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Recapping ESMO, Inside AstraZeneca’s Bold Bet on Antibody Drug Conjugates · Vanguards of Healthcare by Bloomberg Intelligence

0:18
Speaker 1: Welcome to another episode of the Angals of Healthcare podcast.
0:22
Speaker 1: I'm San Fazelli, a senior pharmaceutical analyst and head of
0:27
Speaker 1: Global Industries Research at Bloomberg Intelligence, and this is a
0:33
Speaker 1: podcast where we get the opportunity to speak with the
0:36
Speaker 1: leading figures in the healthcare industry. And today I'm very
0:40
Speaker 1: happy to say that we have Susan gold Braid from
0:42
Speaker 1: AstraZeneca again and now after the ESMO, the European Society
0:47
Speaker 1: for Medical Oncology Conference, to discuss some of the data
0:51
Speaker 1: and of course again astra Zenica was one of the
0:53
Speaker 1: leading companies in the in the at the conference in
0:56
Speaker 1: terms of key data sets being uh reported. And we
1:02
Speaker 1: did one after ASCO which went really well, and I
1:04
Speaker 1: really appreciate the time that Susan offers us. Susan, of
1:08
Speaker 1: course everybody knows executive vice president of Oncology R and
1:12
Speaker 1: D at Astrosenica, which is, if not the leading, one
1:16
Speaker 1: of the top leading oncology plays in the pharmaceutical sector.
1:22
Speaker 1: So Susan, just before we start, I wondered if you
1:25
Speaker 1: wanted to say any introductive words or we can go
1:27
Speaker 1: straight to first question on breast cancer.
1:30
Speaker 2: Well, I would just say I was delighted with the
1:34
Speaker 2: overall presence that we had at the SMO meeting. Asma
1:38
Speaker 2: meeting is getting larger and very impactful. Data that was
1:42
Speaker 2: presented there.
1:44
Speaker 3: You know, what.
1:44
Speaker 2: We were able to show there as well as progression
1:48
Speaker 2: in our early portfolio is very importantly multiple data sets
1:53
Speaker 2: that showed that we're actually deliver again against this vision
1:55
Speaker 2: that antibody drug conjugates can improve on therefore displace chemotherapy
2:02
Speaker 2: from different indications, but also that we can move those
2:05
Speaker 2: into the earlier lines of therapy where the opportunity for
2:09
Speaker 2: improving the potential for cure is that is the highest.
2:12
Speaker 2: So it was a great meeting. It was very exciting
2:15
Speaker 2: to see the data being presented.
2:17
Speaker 1: So that's a perfect lead into our first conversation talking
2:21
Speaker 1: about early intervention with an ADC, and that's of course
2:26
Speaker 1: the data they are presented in breast Cancer now. Just
2:29
Speaker 1: for setting the scene, because we have a whole variety
2:33
Speaker 1: of folks who listen to this podcast, from super experts
2:37
Speaker 1: to more generalists. Just to be setting the scene here
2:42
Speaker 1: breast cancer comes in. I would say, if that's fair enough, Susan,
2:46
Speaker 1: I don't know whether they agree. In three main forms,
2:51
Speaker 1: Homer receptor positive, her too positive, and then of course
2:56
Speaker 1: triple negative breast cancer. Do you agree with that?
3:00
Speaker 2: Yes, I did. I mean hormony receptor positive is the
3:03
Speaker 2: biggest segments of breast cancer at about sixty five seventy
3:07
Speaker 2: percent of patients her too positive, it's fifteen to twenty
3:11
Speaker 2: percent of patients. It's cussibly defined. And then the terminology
3:16
Speaker 2: I don't particularly like is triple negative breast cancer, which defines,
3:20
Speaker 2: you know, what the cancer isn't it's not hormon receptor
3:22
Speaker 2: positive and it's not got her too positivity. But in
3:27
Speaker 2: that group of patients it is really difficult to treat.
3:30
Speaker 2: It is the heterogeneous patient population that she was negative.
3:34
Speaker 2: But yes, you're right, those are the three main groups.
3:37
Speaker 1: Okay, So you have some very interesting and exciting data
3:40
Speaker 1: at OSMO in her too positive space. And these are
3:44
Speaker 1: patients who have an alteration you know, either the expression
3:47
Speaker 1: or mutations in their HER two gene which whoever once
3:52
Speaker 1: we can go and google and find out about it.
3:55
Speaker 1: So you have Destiny breast eleven and Destiny breast of five,
4:00
Speaker 1: both testing in two different settings, and her two, which
4:05
Speaker 1: is the her two a d C that you have
4:09
Speaker 1: us as partnered with Daichi Sankyo. So maybe you want
4:15
Speaker 1: to talk us through that. That's the you know you have,
4:17
Speaker 1: you have, you have a big segment of this population
4:20
Speaker 1: in terms of patients covered. Looking also at destiney Bristol nine,
4:25
Speaker 1: Destiny Bristol three, it begins to cover a whole a
4:30
Speaker 1: whole population almost of the patients. So do you want
4:34
Speaker 1: to tell us what we learned from dB eleven just
4:36
Speaker 1: to shorten it and what it means first for the
4:39
Speaker 1: dB eleven and what it means for patients.
4:41
Speaker 3: Yeah.
4:42
Speaker 2: So, as you rightly points out, with Destiny Bresto three,
4:46
Speaker 2: was in the second line metastatic patients, the patients have
4:49
Speaker 2: already progressed outside of the breast side of the thing.
4:52
Speaker 2: That was the second line, and that showed an improvement
4:54
Speaker 2: over previous standard of care, previous antibody drug conjugates Justice
4:59
Speaker 2: lab h d M one. Then in Destiny Bresto nine
5:04
Speaker 2: at ASCO, we showed the data in the first line
5:06
Speaker 2: metasthatic setting in combination with patusamab. What Destiny brest eleven
5:12
Speaker 2: does is now take this drug that's shown great efficacy
5:16
Speaker 2: in the in the metastatic setting and bring it into
5:18
Speaker 2: this early stage setting patients who are newly diagnosed with
5:22
Speaker 2: early stage breast breast cancer and take it into the
5:25
Speaker 2: neoadjubant setting, which is where you treat patients with treatment
5:30
Speaker 2: regimens before they go for surgery. And the importance of
5:34
Speaker 2: this is that these patients have potentially curative disease. So
5:39
Speaker 2: the Destiny rest eleven compared four cycles of in her
5:42
Speaker 2: two followed by four cycles of a three drug regimen
5:46
Speaker 2: th HP which has a taxing her sceptive and pertusamab
5:50
Speaker 2: in it, and compared that with the current standard of
5:55
Speaker 2: care or one of the current standards of care dose
5:58
Speaker 2: antracycling and cyclophe submid from four cycles then followed by
6:02
Speaker 2: the THHP, So it's it's up against a five drug
6:06
Speaker 2: regimen in that setting. And the primary end point in
6:10
Speaker 2: Destiny Bsted eleven miss a pathologic complete response. And the
6:13
Speaker 2: reason why that's important is we know if you can
6:16
Speaker 2: achieve a pathologic complete response, your five year overall survival
6:19
Speaker 2: act Okay, it's greater than ninety five percent. So in
6:22
Speaker 2: the early stage of breast cancer, maximizing the opportunity for
6:27
Speaker 2: cure is the goal of treatment, and getting to a
6:29
Speaker 2: pathologic complete response is a good indicator that you're en
6:33
Speaker 2: route to that goal. So we saw an eleven percent
6:37
Speaker 2: improvement in that pathologic complete response trait compared with the
6:40
Speaker 2: standard of care. But also importantly, we actually showed an
6:43
Speaker 2: improved safety profile with lower rates of grade through four
6:49
Speaker 2: adverse events.
6:51
Speaker 3: And it was you know, it was.
6:52
Speaker 2: A well tolerated regimen overall, which is also clearly important
6:57
Speaker 2: for somebody that's been treated for curative intent. And there
7:00
Speaker 2: was an early trend to improved event free survival. Very
7:04
Speaker 2: immature data on that, so it's only an early trend,
7:07
Speaker 2: but nonetheless important to see.
7:10
Speaker 1: Now, these are patients, as you rightly say, that are
7:13
Speaker 1: being treated with curative intent. Given that, how long do
7:18
Speaker 1: you think we'd have to wait to see if there's
7:20
Speaker 1: an impact on overall survival? You did say the pathologic
7:24
Speaker 1: complete response, which just to be clear, is when you
7:27
Speaker 1: take tumors out and have a look at them and
7:29
Speaker 1: you find no viable cells. There might be tumor there,
7:32
Speaker 1: but at least a mass there, but no viable cells
7:34
Speaker 1: or very few. What how long would it take before
7:39
Speaker 1: we see whether there's a major or meaningful impact on
7:42
Speaker 1: survival here, which is of course has to be the endgame. Right.
7:46
Speaker 2: So I think in order to answer that question, I
7:49
Speaker 2: think you have to take Destiny Best eleven and Destiny
7:51
Speaker 2: Best five as a complementary studies. The sizing of Destiny
7:59
Speaker 2: Best eleven isn't big enough really to be well powered
8:05
Speaker 2: to show the long term overall survival benefit. But the
8:08
Speaker 2: Destiny BREASTO five study, which takes patients who haven't achieved
8:13
Speaker 2: a pathologic complete response and the higher risk end of
8:16
Speaker 2: that group of patients and looked at then consolidation treatments
8:20
Speaker 2: we like within her two for fourteen cycles in that
8:24
Speaker 2: postal emagulant setting, and there we saw an improvement of
8:31
Speaker 2: fifty three percent in the reduction in the risk of
8:33
Speaker 2: invasive disease free recurrents. So an improvement in invasive disease
8:40
Speaker 2: free survival of fifty three percent, which is really important.
8:46
Speaker 2: And so if you look at those two studies together,
8:50
Speaker 2: what that gives you confidence is that the activity that
8:52
Speaker 2: we've seen within Her too can translate through to this
8:55
Speaker 2: improvement in the longer term outcomes of free survival in
8:59
Speaker 2: those disease free survival and ultimately you know that that
9:04
Speaker 2: can translate through to improvement and noble survival invasive disease
9:07
Speaker 2: re survival is an accepted so get endpoint in the
9:11
Speaker 2: early stage setting as a predictor for that longer term outcome.
9:17
Speaker 2: And I think that effects size that we saw in
9:19
Speaker 2: Destiny Breasto five and was felt to be very impressive.
9:22
Speaker 2: And again the safety profile in Destiny Breasto five is
9:25
Speaker 2: also felt to be uh impressive.
9:30
Speaker 1: Okay, now just back to we come. We'll come to
9:33
Speaker 1: Deily Brestol five in a minute. But in dB eleven
9:37
Speaker 1: you did say, and I think you explained very clearly
9:39
Speaker 1: at the endlyst meeting that I think is freely available
9:43
Speaker 1: on your website for for folks to listen to if
9:46
Speaker 1: they needed to, that although the comparator arm was a
9:57
Speaker 1: standard of care, it's not the only lead standard care.
10:00
Speaker 1: And I think the explanation was also given that don't
10:03
Speaker 1: forget this trial was started even before COVID, right, and
10:07
Speaker 1: then you ended up in a situation where you you know,
10:10
Speaker 1: so over time, of course, when you do these long
10:13
Speaker 1: trials there is a potential for changing standard care. How
10:17
Speaker 1: would we read that in terms of how sure are
10:22
Speaker 1: you if physicians wanted to use this with another combo
10:28
Speaker 1: that they would get similar results? So do you think
10:30
Speaker 1: they would have to be done, further trials have to
10:33
Speaker 1: be done.
10:34
Speaker 2: So I think you know, if you compare the standard
10:36
Speaker 2: of care, so we use those antra cycling and cycloposma.
10:39
Speaker 2: The alternative would be a combination of in and carbo platin,
10:44
Speaker 2: and actually there are other side effects that you get
10:47
Speaker 2: with that regimen. The difference in choice between d d
10:52
Speaker 2: AC or the tc THHP regimen is really a regional choice.
10:57
Speaker 2: If you go to the west coast of the US,
10:59
Speaker 2: a higher proportion of doctors will choose the TCTP, the
11:05
Speaker 2: East coast a higher proportion choose the AC. Actually, if
11:08
Speaker 2: you look at the Destiny Bresto of five study, about
11:10
Speaker 2: half of patients were treated with one or the other regiment.
11:14
Speaker 2: And based on all of the data sets that are
11:16
Speaker 2: out there that have been reviewed, it's accepted that the
11:22
Speaker 2: efficacy is similar between those two regiments. The debate really
11:27
Speaker 2: is about the safety profile of the two because there
11:30
Speaker 2: are adverse events that come from the antra cyclone containing
11:33
Speaker 2: regimen which have determined some of those choices. So I
11:38
Speaker 2: think it's well established that it's an even efficacy bar
11:41
Speaker 2: regardless of which regiment you choose. And then in terms
11:46
Speaker 2: of the safety profile. There are different safety events that
11:50
Speaker 2: you see with one regiment or the other comparing with
11:53
Speaker 2: either of those historical regiments in terms of the safety
11:56
Speaker 2: profile of in her Too for the four cycles in
11:58
Speaker 2: Destiny Brest eleven, I think the general feedback that we're
12:01
Speaker 2: getting is that we was clearly seen to be a
12:04
Speaker 2: overall better tolerated regimen than either of those two previous
12:09
Speaker 2: accepts of regiments, and with good outcomes on but not
12:13
Speaker 2: just the pathologic complete response rate. But as I say,
12:15
Speaker 2: that early trend to improvement in eventsory survival, although it's
12:19
Speaker 2: immature and clearly not statistically significant, and the current point
12:23
Speaker 2: was start to be a robust data set. And again
12:25
Speaker 2: I think people are looking at the overall efficacy for
12:28
Speaker 2: in her To with the totality of data across the
12:31
Speaker 2: Destiny Breast eleven and the Destiny BREASTO five data sets.
12:35
Speaker 2: So I don't think that anybody is feeling that it
12:39
Speaker 2: needs to be another study comparing with TCTCHP in order
12:43
Speaker 2: to something make the loggie spenning.
12:45
Speaker 1: Okay, And one last question on dB eleven before we
12:47
Speaker 1: move on to GVO five, and that is the ILD
12:50
Speaker 1: numanitis rates. ILD is one of the side effects of
12:54
Speaker 1: her too and other her two targeting ADCs, and even
12:58
Speaker 1: some other ADCs. I think so, but you you presented
13:02
Speaker 1: them as a combination. Now, ILD is a if I'm
13:06
Speaker 1: not wrong, and you can correct me if I am wrong,
13:09
Speaker 1: is a relatively has a risk of long term consequences,
13:14
Speaker 1: whereas numonitis is maybe viewed as a more short term issue.
13:20
Speaker 1: Was there much of a difference between the two. I mean,
13:22
Speaker 1: if you had X persent, what was most of it
13:25
Speaker 1: neuon itis versus ILD? How should we think about that?
13:27
Speaker 1: And what would it mean for this patient population that
13:31
Speaker 1: is expected to live a long time.
13:34
Speaker 2: So, just to be really clear, depending on which is
13:38
Speaker 2: the what's called the preferred term that gets centered into
13:40
Speaker 2: the electronic data record, it could be either numinitis or ILD,
13:45
Speaker 2: then there's an adjudication committee that determines whether or not
13:50
Speaker 2: taking into account all of these selves, as an expert
13:52
Speaker 2: committed that view, whether or this is, you know, a
13:54
Speaker 2: drug related ILD event. But they're using that terminology depending
14:00
Speaker 2: on either of the codings that are actually put in there.
14:03
Speaker 2: So the rate that we saw is an adjudicated rate.
14:05
Speaker 2: And again in the dB eleven data set, was a
14:08
Speaker 2: lower rate. Actually that was seen on the control arm,
14:10
Speaker 2: you know, similar but just numerically slightly lower.
14:14
Speaker 3: So you know, I.
14:19
Speaker 2: Don't think there's there's there's the major issue about sputting
14:21
Speaker 2: those two in terms of the long term side effects.
14:25
Speaker 2: Of course, there was one fatal event on both arms,
14:29
Speaker 2: you know, so so that's the first bit of the
14:32
Speaker 2: remaining events that were seen. The vast majority of these
14:36
Speaker 2: have fully resolved, so you know, I think, you know,
14:41
Speaker 2: again with the four dose regimen, relatively short exposure in
14:48
Speaker 2: this in this early stage setting, I really don't think
14:52
Speaker 2: that there's a concern about long term side effects on this.
14:56
Speaker 2: I think it's an acute event which if appropriately treated,
15:00
Speaker 2: you know, it's possible to fully recover from for the
15:02
Speaker 2: vast majority of patients.
15:04
Speaker 1: SODDO five, which was the trial that you've referred to already,
15:09
Speaker 1: was an adjuvant trial i e. Patients were getting whatever
15:14
Speaker 1: new agevent therapy the physician was giving them or none.
15:18
Speaker 1: I'm assuming they all had some kind of new edgement therapy,
15:20
Speaker 1: but you can again detail on that. And then they
15:23
Speaker 1: got their surgery, and then post surgery, if they had
15:26
Speaker 1: residual disease i e. They were not PCR. They gotten
15:30
Speaker 1: her to fourteen cycles plus. Right, So if you want
15:34
Speaker 1: to just tell us a little bit about what you
15:36
Speaker 1: saw in that trial again in that setting, I think
15:39
Speaker 1: you mentioned the fifty three percent improvement.
15:42
Speaker 2: Yeah, so again, what the key endpoint here is the
15:46
Speaker 2: invasive disease free survival That's the primary end point in
15:49
Speaker 2: this study. Again, and on that endpoint, we saw fifty
15:52
Speaker 2: three percent reduction in the improvement in the in the
15:57
Speaker 2: invasive disease PROCE survival rate, which is really very clinically meaningful,
16:02
Speaker 2: and this leads to really important delta in the two
16:06
Speaker 2: year and three year you know, landmark rates. You know, again,
16:12
Speaker 2: we will continue to monitor this and see that you know,
16:17
Speaker 2: follow up. But you know what what I would say
16:20
Speaker 2: is that this is an impressive effect size and people
16:23
Speaker 2: were very impressed.
16:23
Speaker 3: With the data.
16:24
Speaker 2: Is one of the reasons why I got a presidential
16:26
Speaker 2: session and you know, very good commentary following the presentation
16:31
Speaker 2: of the data.
16:32
Speaker 1: Okay, So one of the things that of course a
16:35
Speaker 1: lot of the issues with several cancers is in metastasis
16:39
Speaker 1: to the brain. Here, it wasn't immediately clear whether you
16:43
Speaker 1: had a meaningful or at least the impact on brain
16:47
Speaker 1: METS was not clear. Do you think we can have
16:50
Speaker 1: sufficient evidence in later follow ups to assess the CNS
16:54
Speaker 1: prevention benefit in dB five.
16:57
Speaker 2: So what I would say is that, first of all,
16:59
Speaker 2: and hurt who has shown activity in patients with active
17:03
Speaker 2: brain metastasies, that's impressive. And also in the metastatic settings
17:08
Speaker 2: we have seen a good activity against the time until
17:13
Speaker 2: patients actually.
17:14
Speaker 3: Developed brain metastases.
17:15
Speaker 2: So I would expect that, you know that with time,
17:19
Speaker 2: we can have a look at those effects in these
17:22
Speaker 2: early stage studies as well, you know, and have a
17:26
Speaker 2: look at that because we know that this this drug
17:28
Speaker 2: actually works in those settings. And I think the reason
17:30
Speaker 2: why it works is because of the bystander effect that
17:33
Speaker 2: you get within her too, so you have this cleavable
17:36
Speaker 2: linker and then the payload the muster can payload. Actually
17:42
Speaker 2: you can diffuse across the cell membrane, so even if
17:45
Speaker 2: the there is uneven disruption of the blood brain barrier
17:49
Speaker 2: within a brain metastasis, you will get this biased under
17:53
Speaker 2: effect and spread to surrounding cells.
17:54
Speaker 3: And I think that's one of the reasons why.
17:56
Speaker 2: We're seeing good activity in patients with brain metastasy is
18:00
Speaker 2: so you'd expect to see her over time, and I
18:03
Speaker 2: think we can look at that time until brain and
18:07
Speaker 2: braine recurrence, but it will take time for those to
18:10
Speaker 2: come through.
18:12
Speaker 1: Okay, So last questions here. If you have been a
18:14
Speaker 1: patient who has been treated within her TO in the
18:17
Speaker 1: new adjeven setting and you did not get a major
18:21
Speaker 1: pathologic response so you were positive, still do you believe
18:26
Speaker 1: that you can move on to the DBO five regime afterwards?
18:29
Speaker 3: You know?
18:30
Speaker 2: I think I think obviously the trials have been run
18:33
Speaker 2: with specific patient populations. They're not directly answering the question
18:38
Speaker 2: of if you've had, for example, four cycles and in
18:41
Speaker 2: her too in the BB eleven cents, but you haven't
18:44
Speaker 2: quite achieved a pathology complete response, you know, what's the
18:48
Speaker 2: optimal treatment then in the post new ageant setting. So
18:53
Speaker 2: there will be medical affairs trials that we will look
18:56
Speaker 2: at that will help to address those those care gaps,
18:59
Speaker 2: if you like. But in terms of what the discussions
19:01
Speaker 2: are with investigators that you've heard so far, I think
19:04
Speaker 2: it depends a little bit on the extent of residual disease.
19:08
Speaker 2: If you've seen patients having a very good response to
19:10
Speaker 2: her TOO and then some stabilization on the THHP pard
19:13
Speaker 2: of that new management regiment. It doesn't necessarily mean that
19:16
Speaker 2: they have become resistant to that treatment mechanism by the
19:19
Speaker 2: time you get to the post new reagument setting. And similarly,
19:22
Speaker 2: I think, as in line with general principles of how
19:26
Speaker 2: drugs are used in oncology, if there's a longer disease
19:30
Speaker 2: free interval between treatment in the early stage setting and
19:33
Speaker 2: then a recurrence in the metasthatic setting, you know, it
19:38
Speaker 2: doesn't necessarily mean you need to be resistant to the
19:40
Speaker 2: opportunity for treatment in the metasthetic setting.
19:42
Speaker 3: So I think over.
19:43
Speaker 2: Time we will gather data from real world evidence and
19:47
Speaker 2: from some medical first studies that will help to address
19:50
Speaker 2: those important questions that remain that we haven't actually addressed
19:54
Speaker 2: yet in the design of the trials that we've done
19:56
Speaker 2: so far.
19:56
Speaker 1: Of course, these are questions that are really relevant to
19:59
Speaker 1: our modeling for DBO nine and d WO three two.
20:02
Speaker 1: But let's just consider this question first. Is four cycles
20:06
Speaker 1: enough from what you know about and her too to
20:09
Speaker 1: give you resistance or could it simply be that the
20:12
Speaker 1: patients had you know, biology just trump things. I don't
20:15
Speaker 1: know whatever that means, but you know, well.
20:18
Speaker 2: I mean, you know, there are multiple mechanisms of resistance
20:22
Speaker 2: to any drug. I think we're going to have to
20:26
Speaker 2: again work out over time what the reasons are why
20:31
Speaker 2: a particular patient does well or doesn't do well on particular.
20:36
Speaker 3: Regiment.
20:37
Speaker 2: But I don't think that we're seeing a significant down
20:40
Speaker 2: regulation of the target. For example of her to Remember,
20:43
Speaker 2: of course that her too is an oncogene, so the
20:47
Speaker 2: tumors are relatively they have a growth advantage by having
20:52
Speaker 2: her to highly expressed. That's that's part of the reasons.
20:58
Speaker 2: So if they then donate that receptor, than losing that
21:02
Speaker 2: growth advantage. So there's a you know, just a clonal
21:07
Speaker 2: selection disadvantage from down regulation, which means that I think
21:12
Speaker 2: it's unlikely that you're going to get a substantial down
21:14
Speaker 2: regulation of the hurd to target. The next question is
21:19
Speaker 2: the patient's tumors become resistant to the mechanism of action
21:23
Speaker 2: of the payload or do they upregulate drug exporters so
21:27
Speaker 2: they become relatively less sensitive to that, And I think
21:30
Speaker 2: we're going to have to look at that from with
21:33
Speaker 2: translational science data sets over time to help answer that question.
21:38
Speaker 2: This is one of the reasons why I think very
21:40
Speaker 2: pragmatically physicians will look at that disease free interval and
21:44
Speaker 2: then you can retest and re see whether or not
21:46
Speaker 2: patients have become responsive to the disease.
21:50
Speaker 1: And just to add, there is no known mechanism by
21:53
Speaker 1: which the ADC is excluded from the tumor. So you
21:57
Speaker 1: gave two possible mechanisms, the chemo and the antibody. Is
22:01
Speaker 1: that ever, have you seen any change in the stromal
22:03
Speaker 1: structure or the structure of the tumor even in mise
22:06
Speaker 1: et cetera. I don't know that would suggest that could
22:09
Speaker 1: be a mechanism of resistance.
22:12
Speaker 2: Well, one thing that has been seen, I think, and
22:15
Speaker 2: there's an area of adventures is the expression of jrug
22:21
Speaker 2: E flux pumps. So in some of the pre clinical models,
22:25
Speaker 2: high expression of drug eflux pumps makes them relatively less
22:29
Speaker 2: sensitive to the treatment with the payload. Exactly how frequently
22:34
Speaker 2: that scene as a clinical mechanism of resistance is to
22:38
Speaker 2: be determined. Yeah, but of course there's more data gathered
22:43
Speaker 2: will have greater clarity on that print.
22:45
Speaker 1: Okay, So I suspect you're going to tell me that
22:49
Speaker 1: it's my problem to going and figure out how dB
22:52
Speaker 1: eleven and d WO five impact WO. Nine and WO
22:55
Speaker 1: three use.
22:57
Speaker 2: Well, I think we'll all go over over time. I mean,
23:01
Speaker 2: I think from a patient perspective, just to go back,
23:05
Speaker 2: you know, the idea that we can reduce the incidence
23:08
Speaker 2: of metacetic disease by treating people more effectively in the
23:12
Speaker 2: new adjudant setting, I think it is a you know,
23:16
Speaker 2: is a goal that we all should have. There are,
23:19
Speaker 2: of course, patients that still get diagnosed with denovo and
23:22
Speaker 2: metastic disease, and so again, you know, the this is
23:26
Speaker 2: one of the reasons why the advent of screening in
23:30
Speaker 2: disease is so important, so that we can pick up
23:33
Speaker 2: as many patients as possible where there's still this higher
23:35
Speaker 2: potential for cure in the early stage setting, and ultimately
23:38
Speaker 2: over time reduce the incidence of metastic disease. I'd be
23:43
Speaker 2: very happy to see the reduction in the rate of
23:46
Speaker 2: metathetic disease. Of course, in the context of the overall
23:49
Speaker 2: opportunity with an aging population across the world. Actually, the
23:53
Speaker 2: incidence of cancers are still going up even if we
23:58
Speaker 2: are more effective at diagnosed as an early stage. So
24:02
Speaker 2: you know, I think there's two separate things that are
24:04
Speaker 2: going to to happen here. That will count on one
24:08
Speaker 2: another in terms of a commercial opportunity, and I'll see
24:11
Speaker 2: how that evolves over time.
24:13
Speaker 1: And just it's unfair because I didn't put it on
24:15
Speaker 1: my list of questions when I sent it to you.
24:17
Speaker 1: Do you have on top of your mind the percentage
24:20
Speaker 1: of patients who present the static disease having been through
24:24
Speaker 1: surgery and agimant therapy? Do you have venovo?
24:30
Speaker 2: Yeah, we do have those questions. I'm sorry, I can't
24:33
Speaker 2: quote you.
24:34
Speaker 1: Probably in the in the EPI data that you've been providing.
24:38
Speaker 1: So I'll go back. It's on your website again, right,
24:41
Speaker 1: so people can.
24:42
Speaker 3: Go it will be sorry, right.
24:45
Speaker 1: A couple of questions on HR positive. I mean you
24:48
Speaker 1: didn't really this wasn't a meeting about uh, the oral SERTs,
24:53
Speaker 1: but I think this question was posed during the ANLYST
24:56
Speaker 1: meeting too. But but if you wanted to just touch
24:59
Speaker 1: on it here quickly, what does obviously you have some
25:03
Speaker 1: potential competitors in the space of oral CERTs, RASH, et cetera.
25:09
Speaker 1: So what does RUSH did have some data which was
25:12
Speaker 1: the EVERA or as I call it, ev era, which
25:15
Speaker 1: is I think what it's meant to be trial. How
25:19
Speaker 1: does that what does that mean for the Syrena four
25:22
Speaker 1: or and and the argument Cambria studies. Just to put
25:27
Speaker 1: again into context, companies are trying to develop oral versions
25:30
Speaker 1: of drugs that impact the estrogen receptor complex versus what
25:37
Speaker 1: had been used before, which was injections and probably probably
25:41
Speaker 1: not as well tolerated as should be. So do you
25:43
Speaker 1: want to just tell us about that a little bit? What?
25:45
Speaker 2: Yes, So let me just start with what assert is.
25:49
Speaker 2: It's a selective estgen receptor degrader, so it doesn't inhibit
25:53
Speaker 2: fully inhibits the estrogen receptor, so it's a full antagonist,
25:58
Speaker 2: but it's also a degrader. Now, of the jugs that
26:01
Speaker 2: are called oral serds, not all of them are full antagonists.
26:08
Speaker 2: But chemisestron is a full antagonist of the estrogen receptor,
26:13
Speaker 2: so it has no agonistic activity at all. And it's
26:16
Speaker 2: a very potent degrader. And we've shown that in the
26:20
Speaker 2: Serena three study, which was a window of opportunity study
26:22
Speaker 2: in the early stage where we did detailed translation analysis
26:26
Speaker 2: including mass spectrometwe analysis of the protein degradation and the
26:30
Speaker 2: measure of the effect of that on fuliferation. So the
26:37
Speaker 2: data in the second line setting have typically compared with
26:42
Speaker 2: a full vester back and full vestern is a previous
26:46
Speaker 2: issue receptor degrader, but didn't achieve the same level of
26:48
Speaker 2: degradation at the available dose who it has to be
26:52
Speaker 2: given intramuscularly once a month because there was not good
26:56
Speaker 2: or absorption. So these oral serds are enabled able to
27:01
Speaker 2: some of them are able to achieve this more potent
27:05
Speaker 2: level of degradation and that full antagonism and chemisestrant is
27:08
Speaker 2: one of those. But if you look at the second
27:10
Speaker 2: line data sets, we had a study called Serena two
27:13
Speaker 2: which is a randomized study comparing against a different doses
27:17
Speaker 2: of chemisestrant versus full restrant, and we showed an improvement
27:21
Speaker 2: in the overall intention to treat patient population, just does
27:26
Speaker 2: ever ever has done. And the hazard rature that we
27:31
Speaker 2: showed compared to the previous standard care for vestant was
27:37
Speaker 2: good in that it t population and has the ratio
27:39
Speaker 2: of point seven eight. And then the hazard ratio in
27:41
Speaker 2: the patients that are particularly sensitive to ASSERT, the patients
27:47
Speaker 2: that have got a mutation in these receptor so called
27:49
Speaker 2: e SL one mutation. For those patients, we had a
27:53
Speaker 2: hazard ratio of point three three. So I think the
27:55
Speaker 2: Chemist data compares very well with what has been seen
27:58
Speaker 2: with duridestriant the ocean molecule in.
28:01
Speaker 3: The EVER study.
28:04
Speaker 2: But even in the wild type population in second line,
28:09
Speaker 2: those patients are still less endocrine sensitive than patients that
28:12
Speaker 2: have got newly diagnosed metastatic.
28:15
Speaker 3: Disease in the first line.
28:16
Speaker 2: And that's the patient population that the Serena four study
28:19
Speaker 2: is aiming to improve. Where the design of that study
28:23
Speaker 2: is a combination of chemesestrint with a CDK four six
28:27
Speaker 2: inhibitor compared with standard of care, which is an aromatase
28:31
Speaker 2: inhibitor with a CDK four six inhibita. And if you
28:35
Speaker 2: think about the comparison of the mechaniseraction of camesestron are
28:38
Speaker 2: alsoerd with an aromatase inhibitor. An romatase inhibitor actually reduces
28:43
Speaker 2: the circulating level of the ligand the estrogen. It's in
28:47
Speaker 2: the perphyal circulation that binds to the receptor. It does
28:51
Speaker 2: nothing about antagonizing that transcriptional signaling downstream of the euestrogen receptor,
28:56
Speaker 2: and it does nothing about the overall level of estergen receptor.
29:00
Speaker 2: Whereas the third has two mechanisms of action as built
29:04
Speaker 2: inhibiting folly and reducing the level of the presence, so
29:08
Speaker 2: it becomes insensitive to the amount of lig amber's there
29:12
Speaker 2: and therefore you get an improved activity. And this isn't
29:14
Speaker 2: a patient population that is more endocrine sensitive. So although
29:18
Speaker 2: the vast majority of patients in that first line metasthetic
29:21
Speaker 2: setting do not have any SR one mutation, during the
29:26
Speaker 2: course of first line therapy, it goes from five percent
29:30
Speaker 2: of patients to thirty five to forty percent of patients
29:33
Speaker 2: during that course of treatment develop an SR one mutation
29:38
Speaker 2: when they're on a romatas and hiboity. And what we
29:41
Speaker 2: have already shown with the screen of six data is
29:44
Speaker 2: that when you treat patients that have got an SR
29:46
Speaker 2: one mutation, you really really have a very good effect
29:49
Speaker 2: compared with the romitation inhibitor in improving the time to aggression.
29:54
Speaker 2: So the idea is that in a more endiman sensitive
29:56
Speaker 2: population in the wild type, you will have a bigger effect,
30:00
Speaker 2: but also you will prevent the emergence of SR one
30:03
Speaker 2: mutations in the patient population that are being treated in
30:06
Speaker 2: the first line. Both of those things together should lead
30:09
Speaker 2: to an improvement in the outcome for patients in that
30:12
Speaker 2: first line setter.
30:13
Speaker 4: Well, you've answered my next question, so that's it. So
30:17
Speaker 4: it does there is an opportunity to reduce at least
30:24
Speaker 4: YESR one emergence mutation. What about if you use this
30:28
Speaker 4: in adge it.
30:30
Speaker 1: Could you I mean, I know you, I'm pushing my
30:32
Speaker 1: leg here or at least pushing the lack of biology here.
30:35
Speaker 1: Could it be possible that they can prevent it? And
30:37
Speaker 1: why is it important for patients not to get SR
30:40
Speaker 1: one mutations?
30:41
Speaker 2: Well, it's a key escape mechanism from the signal that
30:45
Speaker 2: you get with the stream receptor. So the patients that
30:48
Speaker 2: have got this, you know, this biggest segment of breast cancer,
30:50
Speaker 2: seventy percent of breast cancer that is commone receptor positive.
30:54
Speaker 2: The key driver of proliferation is the signaling downstream of
30:58
Speaker 2: the estrogen receptor. So a more effective inhibition of that
31:02
Speaker 2: will lead to less recurrence of disease. That's fundamentally why
31:06
Speaker 2: it matters. And in the adjuvant setting, over decades now,
31:10
Speaker 2: we've shown that if you how you can give a
31:13
Speaker 2: hormonal treatment of breast cancer that is more effective on
31:16
Speaker 2: reducing that proliferation, it leads to improvements in these three
31:20
Speaker 2: survival and the risk of recurrent disease, and that leads
31:24
Speaker 2: to improved in the cure rate that was shown with
31:27
Speaker 2: timoksphen it has been shown with the aromatase inhibitors. You're
31:30
Speaker 2: now seeing it with the addition of the CBK four
31:32
Speaker 2: six inhibitors. And the best predictor of outcome in the
31:37
Speaker 2: adjuvant setting is this reduction in the proliferation marker KEY
31:41
Speaker 2: sixty seven in a window of opportunity study, and that's
31:44
Speaker 2: built off the data from the poetic study that was done.
31:48
Speaker 2: What we've shown with Serena three in this window of
31:50
Speaker 2: opportunity study is a robust inhibition of KE sixty seven
31:54
Speaker 2: at a well tolerated dose of cameisestron, and that's what
31:58
Speaker 2: predicts for the potential for good outcomes in the two
32:04
Speaker 2: adjutant studies that we've got Cambria one in Cambria two
32:08
Speaker 2: in that adjudant.
32:09
Speaker 1: So, okay, I think I'll move on to there's a
32:13
Speaker 1: risk that this ends up being entirely about breast cancer.
32:15
Speaker 1: But there were the two big things. But I really
32:18
Speaker 1: want to cover some bladder before we move on. Before
32:21
Speaker 1: we end, but let's just talk about Tropian breast two
32:24
Speaker 1: trial this is that traal way drop to a b
32:28
Speaker 1: C the data, and I'm sure you'll again go through
32:34
Speaker 1: the detail a little bit more here do they just
32:37
Speaker 1: seem better on a response rate basis too? And you know,
32:43
Speaker 1: this is what we do all our lives, comparing trials
32:46
Speaker 1: which shouldn't be compared, but there's nothing else we can
32:48
Speaker 1: do otherwise we will have a job versus through the
32:51
Speaker 1: lv in pdal one negative triple negative breast cancer patients.
32:56
Speaker 1: The os IS, on the other hand, is complicated by
33:00
Speaker 1: the different post progression treatments, for instance in TBO two
33:06
Speaker 1: versus ASSENDO three, which was the Gillietro Delvi trial. Given
33:10
Speaker 1: all this, how important do you think os IS in
33:14
Speaker 1: the trial which may have been driven by post progression issues,
33:20
Speaker 1: et cetera.
33:22
Speaker 2: So I think the first thing is if you think
33:23
Speaker 2: about the situation from a patient perspective in triple negative
33:27
Speaker 2: breast cancer, these women, who are often young women, with
33:32
Speaker 2: this metastatic triple negative breast cancer have the poorest prognosis
33:37
Speaker 2: out of any of those segments of breast cancer that
33:38
Speaker 2: we've got, with less than fifteen percent chance of a
33:44
Speaker 2: five year survival and no improvement in overall survival in
33:48
Speaker 2: over a decade. Seventy percent of those patients do not
33:52
Speaker 2: have PDO one expression, so they're not eligible for a
33:55
Speaker 2: PDO one treatment. So it's the majority of those patients
33:59
Speaker 2: and for the first time we've seen an improvement in
34:01
Speaker 2: overall survival and a very clinically meaningful improvement with a
34:04
Speaker 2: five month improvement. So the next question is why have
34:07
Speaker 2: we seen that in the chopian breast to study. And
34:11
Speaker 2: I think the first thing that you're seeing is that
34:14
Speaker 2: we have a best in class at ADC here. You've
34:17
Speaker 2: got a stable linker that's very important, and that means
34:21
Speaker 2: that you've got less exposure to the payload in the
34:24
Speaker 2: peripheral circulation and you're delivering a higher proportion of it
34:27
Speaker 2: more efficiently to the tumor cells that are expressing chope
34:30
Speaker 2: to and that's you know in driblen negative breast cancer,
34:33
Speaker 2: that's the segment has the highest expression of CHOKE two
34:37
Speaker 2: receptor on the on the tumba cell surface that translated
34:41
Speaker 2: through to us more than sixty percent overall response rate,
34:46
Speaker 2: and so that's really more than double that of the
34:50
Speaker 2: control arm of chemotherapy, which is twenty nine percent. That
34:54
Speaker 2: led to also with good durability of response, and improvement
34:58
Speaker 2: in medium progression free survival of five months. So those
35:01
Speaker 2: are the most important things because these patients progress quickly,
35:04
Speaker 2: and when they progress, many of them don't get to
35:06
Speaker 2: a second line treatment, and the fact that that's then
35:09
Speaker 2: translated through to an overall survival is important. And he
35:11
Speaker 2: brought up the point of the post progression treatment, and
35:14
Speaker 2: just want to be clear on the numbers though in
35:17
Speaker 2: both studies over seventy percent of patients went onto a
35:21
Speaker 2: second line treatment. So for the A cent three, the
35:28
Speaker 2: eighty percent of patients where eighty percent of the seventy
35:32
Speaker 2: something percent that got a second line treatment, So it's
35:35
Speaker 2: overall a fifty six percent rate of crossover onto chiudelvi.
35:41
Speaker 2: In the tropy and breasto to study, around thirty percent
35:46
Speaker 2: of patients ended up on a second line antibody drug conjugate,
35:49
Speaker 2: either a trope to or a HERD two directed antibody
35:52
Speaker 2: drug conjugate. So the rates of crossover aren't as are
35:57
Speaker 2: the difference between those aren't as big as perhaps you know,
36:00
Speaker 2: people when they reacted to the eight percent number. First
36:03
Speaker 2: thing is, you know, and what we saw is even
36:07
Speaker 2: though we got a thirty percent crossover is still translated
36:11
Speaker 2: through to an improvement in this overall survival number. And
36:15
Speaker 2: I think that's a set of data high response rate,
36:20
Speaker 2: good durability response leading to progression of resurvival of five
36:23
Speaker 2: months and a five month improvement in overall survival. The
36:27
Speaker 2: totality of those data really have a compelling argument that
36:32
Speaker 2: this is the best thing. Pass Trope to ABC, and
36:35
Speaker 2: it's great to have an option for patients in a
36:37
Speaker 2: segment of the disease where there hasn't been an improvement
36:40
Speaker 2: for over a decade, so it's very exciting.
36:42
Speaker 1: Yeah, agreed. The one thing I do here from physicians, though,
36:46
Speaker 1: is the stomatitis issue, which even though okay, fifty seven
36:53
Speaker 1: percent in the if I'm not wrong in the TBO
36:56
Speaker 1: two trial, but majority we're low grade either. The low
37:02
Speaker 1: grade seems to bother people a little bit. Do you
37:05
Speaker 1: think this is something about learning to manage it as
37:09
Speaker 1: we go forward, because physicians seem to be always good
37:13
Speaker 1: at dealing with the side effects of cancer drugs to
37:18
Speaker 1: the point that they can. And then of course the
37:21
Speaker 1: competitive drug to Delby has a different type of side
37:24
Speaker 1: effect which potentially increases the risk coming infections et cetera.
37:27
Speaker 1: So just one quick last comment on this and one
37:29
Speaker 1: last question on that way and they will move on.
37:32
Speaker 3: Yeah.
37:32
Speaker 2: Sure, So you're absolutely right that over time physicians learn
37:36
Speaker 2: to deal with the side effects of achiatment. And actually
37:39
Speaker 2: the best cancer positions have had other drugs that they've
37:41
Speaker 2: had experience with strmatitis with some of the pietri e
37:45
Speaker 2: canism hebitis for example. So yes, dermatitis is clearly seen
37:51
Speaker 2: it can be managed with either ice chips during the
37:54
Speaker 2: period of the infusion in the mass or with the
37:58
Speaker 2: corticcasteroid mass washing. Both of those as management techniques have
38:02
Speaker 2: been shut you know, on the experience of investigators are
38:06
Speaker 2: reducing the impact of the stomatitis. But obviously it's important
38:10
Speaker 2: that patients and their caregivers understand what those opportunities are
38:16
Speaker 2: for improven to this and for some patients it does
38:18
Speaker 2: become an issue, but for the majority of patients it
38:22
Speaker 2: hasn't prevented them from taking that away. It's a very
38:25
Speaker 2: low rate of discontinuation due to stomatitis on the on
38:29
Speaker 2: the Datchaway studies, So I do think that reflects that
38:32
Speaker 2: you know, overall, treating phosicians and the patients are learning
38:38
Speaker 2: to manage this side effect over time, and I think
38:42
Speaker 2: it's important just to look at the discontinuation rate on
38:45
Speaker 2: the on the trials and also the more sever adverse
38:48
Speaker 2: event rates and the rate of fatal events. We had
38:52
Speaker 2: no fatal events due to adverse events on the tropy
38:55
Speaker 2: Mbresto to study.
38:56
Speaker 3: I think that's important.
38:58
Speaker 1: Ye, last question, do you think the best partner for
39:01
Speaker 1: a DROP two ADCs? I'll well, I want a leading
39:05
Speaker 1: question here, but I thought i'd leave that to you
39:07
Speaker 1: to call it.
39:08
Speaker 2: Well, we think that the combination of ADCs and immune
39:11
Speaker 2: checkpoints inhibitors is looking very promising in a number of
39:14
Speaker 2: different settings. We also presented an update on the Bogonia
39:18
Speaker 2: data set in triple negative breast cancer, which is a
39:20
Speaker 2: combination of our PDO one inhibitor divinue map together with
39:25
Speaker 2: data way in a later line setting with an eighty
39:29
Speaker 2: percent response for a really impressive durability and response. Again,
39:33
Speaker 2: we saw that in both PDO one high and low
39:37
Speaker 2: patient population. So I think what Chropian Breast two does
39:41
Speaker 2: is it sets the scene for three other studies that
39:44
Speaker 2: we've got ongoing that are looking at that combination. The
39:47
Speaker 2: first is the tropian breast O three study, which is
39:50
Speaker 2: in the post neowagumant setting a bit like the destined
39:52
Speaker 2: BREASTO five setting, And I think that's going to be
39:55
Speaker 2: an important opportunity because again, if patients with triple negative
39:59
Speaker 2: breas can to get metastatic disease, as they've said, the
40:02
Speaker 2: longer term outcomes are much poorer than for patients with
40:06
Speaker 2: hurty positive or disease. So if we can prevent patients
40:10
Speaker 2: getting to that metastatic setting to better treatment in the
40:12
Speaker 2: early stage, I think that will be important. The second
40:15
Speaker 2: studies the Tropy and BRESTO four, which takes it into
40:17
Speaker 2: the neo adjutant setting, more analogous to the destiny breast
40:22
Speaker 2: eleven data that we referred to earlier. And then we
40:24
Speaker 2: have Tropy and Bresto five in the first line metastatic setting,
40:28
Speaker 2: again looking at the combination of dataway and defy Man.
40:31
Speaker 2: So I think with those two studies, I think very
40:33
Speaker 2: much looking forward to the results as I was reading
40:35
Speaker 2: out over the next period.
40:38
Speaker 1: Yeah, and of course my leading question was is the
40:41
Speaker 1: best combo PD one VEG or PDL one VEGEF by
40:44
Speaker 1: specific But I'm going to make a comment and move
40:47
Speaker 1: on to bladder because I'm more interested in your views.
40:49
Speaker 1: I'm definitely interested in your views on bladder and matterhorne, Patomac, etcetera.
40:54
Speaker 1: Patomac at the conference. So the problem I have with
40:58
Speaker 1: what we everyone's been running around digging around Harmony six
41:02
Speaker 1: trial data, and of course when you look at the
41:04
Speaker 1: supplementary details there there was a major focus, as there
41:08
Speaker 1: should have been, on excluding patients with the risk of
41:11
Speaker 1: hymoptosis or history of hymopthesis, and yet there were some
41:16
Speaker 1: bleeding events on the trial. So I still am sitting
41:18
Speaker 1: here a little bit worried that this is just this
41:22
Speaker 1: ends up just being a PDO one plus I don't know,
41:25
Speaker 1: I don't know. I actually do you want to make
41:27
Speaker 1: a comment on that or would you rather not?
41:29
Speaker 2: Well, I mean, I think we have to wait and
41:31
Speaker 2: see whether you're getting the effects size that's seen on
41:35
Speaker 2: pfs translates through to similar effects size on OS. You know,
41:39
Speaker 2: as we said, you know, our strategy has been to
41:43
Speaker 2: take targets where you can address the same cell if
41:47
Speaker 2: you like, with two different targets, so like the PD
41:50
Speaker 2: one tidget or the PD one C to for because
41:54
Speaker 2: we have seen data suggest that that co inhibition on
41:58
Speaker 2: the cells. By having it on one by specific actually
42:01
Speaker 2: makes a biological difference in terms of what you're achieving. So,
42:06
Speaker 2: you know, I think the field is open to be
42:08
Speaker 2: interesting to see that ditas they evolve.
42:11
Speaker 1: I mean, you've definitely thrown the dice seriously on river
42:15
Speaker 1: gostomic and you could save all rostomic two. You know,
42:19
Speaker 1: I don't know. I think we talked about this last time.
42:21
Speaker 1: I counted something like eight thousand patients in total in
42:24
Speaker 1: the various river gostomic trials. I am hopeful. I believe
42:28
Speaker 1: in your translational data. That was beautiful to see at
42:30
Speaker 1: w CLC. And of course I missed this time last
42:33
Speaker 1: year's city presentation, but fingers crossed because I think it
42:37
Speaker 1: would be finally changing people's attitudes to more than LAG
42:42
Speaker 1: three in CTLA four in single agent or combo. So,
42:47
Speaker 1: just to touch on bloody cancer, non Muslims bloody cancer,
42:52
Speaker 1: POTOMAC trial delivered good e FS results point six eight
42:56
Speaker 1: in bcg naive high risk non metals non also invasive
43:01
Speaker 1: bladder cancer, which of course is a key thing there is.
43:04
Speaker 1: To preserve the bladder is what everybody tries to do
43:08
Speaker 1: with a variety of mechanisms very similar to the Fizer
43:11
Speaker 1: Crest study and trial design, but in finsy is used
43:14
Speaker 1: for one year versus a Sandle map for two years.
43:18
Speaker 1: And pat Tomake sured earlier FS curve separation that that
43:22
Speaker 1: was at about three months and Crest, do you want
43:24
Speaker 1: to just talk to us about this comparison on making
43:28
Speaker 1: which is again not head to head of course, and
43:31
Speaker 1: also what it means for the role of infincy non
43:34
Speaker 1: muscle invasive bladder cancer, especially nations with sorry, this particular
43:40
Speaker 1: type of it, which is Carcinomo Institute.
43:43
Speaker 2: Yeah, okay, So the a couple of comments that I
43:46
Speaker 2: would make. First of all, one is that you know
43:50
Speaker 2: there were there have been three trials now in the setting,
43:52
Speaker 2: but the design of the third child, the Album study
43:55
Speaker 2: that wasn't positive, I think, was different in terms of
43:59
Speaker 2: the patientpulation enrolled. So with the Potomac study, we focused
44:04
Speaker 2: on the higher risk patient population, you know, with with
44:10
Speaker 2: with higher risk features, and it was good to see that,
44:13
Speaker 2: you know, you have seen this reduction in eventory survivors
44:17
Speaker 2: or patients that are coming in that have got a
44:19
Speaker 2: high risk disease, risk of having recurrent transireadable receptions. Of
44:24
Speaker 2: of bloody cancer. And you know what that leads to
44:28
Speaker 2: over time is increasing risks that they do have to
44:31
Speaker 2: go onto a systectomy because they're likely to have progression
44:35
Speaker 2: to muscle invasive disease. And obviously you're right, systectomy is
44:39
Speaker 2: a life changing major surgery. So in the term that
44:44
Speaker 2: we included high grade patients with TA or T one
44:48
Speaker 2: and or costinomer incites you, which is multiple and recurrent
44:52
Speaker 2: and large, and I think that that identifies that higher
44:55
Speaker 2: risk patient population and so encouraging to see the early
45:04
Speaker 2: separation that occurs with eventary survivals. So it means that
45:09
Speaker 2: patients don't have to have another reception of disease and
45:15
Speaker 2: fewer of them will go on to have a recommendation
45:17
Speaker 2: for systectomy. Now, with the size of the study that
45:21
Speaker 2: we've seen so far, what we haven't yet shown statistically
45:24
Speaker 2: significantly is an absolute reduction in the rate of systectomy.
45:28
Speaker 2: I think we'll have to wait for longer term follow
45:32
Speaker 2: up for that, but that is the goal of what
45:35
Speaker 2: we're looking to do in both non muscle invasive disease
45:38
Speaker 2: and I think in the induction period with neoadjuvant treatment
45:44
Speaker 2: in the muscle invasive segment. If we could actually get
45:47
Speaker 2: pathologic complete response rates higher, there's an opportunity to save
45:51
Speaker 2: people's bladders in more than one setting. So I think
45:55
Speaker 2: it's very encouraging progress in general with what we're seeing that.
46:00
Speaker 1: Yeah, so just let me move on quickly to thank
46:04
Speaker 1: you for that. The the other data that we saw
46:07
Speaker 1: from Combo that seems to be doing very well in
46:11
Speaker 1: the in the in the setting. So this is the
46:14
Speaker 1: non esthetic m I B C. This was keynote nine
46:17
Speaker 1: oh five. I think it did have an EV number
46:20
Speaker 1: I can't remember, and which was a forutum a thedotin,
46:26
Speaker 1: which is a nctin for ABC that now is owned
46:29
Speaker 1: by Pfizer, plus Key Trudeau, pembridism, good perioperative regime. And
46:36
Speaker 1: I think it got lots of claps, et cetera at
46:38
Speaker 1: the conference because blaody cancer physicians haven't seen data like
46:41
Speaker 1: this in decades in cisplatin ineligible patients. Now, this is
46:47
Speaker 1: obviously a more frail and not necessarily the same patient
46:51
Speaker 1: population that was tested in Niagara. But how do you
46:56
Speaker 1: is there any way or to think about these two
46:59
Speaker 1: trials Niagara and Keynote nine oh five together, what would
47:04
Speaker 1: I take away from making that.
47:07
Speaker 2: Yeah, yeah, Niagara is in the cisplatin eligible population. So
47:11
Speaker 2: it's a combination of the volume map plus germside zisplattin
47:15
Speaker 2: and showed, you know, an improvement in the pathologic complete
47:19
Speaker 2: response rate, but also then that translates through to an
47:21
Speaker 2: improvement in the event free survival rate. What you've seen
47:25
Speaker 2: here is in the platinum ineligible population, you know, a
47:29
Speaker 2: further improvement if you like, in the pathologic complete response
47:33
Speaker 2: rate and a good improvement in event free survival as well.
47:37
Speaker 2: So I think what this says, first of all, is
47:39
Speaker 2: absolutely possible to further improve the pathologic complete response rates.
47:44
Speaker 2: We also have an ongoing study, the Vulga study, which
47:47
Speaker 2: also looks at a combination of EV but with the
47:50
Speaker 2: value maps. So moving from the value map in combination
47:54
Speaker 2: with gemsis chemotherapy to divine map in combination with an ADC,
48:00
Speaker 2: and it's also in the cisplatin ineligible population. The difference
48:05
Speaker 2: between Vulgar and the study that we've the Keynote nine
48:09
Speaker 2: to five study is that the EV regimen is just
48:13
Speaker 2: in the new dulant setting, So there isn't this continued
48:17
Speaker 2: EV dosing in the post surgical setting, and I think
48:21
Speaker 2: it'll be interesting to see both the safety profile from that,
48:24
Speaker 2: but also what that means in terms of events through survival,
48:28
Speaker 2: because I think it's very clear that with the tolerability
48:31
Speaker 2: that you get with EV not all patients are able
48:35
Speaker 2: to make it through that post surgical treatment period because
48:40
Speaker 2: of advers events. So I think there's an opportunity to differentiate.
48:44
Speaker 2: That's that's one difference. The second difference is that we
48:46
Speaker 2: don't just have a combination arm with devalue MAP, but
48:50
Speaker 2: we've also got a combination arm with two doses of
48:54
Speaker 2: tremulum a MAP in that study, and we know that
48:57
Speaker 2: that treatment regimen with a high level of induction of
49:01
Speaker 2: chumnel the member if you can be well tolerated. We've
49:05
Speaker 2: seen that if you like in the Himalaya study with
49:07
Speaker 2: the STRIDE regimen and Inhabita cellular carcinoma. So we hope,
49:10
Speaker 2: but we also know that bladder cancer is one of
49:12
Speaker 2: the most CLA four sensitive tumor types, so we hope
49:16
Speaker 2: that that will translate through to a further improvement in
49:19
Speaker 2: the long term outcomes of event free survival because inhibiting
49:23
Speaker 2: CLA four when the tumor's there, and you've got the
49:27
Speaker 2: kind of mechanism of cell kill, imminogenic cell kill from
49:31
Speaker 2: a treatment with an ABC like before tamen predosing that
49:35
Speaker 2: you can get really good priming of the immune response
49:38
Speaker 2: and that that can translate through to very good long
49:41
Speaker 2: term outcomes. So there's two different reasons why it's it's
49:44
Speaker 2: different from the EV nine oh five study. But I
49:47
Speaker 2: think the data that it's a scene gives us a
49:49
Speaker 2: high degree of confidence that we can hit the pathologic
49:52
Speaker 2: complete response endpoint in the Vulgar study and that that
49:56
Speaker 2: also then translates through to the important of event free
50:01
Speaker 2: survival and ultimately for as a survival.
50:04
Speaker 1: And susan quickly. Historically, has there been you know, this
50:08
Speaker 1: continuous conversation about p d L one versus p D one. Historically,
50:12
Speaker 1: has there been any any data that suggests PD one
50:15
Speaker 1: p d O one or different in the bladder setting?
50:18
Speaker 2: All right, So I think in the context of bloody cancer,
50:20
Speaker 2: I don't think that PDO one is as predictive as
50:22
Speaker 2: it is in some other Oh.
50:25
Speaker 1: No, sorry, sorry, sorry, sorry, sorry, sorry to stop you.
50:27
Speaker 1: I meant antibody I E A PDAL one antibody versus
50:30
Speaker 1: a PG one antibody.
50:32
Speaker 2: Well, I mean, I think you've seen with Niagara that
50:34
Speaker 2: in the context of this perioperative setting, we really have
50:37
Speaker 2: very good data that's led to return improvement in the
50:41
Speaker 2: and the eventary survival uh context for Niagara. So you
50:48
Speaker 2: know in these uh you know, we don't have three
50:50
Speaker 2: perioperative regimens with the value MAPP, Mattter, Horn g and
50:55
Speaker 2: and Niagara. We've all seen very well just effect sizes
50:59
Speaker 2: and the eventation a lot of sizes. It's similar across
51:02
Speaker 2: the class. So I'm not sure that there is a
51:05
Speaker 2: differentiation across that p D O one versus p D one.
51:09
Speaker 1: Okay, Well, so so we're going to be all sitting
51:12
Speaker 1: there comparing PCR rates between TV was it three or four,
51:16
Speaker 1: Keynote nine five, and Vulga. Then so.
51:22
Speaker 2: We look forward to the data when sorry, when are
51:25
Speaker 2: we expecting that? So we will provide an update at
51:30
Speaker 2: the key three results on the timing for the vulgusta Okay?
51:34
Speaker 1: Cool? And then of course we've got the we had
51:37
Speaker 1: the riverlogstomic plus dato in Tropi and panchumer three which
51:43
Speaker 1: includes we've got that coming both first and second line,
51:47
Speaker 1: and what's the plan on that now? I mean, you know,
51:50
Speaker 1: first line to challenge EV pembro is that the idea or.
51:54
Speaker 2: Well, I mean, I think it's going to be very
51:55
Speaker 2: clear that given the data that we've seen, that there's
51:58
Speaker 2: an opportunity for the EV regimen to move into the
52:02
Speaker 2: early line. And so I think there's going to be
52:04
Speaker 2: an opportunity for wanting to have alternative treatments in the
52:10
Speaker 2: metastatic setting for those patients. The vast majority of patients
52:13
Speaker 2: that are diagnosed with Brady cancer are diagnosed you know,
52:19
Speaker 2: not denovo metascetic.
52:20
Speaker 3: But in the in the.
52:22
Speaker 2: Muscle and days of or non muscle and days of
52:24
Speaker 2: settling first before they progressed a metathatic disease.
52:28
Speaker 3: So I think this is going to.
52:29
Speaker 2: Come up as a as a question and having a
52:30
Speaker 2: different target and a different mechanism of action of payload
52:35
Speaker 2: will be an important option for patients with burd cancer.
52:38
Speaker 2: One of the other things that we're obviously looking at
52:40
Speaker 2: is the potential for a biomarker for DEBTA way to
52:44
Speaker 2: improve the patient selection, and I think that's a lot
52:47
Speaker 2: of important for opportunity for differentiation as well.
52:52
Speaker 1: So Susan, we've eaten one hour of your time, which
52:57
Speaker 1: is much more valuable than mine, that's for sure. And
53:00
Speaker 1: we didn't talk about non small cell. We didn't talk
53:02
Speaker 1: about gastric but celling. I had all these things here,
53:06
Speaker 1: correct or variant, et cetera, of course, but that's the
53:10
Speaker 1: problem with astrosanka. You've got you've got things in fingers
53:13
Speaker 1: in all kinds of parts. I just wanted to highlight
53:15
Speaker 1: you did have some artomido one data which I got
53:19
Speaker 1: excited by. I did my mathema maths in the comparison things,
53:24
Speaker 1: which of course is head not head to it, and
53:26
Speaker 1: then I'll go and take the sections of the keynote.
53:30
Speaker 1: Was it forty two year patients and tried to make
53:32
Speaker 1: comparisons which look really good, I have to say, and
53:35
Speaker 1: small numbers of patients.
53:36
Speaker 2: So yeah, looking forward to I am looking forward to
53:40
Speaker 2: the data. I mean the artomido one data as it
53:42
Speaker 2: continues to make sure mature patients are staying on treatment.
53:46
Speaker 2: There's really good tolerability and those durability response data and
53:50
Speaker 2: the percussion free survival data more than twelve months. Medium
53:54
Speaker 2: percussion free survival in the patients that have more than
53:57
Speaker 2: fifty percent of PBO one expression is very encouraging. Obviously,
54:02
Speaker 2: small data set.
54:03
Speaker 3: But yes, you can.
54:04
Speaker 1: You can even in the one to forty nine I
54:06
Speaker 1: was I was interesting. I did a little comparison to
54:10
Speaker 1: Keynote forty two by taking just the patients that had
54:14
Speaker 1: no prior therapy in your data set, and that look
54:17
Speaker 1: that looked from an all our perspective better.
54:20
Speaker 2: Well, yeah, again, I think one of the things that
54:23
Speaker 2: we're seeing with RELVERCOSTOMK is that there is an extension
54:28
Speaker 2: of the range of patients that are likely to respond,
54:31
Speaker 2: and that's across multiple data sets that we've got as well.
54:34
Speaker 2: And then the tolerability profile and the durability of response
54:37
Speaker 2: is also very encouraging. So this is one of the
54:39
Speaker 2: reasons why we've had confidence in the program to advance
54:43
Speaker 2: into multipleity.
54:45
Speaker 1: In your comment there, I hear whether perhaps I should
54:49
Speaker 1: focus on the ten percent plus or twenty percent plus
54:51
Speaker 1: or whatever what we see right, And Susan, it's exactly
54:56
Speaker 1: one hour. Thank you very much for your time. It's
54:58
Speaker 1: always a pleasure talking to I can we can keep
55:01
Speaker 1: going for hours, of course, as I said, but thank
55:04
Speaker 1: you for making the time. Congratulations again on a fantastic
55:08
Speaker 1: ESMO and look forward to ASCO. Although we have a
55:11
Speaker 1: whole bunch of other conferences in between. Thank you for
55:14
Speaker 1: your time, Susan again.
55:15
Speaker 3: Thanks Sam, it's always good to talk to you. Take care,