeted drug,
• 14:48you kill off the HER2
• 14:49positive cells, you leave behind
• 14:50the HER2 negative cells, and
• 14:52the HER2 negative cells then
• 14:53grow up, and now you
• 14:54have a resistant cancer
• 14:55similar to what was shown
• 14:57in in those in the
• 14:58xenograft I just showed.
• 15:00Is this clinically relevant? So,
• 15:03my,
• 15:05colleague,
• 15:06Otto Mesker and I did
• 15:08this IIT,
• 15:10to ask this seemingly pretty
• 15:12straightforward question, but at least
• 15:13as far as we knew
• 15:14that really hadn't been addressed
• 15:15before in the clinic.
• 15:17Are heterogeneous cancers
• 15:19less sensitive to targeted therapy?
• 15:22So the way we did
• 15:23this, we took a hundred
• 15:24and sixty four patients who
• 15:25had newly diagnosed HER2 positive
• 15:27disease,
• 15:28and before we started treatment,
• 15:30we did a biopsy in
• 15:32two different locations of their
• 15:33cancer.
• 15:34And then they treated with
• 15:36TBM one, we threw in
• 15:37another HER2 antibody,
• 15:38called pertuzumab,
• 15:40and and then they had
• 15:41surgery. And so we we
• 15:43took advantage of the fact
• 15:44that we did these two
• 15:45different biopsies, and so we
• 15:46had, and each of those
• 15:47biopsied had three different sections
• 15:49that we looked at. And
• 15:50we looked at whether there
• 15:52was heterogeneity,
• 15:53in terms of HER2 amplification
• 15:55in those different sections.
• 15:57And we scored those cancers,
• 16:01using a standard ASCO,
• 16:04cap definition of heterogeneity.
• 16:07And then we looked at
• 16:07how the heterogeneity
• 16:09played out in terms of,
• 16:11benefit to this treatment.
• 16:12And what we found was
• 16:13that in the cancers that
• 16:15were not heterogeneous, those cancers
• 16:17where there's pretty homogeneous expression
• 16:19or amplification of HER2,
• 16:21fifty five percent of those
• 16:22patients had complete eradication of
• 16:24their tumor just from the
• 16:26HER2 targeted therapy. So in
• 16:28in that situation,
• 16:30this HER2 target therapy is
• 16:31highly effective,
• 16:32and and well tolerated.
• 16:34But then when you looked
• 16:35at the cancers that were
• 16:36heterogeneous,
• 16:37none of them had a
• 16:38pathologic complete response. And so
• 16:40this was highly statistically significant,
• 16:43and it confirmed that actually
• 16:44heterogeneity matters, that if you
• 16:46have a heterogeneous
• 16:47cancer, you're not as likely
• 16:49to respond as completely to
• 16:51HER2 targeted therapy, or at
• 16:53least a HER2 targeted therapy
• 16:54that doesn't have this bystander
• 16:56effect, which TDM one does
• 16:58not.
• 16:59We actually
• 17:00went on to look a
• 17:01little bit more in-depth in
• 17:03collaboration with,
• 17:05a lab at Dana Farber
• 17:07led by Neli Polyak and
• 17:08and Francisca,
• 17:10Mihor,
• 17:11looking at at the single
• 17:13cell level by HER2 amplification,
• 17:15trying to understand what was
• 17:16actually driving,
• 17:18the resistance.
• 17:19And interestingly,
• 17:21at least interesting to me,
• 17:23it was actually the fraction
• 17:24of the non amplified cells
• 17:26within,
• 17:27the population
• 17:28that was strongly correlated with
• 17:30PACER. And it so, originally,
• 17:32we kind of had the
• 17:33idea, okay, a heterogeneous cancer
• 17:35is one where, you know,
• 17:36there's a big c of
• 17:37HER2 positive cells and then
• 17:39there's this little cluster of
• 17:40HER2 negative cells that was
• 17:42gonna stay behind and grow
• 17:43out. But, actually, that's not
• 17:44what we saw. It's actually
• 17:47fairly
• 17:47oftentimes relatively uniform distribution of
• 17:50HER2 positive and HER2 or
• 17:52HER2 amplified and HER2 non
• 17:53amplified cells,
• 17:54that was that was leading
• 17:56to heterogeneity. So you didn't
• 17:57actually have to do those
• 17:58six,
• 17:59biopsy sections. If you just
• 18:01look at one section and
• 18:02you quantitate,
• 18:04how,
• 18:05much how many of these
• 18:06HER2 non amplified cells are
• 18:08there, you can actually predict
• 18:10PCR,
• 18:11very strongly,
• 18:13which which is
• 18:15which is kind of interesting.
• 18:16And,
• 18:17we actually that our data
• 18:19was subsequently replicated a few
• 18:21years later, in a in
• 18:22a larger trial where they
• 18:23went back and looked at
• 18:24the same population patients treated
• 18:26with TDM one and pertuzumab.
• 18:28And, again, those who had
• 18:30heterogeneous
• 18:31positivity for HER2 had no
• 18:33pass ERs, whereas those that
• 18:34were homogeneous had a a
• 18:36over fifty percent pass ER
• 18:37rate.
• 18:38Okay. So
• 18:41getting back to TDXD,
• 18:43it's got this
• 18:45bystander effect, at least in
• 18:47vivo.
• 18:48Does that matter in terms
• 18:49of improving efficacy?
• 18:53So it does.
• 18:54Or at least somehow it
• 18:56has much better efficacy, whether
• 18:57how much of that's bystander
• 18:58effect or some of the
• 18:59other,
• 19:01aspects that we don't really
• 19:02know at this point. But
• 19:03this was the,
• 19:04phase two single arm study
• 19:05that that,
• 19:07we were involved with,
• 19:10that demonstrated
• 19:11of in heavily pretreated patients,
• 19:13patients who had already had
• 19:14all the standard HER2 therapies,
• 19:16I think, the median of
• 19:16six prior lines. So these
• 19:18were seventh line metastatic
• 19:20patients, and the response rate
• 19:21to TDXD alone was over
• 19:23sixty percent. It was very
• 19:24durable. The patients,
• 19:26had a, a were on
• 19:27study for over twenty months,
• 19:29and virtually a hundred percent
• 19:31of patients had some benefit
• 19:32as shown in this waterfall
• 19:33plot.
• 19:36The trade off was that
• 19:37there was more toxicity. So
• 19:38unlike TDM one,
• 19:40with this drug,
• 19:42most patients get some nausea,
• 19:43there's fatigue, there's,
• 19:47hair loss in some patients,
• 19:49and
• 19:50in ten to fifteen percent
• 19:51of patients,
• 19:53they get a serious complication
• 19:54called interstitial lung disease or
• 19:56pneumonitis,
• 19:58which is typically manageable, but
• 20:00it's definitely something that you
• 20:01have to pay attention to
• 20:02because it can be fatal.
• 20:04So,
• 20:06because of the incredible efficacy
• 20:08in very refractory patients,
• 20:10these data led to the
• 20:12the accelerated approval of of
• 20:13TDXD,
• 20:15in in this,
• 20:17kind of refractory setting.
• 20:20But then we went on,
• 20:21there were several other trials.
• 20:22This was a phase three
• 20:24style
• 20:24phase three trial looking specifically
• 20:26at patients who had already
• 20:27had the other ADC, TDM
• 20:29one, and comparing TDXD versus
• 20:32standard,
• 20:33HER2 therapy,
• 20:34and TDXD was much better.
• 20:38And this demonstrated,
• 20:41that you actually can
• 20:43have benefit from one antibody
• 20:45drug conjugate followed by another,
• 20:46even though they have the
• 20:47same target, but they have
• 20:48different payloads. So by switching
• 20:49payloads, you're able to,
• 20:51provide,
• 20:52more efficacy.
• 20:54And at least in my
• 20:55mind, this supports
• 20:56the paradigm,
• 20:58that you could treat patients
• 20:59with sequential ADCs with different
• 21:01payloads, and we'll we'll talk
• 21:03more about that,
• 21:04later.
• 21:08This went on to now
• 21:09look head to head at
• 21:11TDXD
• 21:11versus PDM one, so two
• 21:13ADCs against each other. Probably
• 21:15the only trial that's done
• 21:16that.
• 21:17And again, TDXD was was
• 21:19far superior to to TDM
• 21:21one,
• 21:22fourfold greater
• 21:24progression free survival, so almost
• 21:26twenty nine months progression free
• 21:27survival,
• 21:28a level that I don't
• 21:29think had ever been seen
• 21:31before in pretreated
• 21:32patients with breast cancer.
• 21:34So very effective
• 21:36survival was also beneficial,
• 21:38and this established tDxD as
• 21:40the standard
• 21:41care for patients,
• 21:43with her trophosid metastatic disease.
• 21:47But
• 21:49there was a question at
• 21:50that time of what about
• 21:51patients with progressive brain mets?
• 21:52And, unfortunately, that's a big
• 21:54problem in HER2 positive disease
• 21:56because,
• 21:57for reasons that aren't completely
• 21:59clear, there's a strong predilection
• 22:00for HER2 positive breast cancer
• 22:02to go to the brain.
• 22:04It may partly, it may
• 22:05be because,
• 22:06or part of it may
• 22:07be
• 22:09the the conventional wisdom that
• 22:11that drugs like that we
• 22:12use in HER2 positive disease,
• 22:14like antibodies, antibody drug conjugates,
• 22:16don't get into the brain
• 22:17into into the the brain
• 22:19because of the blood brain
• 22:20barrier. So it's kind of
• 22:21a a sanctuary site, and
• 22:22that's why we see so
• 22:23much of it. But there's
• 22:24also some biology involved that
• 22:26these cancers are just have
• 22:27a tropism to the brain.
• 22:29But as I said,
• 22:30you know, the the idea
• 22:32was antibodies don't get into
• 22:33the brain, therefore, antibody drug
• 22:35conjugates don't get into the
• 22:36brain, so how are we
• 22:37gonna how could a drug
• 22:38like tDxD
• 22:40work in this very common
• 22:41situation?
• 22:43But it turns out that
• 22:45actually antibodies can get into
• 22:46the brain at least somewhat.
• 22:48This is a pet label,
• 22:50trastuzumab
• 22:51study, and you can see
• 22:52on the bottom there,
• 22:54that actually the antibody does
• 22:57get to the to the
• 22:58brain metastases at least to
• 22:59some level.
• 23:01Probably because
• 23:02the blood brain barrier breaks
• 23:03down a little bit when
• 23:04you have a cancer there
• 23:06and it's disrupting, you know,
• 23:07causes dysregulation of of vascular
• 23:09genesis, so the blood brain
• 23:11barrier isn't quite as intact.
• 23:13But regardless,
• 23:15some antibody can get there.
• 23:17And so we actually went
• 23:18back and looked at,
• 23:20the the large studies I
• 23:22just had shown you, and
• 23:23there were a small number
• 23:24of patients on those studies
• 23:25that actually had progressive brain
• 23:27metastases
• 23:27at baseline.
• 23:29And we looked at the
• 23:30intracranial response of TDXD,
• 23:33and, actually, there there was
• 23:34some response. It was about
• 23:35a forty something percent response
• 23:36rate in the brain with
• 23:38this ADC, but the sample
• 23:39size was was pretty small.
• 23:42But just recently presented,
• 23:45at ESMO a few months
• 23:46ago was a prospective study
• 23:48of over two hundred and
• 23:49fifty patients with brain metastases,
• 23:52treating with tDxD.
• 23:54And as you can see,
• 23:56response rate in the brain
• 23:57with active brain metastases was
• 23:59over sixty percent. So I
• 24:00think we now have pretty,
• 24:02definitive data,
• 24:04that these ADCs actually are
• 24:05quite active in the brain.
• 24:07I think that's important to
• 24:08know since we obviously
• 24:10have a lot of cancer
• 24:11types that that have, brain
• 24:12metastases as a major problem.
• 24:15And so this idea that
• 24:16you have to use small
• 24:16molecules,
• 24:18is probably not true.
• 24:21So as you might expect,
• 24:24with the efficacy of of
• 24:26of these conjugates in patients
• 24:27with metastatic disease, there was
• 24:29interest in seeing whether these
• 24:30conjugates could also,
• 24:33work in preventing recurrences in
• 24:35patients with early stage disease.
• 24:37And so there originally, there
• 24:38was a large trial that
• 24:39looked at patients who had
• 24:40a high risk early stage
• 24:42disease because their cancers did
• 24:43not respond all that well
• 24:44to neoadjuvant
• 24:46therapy,
• 24:47neoadjuvant HER2 therapy, and randomized
• 24:49those patients to either the
• 24:50standard back then, which was
• 24:51just continuing trastuzumab
• 24:53or using TDM one,
• 24:56and the TDM one showed
• 24:58about almost a fifty percent
• 24:59reduction in recurrences,
• 25:02compared to trastuzumab. So that's
• 25:04now the standard of care.
• 25:07One issue was that the
• 25:08brain metastases,
• 25:10actually was not significantly reduced
• 25:12with t d m one
• 25:13compared to trastuzumab, and I
• 25:14know that goes against a
• 25:15little bit about what I
• 25:16just said about brain metastases.
• 25:18And maybe we can talk
• 25:18about why that might be,
• 25:20in our
• 25:21very interesting question answer period
• 25:23that's gonna follow this talk.
• 25:27But it has led us
• 25:28to do this study in
• 25:30in the alliance
• 25:31where we're taking
• 25:33those patients who had,
• 25:36residual disease after neoadjuvant therapy
• 25:37and randomizing them to TDM
• 25:39one or TDM one plus
• 25:41this, potent HER2 tyrosine kinase
• 25:43inhibitor called tucatinib. And this
• 25:44study is underway
• 25:46here, at Yale, so you
• 25:48can put patients on this,
• 25:49and I will designate that
• 25:50by the handsome Dan icon
• 25:51as you'll see for the
• 25:52rest of the talk here.
• 25:55We also were looking at
• 25:56whether you can,
• 25:57use the the very well
• 25:59tolerated nature of TDM one
• 26:01to deescalate
• 26:02therapy in patients with earlier,
• 26:05or lower risk HER2 positive
• 26:06disease.
• 26:08So my then colleague at
• 26:10Dana Farber, Sarah Talaney, and
• 26:11I, did this, investigator initiated
• 26:14trial
• 26:14looking at patients with stage
• 26:16one HER2 positive cancers,
• 26:17randomizing them to,
• 26:19the previous standard that was
• 26:20actually established by Eric of
• 26:22paclitaxel and trastuzumab or TdM
• 26:25one,
• 26:26and, the TdM one was
• 26:27associated with incredibly good outcomes.
• 26:29There was,
• 26:31less than
• 26:32one percent distant recurrence at
• 26:34five years.
• 26:35So clearly this was effective.
• 26:37We had assumed it was
• 26:38gonna be much better tolerated
• 26:40than the the the taxane,
• 26:42trastuzumab
• 26:43regimen,
• 26:44and it turned out it
• 26:45it had less some of
• 26:47the standard chemotherapy toxicities,
• 26:49but people were discontinuing the
• 26:51TDM one, which was given
• 26:52for a year in this
• 26:53study,
• 26:54earlier,
• 26:55than they were discontinuing the
• 26:56trastuzumab in the in the
• 26:57other arm of the study.
• 26:59So, that's led,
• 27:02Sarah to go on to
• 27:03do this second version of
• 27:05the study,
• 27:06comparing just six cycles of
• 27:07TDM one, because we think
• 27:09that might be all you
• 27:09need,
• 27:10versus,
• 27:11the same
• 27:13control arm. Again, this is
• 27:14a study that's ongoing at
• 27:16at Yale,
• 27:17and it's actually a very
• 27:18good study for these patients,
• 27:20in my opinion.
• 27:22There's also studies going looking
• 27:24at TDXD, this more potent
• 27:25ADC. This is a study,
• 27:27actually comparing TDM one to
• 27:29TDXD in this adjuvant setting,
• 27:30and then there's a neoadjuvant
• 27:31file as well.
• 27:32Okay.
• 27:33So,
• 27:35switching gears a little bit,
• 27:36and this, I think, is
• 27:37where it gets really interesting.
• 27:41All the data I've showed
• 27:42you before is for these
• 27:43HER2 amplified cancers. These are
• 27:45the cancers that have incredibly
• 27:47high levels of HER2.
• 27:49In breast cancer, there's actually
• 27:51a continuum of HER2 expression.
• 27:52So you got these super
• 27:53high
• 27:54amplified cancers with a million
• 27:56or two million copies of
• 27:57HER2, and then you've got
• 27:59everything in between,
• 28:00moderate, lowish levels of HER2,
• 28:02a hundred thousand, fifty thousand
• 28:04HER2 proteins. And we call
• 28:06those HER2 low by immunohistochemistry.
• 28:08They're called one plus or
• 28:09two plus, but they're not
• 28:10amplified.
• 28:11And then you have the
• 28:12very negative,
• 28:13cancers, which we're gonna call
• 28:15HER2 negative.
• 28:18And it turns out that
• 28:19these lowish levels of HER2
• 28:21are actually very common. In
• 28:22fact, the majority of breast
• 28:24cancer has some level of
• 28:26HER2 expression.
• 28:29So given that, and given
• 28:30that we have this monoclonal
• 28:31antibody called trastuzumab
• 28:33that we know works,
• 28:35with chemotherapy,
• 28:37The NSABP,
• 28:39did this very large trial
• 28:41where they took patients with
• 28:42HER2 low early breast cancer,
• 28:43and they randomized them to
• 28:45chemotherapy with or without trastuzumab,
• 28:47the same thing that had
• 28:48shown to be very effective
• 28:49in HER2 amplified cancers.
• 28:52Unfortunately, this was completely not
• 28:53effective, so adding trastuzumab for
• 28:55these HER2 low cancers did
• 28:57absolutely nothing,
• 28:58and you can see the
• 28:59IDFS has a ratio is
• 29:01point nine eight shows randomization
• 29:03was very effective,
• 29:04there,
• 29:05but no benefit.
• 29:07So then
• 29:11because trastuzumab works by, at
• 29:13least in part, by inhibiting
• 29:14HER2 signaling,
• 29:16it suggests that HER2 signaling
• 29:18really isn't important in these
• 29:19HER2 low cancers, so blocking
• 29:21it doesn't do anything.
• 29:23But it's still there. The
• 29:24HER2 is still there, and
• 29:25we have an antibody drug
• 29:26conjugate, which is basically looking
• 29:27for a target. And we
• 29:29use these antibody drug conjugates
• 29:31to
• 29:32to use the HER2 that's
• 29:33on the surface of these
• 29:34low cancers
• 29:35just as an address, a
• 29:36place, you know, a way
• 29:37to deliver our cytotoxic agent.
• 29:42So we now we had
• 29:44TDXD, and in the phase
• 29:45one trial of TDXD, we
• 29:47did have some cohorts
• 29:48of HER2 low cancers,
• 29:50and it actually looked like
• 29:51there was some activity in
• 29:52these HER2 low cancers.
• 29:54That prompted this very large
• 29:56trial
• 29:57of
• 29:57patients with metastatic HER2 low
• 29:59breast cancer. Again, the most
• 30:01common kind of breast cancer,
• 30:03there is sixty at least
• 30:04sixty percent of breast cancers,
• 30:06and randomized them to tDxD
• 30:07or chemotherapy because chemotherapy was
• 30:09a standard for these non
• 30:11HER2 amplified cancers,
• 30:13and tDxD was much better
• 30:14than chemotherapy in terms of
• 30:16survival,
• 30:17progression, response rate.
• 30:20And that led to the
• 30:21approval of tDxD in these
• 30:23HER2 low cancers, the first
• 30:24approval for of anything in
• 30:27HER2 low cancers,
• 30:28because it really wasn't a
• 30:29thing before the drug worked
• 30:31there.
• 30:32And it said, well, okay,
• 30:33if if it worked in
• 30:35these HER2 low cancers, and
• 30:36in fact, you know, I
• 30:37talked about that there's these
• 30:39one plus level and two
• 30:40plus levels.
• 30:42Two plus is more than
• 30:43one plus.
• 30:45If it in the trial,
• 30:46it actually the efficacy was
• 30:47pretty similar between the one
• 30:49plus and two plus. So
• 30:49that kind of begged the
• 30:51question, okay, well, can you
• 30:52go? How how low can
• 30:53you go?
• 30:54And in about twenty percent
• 30:55of cancers, there's, like, really
• 30:57marginal levels of HER2. So
• 30:59not even one plus, it's
• 31:01just like you can, you
• 31:01know, if you look real
• 31:02close, you can see a
• 31:03little smidgen of HER2 on
• 31:05the surface, but they're not
• 31:06completely
• 31:07stone cold zero.
• 31:09And so,
• 31:10we just so there are
• 31:12just another trial that was
• 31:13just presented over the summer.
• 31:16Same almost the same trial
• 31:17as I just showed you,
• 31:18but now,
• 31:20slightly different setting,
• 31:21but now this trial included
• 31:23a population of these ultra
• 31:25what we're now calling ultra
• 31:26low cancers. So just the
• 31:28smallest amount of HER2,
• 31:30not enough to be one
• 31:31plus.
• 31:33And what was seen, surprisingly
• 31:35somewhat,
• 31:37was that,
• 31:38actually, tDxD was much better
• 31:40than chemotherapy in these ultra
• 31:41low cancers. Seemed like the
• 31:42benefit was pretty similar to
• 31:43what we saw with the
• 31:44low cancers.
• 31:46Survival also seemed to be
• 31:47trending in the right direction,
• 31:48although immature.
• 31:49But I think what was
• 31:50particularly important or what was
• 31:52striking was that response rate
• 31:53in these ultra low cancers
• 31:55was sixty two percent. These
• 31:56were pretreated patients,
• 31:58and,
• 31:59you can see that it's
• 32:00actually the response rate in
• 32:02the ultra low is pretty
• 32:02similar to the HER2 low.
• 32:04And again, we can kinda
• 32:05talk about why that that
• 32:07might be,
• 32:08towards the end.
• 32:11It's funny, you know, when,
• 32:13in some of this original
• 32:14steering committee meetings of of
• 32:15TDXD,
• 32:16when the original ultra low
• 32:18date I'm sorry, when the
• 32:19original HER2 low data came
• 32:20out,
• 32:21people that I remember one
• 32:22specific person raising their hand
• 32:23and say, why don't we
• 32:24look at HER two zero
• 32:25cancers? And it was like,
• 32:26everybody kinda laughed because it's
• 32:27a HER two targeted drug.
• 32:29Of course, it's not gonna
• 32:29work in HER two zero
• 32:30cancers.
• 32:32But it seems to work
• 32:33in these ultra low cancers,
• 32:34and now there's a question
• 32:35of could it even work
• 32:36with pretty undetectable levels of
• 32:38HER2?
• 32:39And to test that, Adrianna
• 32:41Khan is doing,
• 32:43this IIT
• 32:44looking specifically at HER2 zero
• 32:46cancers,
• 32:47treating with TDXD,
• 32:48and then using some of
• 32:50David Rymm's,
• 32:51you know, very sophisticated,
• 32:53assays for HER2 to see
• 32:55if you can really identify
• 32:56whether there really is a
• 32:57threshold of HER2 expression below
• 33:00which you don't see activity.
• 33:01So that study hopefully will
• 33:03open, very soon.
• 33:06So what have we learned
• 33:07about HER2 ADCs?
• 33:09So clearly,
• 33:10they're superior to trastuzumab and
• 33:13chemotherapy,
• 33:14both in early stage and
• 33:15late stage disease.
• 33:17They've,
• 33:18TDXD is better, more efficacious
• 33:20at least than TDM one,
• 33:21but it also has more
• 33:22toxicity. And I think that
• 33:23like likely reflects the trade
• 33:25off, for these cleavable linkers
• 33:28versus non cleavable linkers.
• 33:30You get the bystander effect,
• 33:32but the bystander effect also
• 33:33can,
• 33:35hit normal tissue, not just,
• 33:38to other tumor cells.
• 33:41And, you know, this very
• 33:42interesting finding of tDxD being
• 33:43affected even in minimal levels
• 33:45of HER2, which may be
• 33:46because of this bystander effect,
• 33:48although we haven't proven that.
• 33:51So I just wanna take
• 33:52a slight,
• 33:57divergence here and and and
• 33:59bring up this question,
• 34:01just because I think it's
• 34:01really cool,
• 34:03of the fact that given
• 34:04that we have these very
• 34:06effective HER2 therapies, you know,
• 34:07progression free survival of thirty
• 34:09months and, you know, very
• 34:11long durations of response. And
• 34:12we actually have there's actually
• 34:14eight drugs now approved for
• 34:15HER2 positive disease, different mechanism
• 34:17of action.
• 34:19So given all of these
• 34:20highly effective drugs,
• 34:23can we really move the
• 34:24needle of treating patients with
• 34:26metastatic disease and go away
• 34:27from treating in a non
• 34:29curative setting, which is the
• 34:30way we do it now,
• 34:31and move it, to a
• 34:32curative setting?
• 34:34And by for those of
• 34:35you who don't treat patients,
• 34:37with metastatic disease,
• 34:39nowadays, we treat with one
• 34:40treatment. We wait for the
• 34:41cancer to become resistant, and
• 34:42then we switch to the
• 34:43other drug. And we're we
• 34:44try to string along our
• 34:46treatments,
• 34:47to keep patients with disease
• 34:49control as long as possible
• 34:50because we know we can't
• 34:51cure them. So there's no
• 34:52use giving a lot of,
• 34:53you know, kind of piling
• 34:55on your therapies. You wanna
• 34:56stretch them out so they
• 34:57last as long as possible.
• 34:59But by doing that, generally,
• 35:01you're you're gonna get resistance
• 35:03because you're only giving one
• 35:04drug, and, eventually, the cancer
• 35:05is gonna learn to become
• 35:06resistant. And that's why metastatic
• 35:07disease is typically felt to
• 35:09be not curable.
• 35:10So maybe that's not true,
• 35:11though, given the fact that
• 35:13we have these highly effective
• 35:14drugs.
• 35:15And so,
• 35:18a trial that's gonna be
• 35:20launched here at Yale shortly
• 35:21that's being run-in this consortium
• 35:23called the TBCRC,
• 35:25is trying to address, can
• 35:26we cure HER2 positive metastatic
• 35:28disease?
• 35:29So to do this, we're
• 35:31gonna deviate from the normal
• 35:32practice and take newly diagnosed
• 35:34patients and treat them with,
• 35:37twelve weeks of of ataxane
• 35:39and and trastuzumab, and then
• 35:41give them TDXD for eighteen
• 35:43weeks, and then give TDM
• 35:44one with the kinase inhibitor,
• 35:46and then give more kinase
• 35:47inhibitor,
• 35:48for about a year, and
• 35:49then just stop treatment and
• 35:51just follow patients with c
• 35:53tDNA and c and CAT
• 35:54scans with the idea
• 35:56that we're gonna try to
• 35:58improve the percentage of patients
• 35:59who don't have progression after
• 36:01four years essentially are cured.
• 36:03You know, this is way
• 36:04leukemias are treated, lymphomas are
• 36:06treated, you pile on mass
• 36:08you know, lots of different
• 36:09drugs,
• 36:10you know, in a very
• 36:11intensive way,
• 36:12even though kind of leukemia
• 36:13is kind of metastatic,
• 36:15to begin with, but it
• 36:16it works. Can we do
• 36:18that for a solid cancer?
• 36:19In the past, we really
• 36:20just didn't have the effective
• 36:22therapies to do that. Now
• 36:23that we do,
• 36:25can we change the paradigm?
• 36:26So this is a trial
• 36:27that should open soon here,
• 36:28and and, again, I think
• 36:29it's really worth exploring. It
• 36:31may be wrong, may not
• 36:32work, but it's worth trying.
• 36:35Okay.
• 36:36Enough of HER2.
• 36:37Other HER2 there other targets.
• 36:40So I guess I didn't
• 36:41realize I have a slide
• 36:42on HER2 here. So when
• 36:45when,
• 36:46you know,
• 36:47when we were, you know,
• 36:48those of us in the
• 36:49field were working on HER2
• 36:51ADCs, we said, hey. This
• 36:52is great. These drugs are
• 36:53working really well,
• 36:55but it's probably just because
• 36:57HER2 is just this amazing
• 36:58target for an ADC.
• 37:00Why is it amazing for
• 37:01ADCs? Well, first, you have
• 37:02tons of it on the
• 37:03surface. And so the more
• 37:05protein you have on the
• 37:06surface, the more ADCs combined,
• 37:08and therefore, the more the
• 37:10more ADC you can get
• 37:11inside the cell.
• 37:13The normal tissue tended to
• 37:14have very low amounts of
• 37:15HER2.
• 37:16The internalization of HER2 is
• 37:18very fast, and it doesn't
• 37:19down regulate. And you can
• 37:20see in this photomicrograph,
• 37:22if you coat the cell
• 37:23with a fluorescent HER, trastuzumab
• 37:25and then wait a few
• 37:26hours, all of it gets
• 37:28inside the cell. So all
• 37:29those HER2s are getting internalized,
• 37:31which if there's a ADC
• 37:32attached, it'll bring it with
• 37:34it. So internalization is important
• 37:35for ADCs, and the tumors
• 37:37are addicted to their HER2.
• 37:39As I said, it's the
• 37:40HER2 that's driving these cells,
• 37:41so they really need the
• 37:43signaling. So it's really hard
• 37:44for them to down regulate
• 37:45as a way to escape
• 37:46the effects of a d
• 37:47of the ADC.
• 37:48So we thought, hey. It
• 37:49all makes sense that these
• 37:50drugs are gonna work in
• 37:51HER2,
• 37:52but they're probably not gonna
• 37:53work other with other targets
• 37:55because the other targets don't
• 37:56have all these great characteristics.
• 37:58Fortunately, I was wrong, as,
• 38:00as often is the case.
• 38:02We now have the twelve,
• 38:03I think, roughly twelve ADCs,
• 38:09that are FDA approved, and
• 38:10you can see across a
• 38:11wide range of targets.
• 38:14And I forgot to mention,
• 38:16TDXD,
• 38:17just got approved yesterday
• 38:19for treating those ultra low
• 38:20patients, so that's kind of
• 38:22exciting. Another group of cancers
• 38:23to be treated.
• 38:25But you can see we
• 38:25have, activity of ADCs across
• 38:28liquid tumors and solid tumors,
• 38:31with a broad range of
• 38:33of of, targets.
• 38:34So I'll talk of just
• 38:36a brief, in the last
• 38:37few minutes, some of the
• 38:38other targets.
• 38:40Trope two is being tested
• 38:42and is is is been
• 38:43validated in breast cancer. It's
• 38:44being tested in other cancers.
• 38:48So COP two is a,
• 38:49cell surface protein that's pretty
• 38:51widely expressed in breast cancer
• 38:52associated with the worst prognosis.
• 38:55And there's a drug called
• 38:56sacituzumab
• 38:57gobletikin, which is an ADC,
• 38:59also with the topoisomerase
• 39:01pay payload, and it it's
• 39:02set up its linker a
• 39:04little differently. So in addition
• 39:05to being cleavable inside the
• 39:07cell, it's also cleavable
• 39:09by,
• 39:10low pH environments outside the
• 39:12cell, so it can it
• 39:13can release the payload both
• 39:14extracellularly
• 39:15and intracellularly.
• 39:18And it's been tested in
• 39:19triple negative breast cancer compared
• 39:21to chemo where it's much
• 39:23better, and it's approved in
• 39:24that setting.
• 39:26And its toxicity profile is
• 39:28quite is different,
• 39:29than PDXDs.
• 39:31It's all myelosuppression
• 39:33and a little GI toxicity.
• 39:35And interestingly,
• 39:37datapodimab
• 39:38daroxetine, which is another trope
• 39:40two ADC,
• 39:41same antibody as sacituzumab,
• 39:43same class of payload as
• 39:45sacituzumab,
• 39:46but with a daroxican
• 39:48linker, which is a little
• 39:49different.
• 39:50It's it's
• 39:51purely protease cleavable. It's not
• 39:53pH cleavable.
• 39:55And this is an active
• 39:57drug. In our in the
• 39:58phase one trial, we showed
• 39:59that it was active and,
• 40:01even in patients who had
• 40:02already progressed on sacituzumab, there
• 40:04was some activity.
• 40:06But interestingly, again, same payload
• 40:08essentially, same antibody. The toxicity
• 40:10is completely different. So there's
• 40:12virtually no myelosuppression
• 40:14with dapotumab,
• 40:16stomatitis is the toxicity showing
• 40:18how important those linkers are
• 40:20in driving the the characteristics
• 40:21of these ADCs.
• 40:23Dapotumab
• 40:24actually just got approved last
• 40:25week,
• 40:26for hormone receptor positive breast
• 40:28cancer based on another study.
• 40:30And then lastly,
• 40:31HER3,
• 40:32which is another,
• 40:34tyrosine kinase. Actually, it's not
• 40:36a tyrosine kinase. It's it's
• 40:37related to the other tyrosine
• 40:38kinase, the HER2 tyros HER
• 40:41family tyrosine kinases. It itself
• 40:43doesn't have an active kinase,
• 40:45but it's important in in
• 40:46signaling,
• 40:47and is overexpressed in a
• 40:49number of breast cancers.
• 40:50And there's a a conjugate
• 40:52called HER3 DXD or pertitumab
• 40:54daroxetin,
• 40:55which we showed also has
• 40:56activity across breast cancers. But
• 40:58not really sure how this
• 40:59one's gonna develop get developed
• 41:01because,
• 41:02the field is getting crowded,
• 41:04lots of,
• 41:05antibodies with the same payload.
• 41:07So where this one's gonna
• 41:08fit in is unclear.
• 41:12So there are other conjugates
• 41:14being developed.
• 41:16There are ones with fancy
• 41:18new protein structures. So there's
• 41:20biparotropic
• 41:21ADCs that bind two different
• 41:22epitopes of the same,
• 41:24molecule. There's bispecific ADCs binding
• 41:26two different molecules.
• 41:27There's probody conjugates that get
• 41:29activated,
• 41:31in the microenvironment.
• 41:32There's new payloads
• 41:34beyond very potent cytotoxic drugs.
• 41:36There are targeted,
• 41:39therapy kinds of payloads like
• 41:40kinase inhibitors and apoptosis promoting
• 41:43drugs. There's immunomodulatory
• 41:45payloads,
• 41:46radionuclides,
• 41:47and,
• 41:49there are new antigens not
• 41:50targeting the tumor anymore, but
• 41:51actually targeting the the microenvironment.
• 41:53All of these things are,
• 41:55currently,
• 41:56in development. So
• 41:57lots to more to come.
• 41:59I just wanted to close
• 42:00by bringing up a few
• 42:01what I think are important
• 42:02unanswered questions.
• 42:04One is and this is
• 42:05a little
• 42:06wonky, I appreciate.
• 42:08Should we be making more
• 42:10ADCs with non cleavable linkers?
• 42:12Right now, TDM one is
• 42:13the only approved ADC with
• 42:15a non cleavable linker. All
• 42:16the other ones have different
• 42:17types of cleavable linkers.
• 42:21And,
• 42:23you know, there's reasons for
• 42:24the cleavable linkers. You get
• 42:26the bystander effect,
• 42:27but you also get more
• 42:28toxicity. And I always wondered
• 42:30whether if you took a
• 42:31really potent cytotoxic drug and
• 42:33made it with a noncleavable
• 42:34linker, whether you could get
• 42:35efficacy and still keep the
• 42:36toxicity down. Because
• 42:38TDM one is still really
• 42:39the only drug with that
• 42:40really favorable,
• 42:42toxicity profile, which, again, was
• 42:43one of the original visions
• 42:44of an ADC.
• 42:47How should we sequence ADCs
• 42:49with different targets? So I
• 42:50I mentioned,
• 42:51we had a trial where
• 42:52we use the same target,
• 42:54but two different payloads, one
• 42:55ADC after another. What about
• 42:57the kind of the opposite?
• 42:58And now we have the
• 42:59tools to do that. So
• 43:00in the trade trial, which
• 43:02is gonna open here, hopefully
• 43:03soon,
• 43:05Patients are gonna be randomized
• 43:06to either tDxD or dapodimab,
• 43:09the trop two ADC,
• 43:10and then when they progress,
• 43:11they'll switch to the other
• 43:12one to see and then
• 43:14we'll try to figure out
• 43:15using biomarkers which is the
• 43:16best sequence for each individual
• 43:19answer. We don't know how
• 43:20to do that yet.
• 43:22And then,
• 43:23lastly,
• 43:25and this kinda gets back
• 43:26to the point I made
• 43:26at the beginning,
• 43:28can we get rid of
• 43:30conventional chemotherapy altogether?
• 43:33Ideally, why would you use
• 43:34conventional chemotherapy, which goes everywhere
• 43:36in the body and causes
• 43:37nonspecific toxicity? Why would you
• 43:39use that when you can
• 43:40link it to an antibody
• 43:41and deliver it to the
• 43:42cancer cell?
• 43:44To do that, you're gonna
• 43:45need anti ADCs with different
• 43:47payloads.
• 43:48Just like, you know, in
• 43:50practice with metastatic disease, we
• 43:51use chemotherapy a. Patients progress,
• 43:54we use chemotherapy b, and
• 43:55so on.
• 43:56You could do ADC a,
• 43:58ADC b, each just switching
• 44:00payloads.
• 44:01The problem is we don't
• 44:03have those drugs other than
• 44:04TDM one and TDXD I
• 44:06showed you. We don't have
• 44:07a lot of different payloads,
• 44:08and that's partly because the
• 44:10success of trastuzumab daroxetine
• 44:12was so high
• 44:13that everybody's jumping on the
• 44:15bandwagon of these topoisomerase
• 44:16inhibitor payloads.
• 44:18And you can see this
• 44:19is,
• 44:20from a review that just
• 44:21came out,
• 44:23showing, the different payloads that
• 44:25are being used.
• 44:26There's a hundred and seven
• 44:28in clinical development using,
• 44:30camptothecans or or basically topoisomerase
• 44:32inhibitor payloads.
• 44:33Almost all of them as
• 44:34shown in this graph are
• 44:36topoisomerase inhibitors.
• 44:37So they work,
• 44:39but we're getting very crowded,
• 44:41and you can imagine, and
• 44:42we have data now developing,
• 44:44that cancers can become resistant
• 44:45to the payload by,
• 44:47mutating topoisomerase.
• 44:51And then once you've got
• 44:53resistance to the payload, it
• 44:54doesn't matter which antibodies you
• 44:55hook up to it. It's
• 44:56it's not gonna work. So
• 44:58we need to diversify our
• 44:59payloads.
• 45:00So with that, I will
• 45:01stop. I'm happy to take
• 45:03questions.
• 45:10Oh,
• 45:11yep. Dan.
• 45:17Excellent talk, and I have
• 45:19two questions.
• 45:20Number one,
• 45:21I'm fascinated by this,
• 45:23observation about responses in brain
• 45:25metastases.
• 45:27It's known that in hyperprolisular
• 45:29vascular endothelium that HER-twoneu is
• 45:31expressed. Have you looked at
• 45:32the HER-twoneu expression in the
• 45:33vascular endothelium
• 45:35in addition to the tumor
• 45:36cells in those brain mets?
• 45:37Because it would certainly make
• 45:38sense if they have a
• 45:40bystander effect,
• 45:41that may that may be
• 45:42the actual mechanism of action.
• 45:44And the second question is
• 45:45about interstitial lumenitis. This is
• 45:46something we've seen with enfortumab
• 45:48vedotin.
• 45:49It's not really clear whether
• 45:50that's because of the interaction
• 45:51between checkpoints and enfortumab.
• 45:53But what do you think
• 45:54is the mechanism,
• 45:55with the HER2 targeted agents
• 45:57with that? Yeah. So both
• 45:58good questions.
• 46:00You know, when you look
• 46:01at the
• 46:02you know, I
• 46:03don't know
• 46:05I haven't seen data on
• 46:06looking at at the HER2
• 46:08expression on the vasculature,
• 46:11around tumors specifically in solid
• 46:13cancers. It's a great question
• 46:14and
• 46:15should be able to be
• 46:16looked at. We do enough,
• 46:17you know, resections of these
• 46:18cancers.
• 46:20You know, it's,
• 46:22you know, the the alternative
• 46:24you know, so if it's
• 46:24not just breakdown of the
• 46:25blood brain barrier,
• 46:27you know,
• 46:28is it released in the
• 46:29microenvironment?
• 46:31There are some data that
• 46:32I didn't have time to
• 46:33show you.
• 46:36But I think very provocative
• 46:37data that was presented at
• 46:38our San Antonio Breast Cancer
• 46:40meeting last month, just as
• 46:41a poster because I don't
• 46:42think people appreciated
• 46:44the impact,
• 46:46suggesting that it's actually
• 46:48cathepsins in the microenvironment.
• 46:50They're actually cleaving these conjugates,
• 46:52and that's why they work
• 46:53in, you know, potentially HER2
• 46:56null or HER2 very low,
• 46:58because they're really they're hurt
• 46:59it's you don't need the
• 47:00HER2. It's just the microenvironment
• 47:02has enough cathepsins there,
• 47:04that you get selective cleavage
• 47:06around the tumor.
• 47:07So that could be a
• 47:08alternative explanation. But,
• 47:11also, if you had anchoring
• 47:12because of HER2 overexpression in
• 47:14the vasculature,
• 47:15you could imagine,
• 47:17having efficacy there
• 47:20and perhaps
• 47:21causing more disruption by causing
• 47:24some apoptosis of the endothelium,
• 47:26causing more disruption, allowing more
• 47:27ADC in there. So I
• 47:28think that's a great question,
• 47:30and I don't have a
• 47:30great answer for that. And
• 47:31in terms of the ILD,
• 47:34we we we don't know
• 47:36the the mechanism. It it,
• 47:39actually,
• 47:40Adriana Khan is looking at
• 47:41trying to do lung biopsies
• 47:43in patients who get pneumonitis
• 47:44or or who are getting
• 47:45these drugs and get pneumonitis,
• 47:47to try to kinda clarify
• 47:49that.
• 47:50You know, certainly, there is
• 47:51HER2,
• 47:52in in in some lung
• 47:54tissue,
• 47:57whether it's through direct target
• 47:59mediated, although as you pointed
• 48:00out, there are multiple targets
• 48:02that are that are seeing
• 48:03ILD.
• 48:04There are,
• 48:06you know, with TDM one,
• 48:08which is HER2 target, you
• 48:09don't you know, the ILD
• 48:10rate is is is very,
• 48:12very low.
• 48:14And so we have ILD
• 48:15in some drugs where you
• 48:17change the payload or change
• 48:18the linker and you you
• 48:19you change the ILD rate
• 48:21substantially.
• 48:23So we don't know. You
• 48:24you know, is it macrophage
• 48:25uptake because of FC receptors?
• 48:27I think there's a lot
• 48:28of hypotheses, but I don't
• 48:29think there's any definitive,
• 48:31data.
• 48:32And, you know, it is
• 48:33certainly a problem for some
• 48:34of these drugs that limits
• 48:36their their, you know, applicability.
• 48:39Thanks.
• 48:41Yeah.
• 48:46Okay.
• 48:47Thank you for your talk.
• 48:49I had a question about
• 48:50the brain mets.
• 48:52Have you seen any coexpression
• 48:53of cell adhesion molecules that
• 48:55you could then use as
• 48:57a, like, HER2 bispecific
• 48:59to increase internalization
• 49:01in those brain meds specifically
• 49:03or the potential Yeah. So,
• 49:04I mean, again, this gets
• 49:05back to, Dan's question and
• 49:07and then,
• 49:08you know,
• 49:09whether we can learn from
• 49:11some of these
• 49:13datasets where people are doing
• 49:14resections of of brain metastases
• 49:16and and looking at, dysregulation
• 49:18of adhesion molecules and as
• 49:20a way of potentially doing
• 49:21bispecifics. I mean, there have
• 49:22been some
• 49:24ADCs looking at at those
• 49:27at at adhesion molecules to
• 49:28try to get at the
• 49:29at the, microenvironment, but I
• 49:31I don't know of any
• 49:32of that with her too.
• 49:34But it's a good idea
• 49:35and and kinda looking at
• 49:36that. Because, again, the BRAINMET
• 49:37issue is a is a
• 49:38real problem. And, where we've
• 49:40seen we see benefit with
• 49:42ADCs in the brain as
• 49:43I showed you, but they're
• 49:44not,
• 49:45you know, they're not,
• 49:46eliminating the brain metastases. And,
• 49:48generally, what we see with
• 49:50our patients, once a patient
• 49:51has brain metastases,
• 49:53that's progressed after radiation,
• 49:55they always progress in the
• 49:57brain. And so it becomes
• 49:58the rate limiting step for
• 50:00a lot of patients. So
• 50:01we we need new treatments,
• 50:02but that's a good question.
• 50:04Yeah. Great talk, Ian. I'm
• 50:05one of the best molecular
• 50:07pathologist.
• 50:08The trial you presented, was
• 50:09AutoMedigar when you predicted the
• 50:11pathologic complete response by the
• 50:13heterogeneity
• 50:14Yeah. In HER2.
• 50:15I we encounter heterogeneity on
• 50:17IHC all the time. And
• 50:18sometime when we go for
• 50:19fish, it doesn't translate to
• 50:21heterogeneity in fish in this
• 50:23area. But also on FISH,
• 50:25any FISH I review, there
• 50:26is negative cells in the
• 50:28FISH.
• 50:29Can how can we make
• 50:30this clinically applicable?
• 50:32And can this patient go
• 50:33instead of going getting new
• 50:35adjuvant antibody drug conjugate? Because
• 50:37they're not gonna achieve BCR
• 50:39with the regular regimen. Thank
• 50:40you.
• 50:41Yeah. So, I mean, with
• 50:43TBM one, we've definitely seen
• 50:46in in
• 50:47in both of the studies
• 50:48I showed you and and
• 50:49pretty much every study of
• 50:50TBM one, which, again, non
• 50:52cleavable link are very dependent
• 50:54on HER2 expression,
• 50:55that you see less substantially
• 50:58less activity as you go
• 50:59down to either lower expression
• 51:01levels of HER2 or heterogeneity.
• 51:03But in truth, we don't
• 51:04use TDM one in the
• 51:05neoadjuvant setting. It's not it's
• 51:07it's not clinically
• 51:08used.
• 51:10And
• 51:11as Eric has been potting
• 51:13me for years
• 51:14to go back and redo
• 51:15that trial of heterogeneity with
• 51:17one of these conjugates that
• 51:18has by standard effect to
• 51:20see whether we eliminate that
• 51:23disparity.
• 51:24You would expect we would
• 51:25if the hypothesis was correct,
• 51:28but we haven't proven it.
• 51:29But one of the as
• 51:30I said, there's a big
• 51:31trial that's just been it's
• 51:32been completed. We're waiting for
• 51:34the results. We should get
• 51:35it sometime this year of
• 51:36neoadjuvant
• 51:37TDXD,
• 51:38the one with the payload,
• 51:40spreading, the one with,
• 51:42bystander effect.
• 51:44And, hopefully,
• 51:47I'm not involved in that
• 51:48trial, but, hopefully,
• 51:49they'll look at that question
• 51:50and and and hope and,
• 51:52hopefully, we won't see that
• 51:53just big disparity
• 51:55by HER2 level,
• 51:56because of the unique features
• 51:58of this conjugate.
• 51:59But if we do, then,
• 52:00again, it brings up your
• 52:01point and says, hey. You
• 52:03know, a a one size
• 52:04fits all approach is not
• 52:05right, and the heterogeneous cancer
• 52:07should be treated in different
• 52:08ways,
• 52:10which probably is
• 52:12you know? I didn't have
• 52:13time to talk about resistance
• 52:14or biomarkers,
• 52:16but we're not good at
• 52:18figuring out either one of
• 52:19those,
• 52:20areas right now. We need
• 52:21a lot more work on
• 52:22identifying
• 52:23whether there are biomarkers that
• 52:24predict benefit of any of
• 52:25these drugs. We haven't been
• 52:26able to figure that out
• 52:27yet. Eric, do you have
• 52:28a follow-up?
• 52:30Question from online.
• 52:32So this is the limitation
• 52:34of PCR
• 52:35versus long term.
• 52:37Because just because someone doesn't
• 52:39achieve a PCR
• 52:40doesn't necessarily mean for going
• 52:42to have a good
• 52:44answer.
• 52:45So some of those cells
• 52:46that may be first and
• 52:47negatives
• 52:48may also be ER positive
• 52:50in response to anything therapy,
• 52:52maybe biologically
• 52:53less aggressive.
• 52:55So it's it's not
• 52:57absolutely the case when you
• 52:58have to eradicate every single
• 53:00one of their
• 53:01cell. The question
• 53:05online,
• 53:06was,
• 53:07do you think it would
• 53:08be possible using antibody drug
• 53:10conjugate
• 53:11technology to deliver non chemotherapy
• 53:14agents like,
• 53:17immune checkpoints
• 53:18or such?
• 53:20Yeah. So, yeah, so it's
• 53:21a great question, and then
• 53:22there's been a lot of
• 53:23interest in in in delivering
• 53:25everything with that,
• 53:27antisense,
• 53:29you know, as I said,
• 53:30DNA damage,
• 53:32inhibit you know, repair inhibitors,
• 53:36I think you name it.
• 53:37I think the the problem
• 53:39the the concern people have
• 53:41with going that direction,
• 53:43not that it's not being
• 53:44tried, but the concern is
• 53:45just gonna be, you know,
• 53:49the amount of ADC that
• 53:50actually gets the tumor cell
• 53:52is very low,
• 53:53because they get taken up.
• 53:54Even though,
• 53:56you know, we talk about
• 53:57it being a guided missile,
• 53:59most of the drug actually
• 54:00ends up in just
• 54:02random tissue just because it
• 54:04just antibodies get stuck places.
• 54:06So, you know, data suggests
• 54:08that, like, one percent of
• 54:09the dose that you give
• 54:10actually gets to the tumor.
• 54:11So you don't really getting
• 54:12a whole lot of of
• 54:13the payload to the cancer
• 54:15cell. And so
• 54:17there's been a push to
• 54:18get very high potency
• 54:21payloads
• 54:22with the idea that you
• 54:23can get away with that
• 54:23because they're being somewhat selectively
• 54:25delivered,
• 54:26because you you we're not
• 54:27getting a whole lot into
• 54:28the cancer, so you you
• 54:29want what you get in
• 54:30there to be very potent.
• 54:32And the problem with most
• 54:33of these small molecules,
• 54:36is that they're not as
• 54:37potent as as they need
• 54:39to be or the concern
• 54:40is they're not as potent
• 54:41as they need to be.
• 54:42We'll see. I mean, again,
• 54:42there's a lot of them
• 54:43in development, but that's the
• 54:45problem with,
• 54:47with your payload is if
• 54:48it's not
• 54:49quite potent,
• 54:51it may not be effective
• 54:52enough even if
• 54:53the general
• 54:54hypothesis is a good one
• 54:56of of of doing that.
• 54:57So but, you know, none
• 54:58of them have been approved
• 54:59as far as I know.
• 55:00We'll have to we'll have
• 55:01to see as they pan
• 55:02out. It's a it's a
• 55:03good idea.
• 55:04Did did you have a
• 55:05question?
• 55:06Yeah.
• 55:17Is is autoimmune, like is
• 55:19autoimmune
• 55:20toxicity?
• 55:22So well, autoimmune meaning anti
• 55:24antibody.
• 55:25Yeah. So so,
• 55:32antihuman antibodies or anti
• 55:35conjugate antibodies
• 55:36don't seem to be a
• 55:37big problem with these. It's
• 55:39it's a good question because
• 55:40you would expect you've, you
• 55:41know, you've got a a
• 55:42humanized antibody. You've got derivation
• 55:44of that antibody.
• 55:46Could that be immunogenic?
• 55:48It's it hasn't been a
• 55:50a problem.
• 55:53You don't see much hypersensitivity
• 55:54with these.
• 55:56I mean, you can't at,
• 55:57you know, low percentages.
• 55:59But but antibody you know,
• 56:01anti ADC antibodies haven't been
• 56:03clinically significant,
• 56:04and autoimmune disease really hasn't
• 56:06been. You know, whether the
• 56:07the pneumonitis that we see
• 56:08could be an autoimmune reaction
• 56:09is certainly possible, but but
• 56:11we other than that, we
• 56:12really haven't seen it.
• 56:25Yeah. So, you know, meaning
• 56:26if the ADC bot is
• 56:28is encounters an immune cell,
• 56:30it kills it because of
• 56:31the cytotoxic
• 56:32moiety. Yeah. I think that
• 56:33that's that's certainly possible.
• 56:37But,
• 56:38and then that's a good
• 56:39thought.
• 56:40Fortunately, I said clinically, it
• 56:41just really hasn't been an
• 56:42issue.
• 56:50Pan,
• 56:51I had, like, twenty questions,
• 56:52but I'll Absolutely. Eliminate them.
• 56:55So so
• 56:56with with the ultra low,
• 56:58you're you're assuming that you're
• 56:59dealing with with
• 57:00probably a small percentage of
• 57:02cells that are actually expressing.
• 57:04By definition. And I guess
• 57:06the I understand the idea
• 57:07of cathepsins doing this. But
• 57:08I guess the other question
• 57:09is for the spreading effect,
• 57:11do we think this is
• 57:11apoptotic cell death, or do
• 57:12we think this is cell
• 57:13death that's actually messier? And
• 57:15if so,
• 57:16has anyone thought of immune
• 57:19in combination,
• 57:20you know, like p one?
• 57:22So I didn't talk about
• 57:23biomarkers. I'm sorry. I was
• 57:24just last night. I don't
• 57:25wanna forget. Forget. Brady and
• 57:26Anna's thing. I know David
• 57:27Brim is gonna be doing,
• 57:29QIF. Are you also gonna
• 57:31be doing IHC at the
• 57:31same time? Because I think
• 57:32you sort of I go
• 57:33on and do both
• 57:35because I mean, at least
• 57:36David's not here. Right? He's
• 57:37been testing,
• 57:40you
• 57:43know, Yeah. We're we're actually
• 57:45see if it's covered because
• 57:45Yeah. So the actual correlate.
• 57:47Yeah. Yeah. The actual analysis
• 57:49plan is to do multiple
• 57:50HER2 assays, both
• 57:52protein and genomics
• 57:53to try to come up
• 57:54with, you know, the best
• 57:55predictor.
• 57:57So good question.
• 58:00In terms of of immunogenic
• 58:02cell death, it certainly looks
• 58:03like these are causing immunogenic
• 58:04cell death.
• 58:06You know, again, the payloads
• 58:08are standard chemotherapies, essentially, and
• 58:10you're getting a lot of
• 58:11it. You know, they're they're
• 58:12potent. So there's there are
• 58:13actually some interesting papers that
• 58:14you get particularly good immunogenic
• 58:17cell death for reasons that
• 58:18I I don't know how
• 58:19well they they've been validated.
• 58:21And there there are combinations
• 58:23of,
• 58:24ADCs plus checkpoint inhibitors,
• 58:27which have shown some promise.
• 58:30In smaller studies, there's some
• 58:32studies that have shown incredible,
• 58:33you know, response rates, eighty,
• 58:34ninety percent,
• 58:37and with and there have
• 58:38been some small randomized trials
• 58:40of of TDM one plus,
• 58:42checkpoint inhibitors, which show
• 58:44a signal, but not overwhelming
• 58:46signal. So I think,
• 58:50we'll have to wait,
• 58:52for
• 58:53there are randomized trials right
• 58:54now with the FOC two
• 58:56ADCs ADCs with or without,
• 58:58checkpoint inhibitors,
• 59:00being,
• 59:01being conducted, and we should
• 59:02have the results actually pretty
• 59:03quickly.
• 59:04The hope is that those
• 59:05are gonna be, you know,
• 59:07really,
• 59:08impressive combinations,
• 59:09both because we know that,
• 59:11you know,
• 59:12checkpoint inhibitors plus chemotherapy work
• 59:14well in triple negative breast
• 59:15cancer, but particularly because of
• 59:18the the the having an
• 59:19antibody there, maybe you're getting
• 59:21more,
• 59:22antigen presentation, maybe you're getting
• 59:24more immunogenic cell death that
• 59:25it's really gonna be,
• 59:27truly synergistic. So it's a
• 59:29great question, and we'll have
• 59:30data by the end of
• 59:31this year
• 59:32on that.
• 59:33Barbara?
• 59:39Wonderful talk. And I'm so
• 59:42fascinated by the HER2 low
• 59:44because, I guess,
• 59:45I think we have some
• 59:46head and neck cancers that
• 59:47are like that. But so,
• 59:49you know, in the in
• 59:50the amplified,
• 59:51you always have the same
• 59:52target, and you're just changing
• 59:53your payload, you're changing your
• 59:54link area, and it keeps
• 59:55working for years.
• 59:56And in the HER2
• 59:58low,
• 59:59I'm assuming that to the
• 01:00:00extent that that HER2
• 01:00:02is doing something biologically,
• 01:00:04it's heterodimerizing
• 01:00:05with EGFR or HER3. Right?
• 01:00:08And so I wondered either
• 01:00:10with a panHER kinase inhibitor
• 01:00:12or,
• 01:00:13you know, cetuximab or something
• 01:00:15like that, have there been
• 01:00:16attempts to kinda cotarget
• 01:00:18what HER2 is is hanging
• 01:00:20out with in the in
• 01:00:21those cancers? Yeah. So great
• 01:00:23question as always, Barbara.
• 01:00:25So as I was gonna
• 01:00:27tell Mike, you know, so
• 01:00:27we didn't talk about biomarkers
• 01:00:29or resistance. We also didn't
• 01:00:30talk about combinations.
• 01:00:33Combining things with ADCs has
• 01:00:34been more complicated than we
• 01:00:36would like. The the checkpoint
• 01:00:37inhibitors actually are an exception.
• 01:00:40There have been studies looking
• 01:00:42at kinase inhibitors for the
• 01:00:43reason you talked about.
• 01:00:46So far, the data don't
• 01:00:47look great.
• 01:00:51It's funny you bring that
• 01:00:52up. Jingde and I are
• 01:00:53just,
• 01:00:54in the process of submitting,
• 01:00:57a
• 01:00:58concept
• 01:00:59for,
• 01:01:01the combination of a HER2
• 01:01:02ADC plus the HER3 ADC
• 01:01:04that you're working on,
• 01:01:06for that very reason. Also,
• 01:01:07knowing that HER3 gets upregulated
• 01:01:09when you block HER2,
• 01:01:10can you, you know, can
• 01:01:11you leverage that by combining
• 01:01:13those two ADCs?
• 01:01:15But just
• 01:01:16from lots of unfortunate personal
• 01:01:18experience, combining ADCs with other
• 01:01:20drugs has not been as
• 01:01:21easy as we would have
• 01:01:22thought.
• 01:01:23Even TDM one, which, you
• 01:01:24know, is such a good
• 01:01:25toxicity profile, it's been hard.
• 01:01:28So
• 01:01:31Alright. Thank you very