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Yale ASH 2021 Highlight: Leukemia

 .

Yale ASH 2021 Highlight: Leukemia

March 28, 2022

March 25, 2022

Hosted by Dr. Amer Zeidan

Presentation by: Dr. Rory Shallis

ID
7618

Transcript

  • 00:00Much for joining us today for another
  • 00:04edition of the highlights of the
  • 00:06American State of Hematology meeting
  • 00:07that was held in December 2021.
  • 00:10My name is Ammar.
  • 00:13I'm joined today by Doctor Nicola and
  • 00:16Doctor Rory Chalice and we will be together
  • 00:20presenting on myeloid malignancies.
  • 00:22I will start by talking about
  • 00:25MD's for around 15 minutes.
  • 00:27Doctor Cialis will follow
  • 00:29with highlights of XAML.
  • 00:31For another 15 minutes and
  • 00:32then Doctor will finish.
  • 00:33Will highlights of Milo
  • 00:36proliferative neoplasms?
  • 00:37Feel free to post your questions in the chat.
  • 00:42At the end,
  • 00:43we are going to have 10 to 15 minutes.
  • 00:45We'll try to finish around 12:50 so that
  • 00:48you can ask your questions directly.
  • 00:50Or if you want,
  • 00:51if you prefer,
  • 00:52you can type them during the presentations
  • 00:55so that we can also tackle them at the end.
  • 01:00Thank you so much for joining
  • 01:01and I'm going to get started.
  • 01:07So for MTS, basically, UM,
  • 01:10this has been a very exciting field.
  • 01:13These are my disclosures.
  • 01:14There has been a lot of new developments
  • 01:16in MD's over the last couple of years,
  • 01:19and I think this is an area where we
  • 01:21continue to have new drugs approved.
  • 01:23So one of the drugs that has been recently
  • 01:27approved is a combination of oral.
  • 01:30Put in so the site being is a standard
  • 01:32of care treatment for higher risk
  • 01:34MD's that's given intravenously.
  • 01:36The problem is that this drug cannot
  • 01:39be given orally because it undergoes
  • 01:41first passed in the liver and the gut
  • 01:45and therefore has not been able to do
  • 01:48orally subsequently which inhibits
  • 01:50the enzyme cytidine dominates as
  • 01:52you can see in this slide basically
  • 01:55allows the desire to be in to be given
  • 01:58orally and in a phase three trial.
  • 02:00All that certain trial that
  • 02:02we participated in at at Yale.
  • 02:04It was shown to have the
  • 02:06same pharmacokinetics,
  • 02:07which is the primary endpoint of the study,
  • 02:09such as intravenous decided
  • 02:11and based on this data,
  • 02:13the drug was approved in the year 2020.
  • 02:16The clinical results have
  • 02:17been presented more than once,
  • 02:19but the paper has not been published yet,
  • 02:24so this is the presentation of the
  • 02:27overall data from 2020 where the
  • 02:29complete response rate was shown
  • 02:31to be around 20%.
  • 02:33And many patients achieved as you
  • 02:36can see platelets and erythrocytes.
  • 02:38Transition independence around
  • 02:4050% of patients.
  • 02:42And you can see the CR was
  • 02:45durable around 14 months.
  • 02:46The patients are still being followed for.
  • 02:49Long term survival I think.
  • 02:53Important update that was presented
  • 02:56in in this ASH in December was
  • 02:59the activity in the lower risk.
  • 03:01Andy Ashby,
  • 03:01'cause some patients had intermediate
  • 03:041 tips and as you can see the
  • 03:07complete response rate was also
  • 03:10seen in those patients around 23%.
  • 03:13So it seems that even for lower
  • 03:15risk MD SIDEK has activity,
  • 03:17which is something we see.
  • 03:19Also the intravenous decide.
  • 03:22However,
  • 03:22it's not clear if this is the
  • 03:24right dose for these patients,
  • 03:26because we certainly see neutropenia
  • 03:28and thrombocytopenia and therefore
  • 03:30a phase two study randomized phase.
  • 03:32Two study was initiated where
  • 03:34the Sidik is given in two doses,
  • 03:37lower doses than the approved dose
  • 03:39in patients with lower risk MD's
  • 03:41who are not responding to her
  • 03:44therapist stimulating agents.
  • 03:45So this study is open currently
  • 03:47at the main campus for any lower
  • 03:49risk MD's patient,
  • 03:50feel free to discuss any patients
  • 03:52who might have. For this study.
  • 03:55Another drug that has been also approved
  • 03:57in the year 2020 as Los Patterson,
  • 04:00solo spatter said,
  • 04:01basically is a transforming
  • 04:03growth factor pathway inhibitor.
  • 04:05So these transforming growth
  • 04:08factor pathway proteins have been
  • 04:11shown to interfere with.
  • 04:13Luis is and what does low specific
  • 04:16do its ligand trap so it removes it,
  • 04:18removes the inhibitory effect
  • 04:21on erythropoiesis and therefore
  • 04:23stimulating red blood cell production?
  • 04:25The drug has been shown to improve
  • 04:28transfusion independence rates.
  • 04:30You can see here the pivotal
  • 04:32trial results from the MIDDLE'S
  • 04:34trial which was published in 2020
  • 04:37yet participated in that around
  • 04:401/3 of the patients achieved
  • 04:42transfusion independence, so this was.
  • 04:44Refractory setting after yes, a failure.
  • 04:47We currently have the commands trial
  • 04:50which is in the frontline setting,
  • 04:52so this is open actually in
  • 04:54several of the Cancer Center.
  • 04:58Satellite centers basically this
  • 05:00is available for a front drawing.
  • 05:03Randomization against erythropoiesis,
  • 05:04stimulating agents and this is
  • 05:07regardless whether you have the
  • 05:08patient has rings to drop class or not,
  • 05:10so please feel free to refer patients
  • 05:14for this or again it's open in many of
  • 05:17the care centers so the patients can
  • 05:19be treated on the trial right there.
  • 05:22That is another drug first in class
  • 05:26TELOMERS inhibitor that has shown
  • 05:28also good data in the refractory labs.
  • 05:31Lower risk MD.
  • 05:32As you can see here the presentation
  • 05:35from the phase two part of the
  • 05:38emerge study which showed a rate of
  • 05:41transfusion independence of around 42%.
  • 05:43So a good number of patients are achieving
  • 05:46transfusion independence with this drug.
  • 05:48So this trial has a phase
  • 05:50three component called.
  • 05:52Also the emerge which has been open
  • 05:55at the main part of the study has
  • 05:58actually been fully accrued and closed.
  • 06:00But there is an extension of this study.
  • 06:02So currently if you have patients
  • 06:04who have lower risk MD's who are.
  • 06:08First line,
  • 06:09they can be considered for the
  • 06:11commands trial if they have received
  • 06:13essays and they are not responding.
  • 06:15We have two options.
  • 06:16I merge trial with that as well as
  • 06:19the lower dose of the oral disability
  • 06:22being available for these patients.
  • 06:25How about higher risk MD's so many
  • 06:27of you are aware of any talk lacks
  • 06:31having very good activity in XAML.
  • 06:34It's a standard approved drug.
  • 06:36Now it's an oral pill that's given for
  • 06:39older patients with acute myeloid leukemia,
  • 06:41and we've been using it
  • 06:43for several years now,
  • 06:45so there has been a lot of interest in
  • 06:48exploring that in patients who have higher
  • 06:50risk MD's as well with excess players,
  • 06:53and we have preclinical data
  • 06:54suggesting synergy with.
  • 06:55There's a side to Dean because one of
  • 06:58the common resistance mechanisms to.
  • 07:01Cited in is actually up regulation
  • 07:03of PCL two,
  • 07:04so trial was two trials were
  • 07:06designed basically as early phase
  • 07:08trials in the frontline as well as
  • 07:10in the relapse refractory setting.
  • 07:13After HMA failure,
  • 07:15combining venetoclax with you
  • 07:17can see in this slide that those
  • 07:20escalation design of that study that
  • 07:23subsequently went to those expansion
  • 07:25and this is in the frontline setting.
  • 07:28Very important to note that venetoclax
  • 07:30here was given for 14 days.
  • 07:32So it's not continuously given
  • 07:34like it is in AML only 14 days and
  • 07:37doses 400 milligram,
  • 07:38which is the same dose that
  • 07:40we do in patients with AML.
  • 07:42However has a lot of drug interactions
  • 07:44and it's important to adjust those
  • 07:47accordingly and monitor the patient
  • 07:49closely for infections which are
  • 07:51common because you get neutropenia,
  • 07:53those patients should be
  • 07:56on prophylactic antibiotics
  • 07:57and should be treated very
  • 07:58aggressively if they have an infection.
  • 08:00They need a lot of transfusion care as well.
  • 08:03Especially during the
  • 08:04first one to two cycles.
  • 08:06So the patient should be seen at least
  • 08:08twice a week and given transitions as needed.
  • 08:12With all of that being said,
  • 08:13basically we are seeing early
  • 08:16activity in with this combination,
  • 08:19so the complete response rate is around 35%,
  • 08:22which is similar to what
  • 08:24was observed in XAML.
  • 08:25However, many of the other patients
  • 08:27are achieving also more OCR where the
  • 08:29plants are less than 5% and they are
  • 08:32achieving hematologic improvement.
  • 08:33You can see that the response
  • 08:36is achieved relatively quickly.
  • 08:38The first response is seen within one
  • 08:40month and those responses are durable.
  • 08:4212 months you can see also that
  • 08:45there is and this is the main update
  • 08:47that was presented in ASH 2021.
  • 08:49You can see that many patients achieve
  • 08:52no molecular clearance where the TP 53
  • 08:55for example molecular load is decreased.
  • 08:58However,
  • 08:58the question in TP 53 in particular is
  • 09:01whether overall survival is improved or not.
  • 09:04So I think this data is encouraging.
  • 09:07Clearly, however,
  • 09:07this is a single ARM study.
  • 09:09It's not randomized.
  • 09:11Study less than 70 patients were enrolled.
  • 09:13And therefore we have an ongoing
  • 09:16registration study called DEVARONA.
  • 09:18Which is also open at Yale.
  • 09:21This is a randomized phase three
  • 09:23study in which patients are
  • 09:24randomized in a double blind,
  • 09:25placebo controlled fashion to receive.
  • 09:28Either as a sighted in with venetoclax
  • 09:31or azacitidine with placebo,
  • 09:33and we have presented the schema
  • 09:36of this study in ASCO 2021.
  • 09:38You can see here 500 patients will be
  • 09:41enrolled and this study continues to
  • 09:43be open and we encourage you to refer
  • 09:45patients who have higher risk MD's.
  • 09:48I currently discourage people from using.
  • 09:52Plaques off label in the frontline
  • 09:54setting because we still don't
  • 09:56fully understand if it actually is
  • 09:59better than is cited in monotherapy.
  • 10:01And that's I think another reason to
  • 10:03consider enrolling patients on this study,
  • 10:05which is open at yet.
  • 10:07In the refractory relapse setting,
  • 10:10Yale has participated in a study
  • 10:12that was led by.
  • 10:14The sponsor or organized by the sponsor,
  • 10:18similar design,
  • 10:18those escalation followed by those
  • 10:21expansion and this was a smaller
  • 10:23study than the frontline study.
  • 10:2444 patients were treated same dosing,
  • 10:27400 milligram of Veneto class given for
  • 10:29two weeks and venetoclax was added to
  • 10:32a society in so the patient had a failure.
  • 10:35But the patient continued in the MA so it is.
  • 10:39And you can see here that
  • 10:42response rate was seen in 39%.
  • 10:44However, many of those were more hours.
  • 10:46The CRA was 7%,
  • 10:48but those responses were durable.
  • 10:50As you can see, the duration was nine
  • 10:53months of the CR or the more OCR.
  • 10:56But most importantly,
  • 10:57we are actually seeing.
  • 10:59I think mean clinically meaningful responses.
  • 11:02You can see that platelets and red blood
  • 11:05cell transfusion independence among
  • 11:07patients who were transfusion dependent.
  • 11:09OK fine, so the patient was needing
  • 11:12blood or platelets around 1/3
  • 11:14of those patients are becoming
  • 11:16transfusion independent with by
  • 11:18adding venetoclax to exercise and you
  • 11:21can see that many patients achieve
  • 11:24hematologic improvement as well,
  • 11:2543% and the median overall
  • 11:27survival was 12 months.
  • 11:29We know historically that median
  • 11:31overall survival after a jammy
  • 11:33failure is around six months,
  • 11:36so it does seem that.
  • 11:38We are seeing promising activity with this
  • 11:42combination in the refractory labs setting.
  • 11:46I think another important study
  • 11:48from this hash meeting was the
  • 11:51phase three update using that,
  • 11:53so people need this stat.
  • 11:54Is it activating enzyme inhibitor?
  • 11:56It works upstream of the protein zone so
  • 11:58this is a negative phase three study.
  • 12:00The reason why I think this is an
  • 12:03important presentation is because there
  • 12:05has been a lot of early data with.
  • 12:07That we had a randomized phase
  • 12:10two study with people instead that
  • 12:12showed the CR rate was 50% more than
  • 12:15double death of his immunotherapy,
  • 12:18and we had durable responses.
  • 12:21So there was a lot of excitement
  • 12:23about this drug and we did participate
  • 12:25in the phase two part of this.
  • 12:27Evaluation, but not in the phase three.
  • 12:30However,
  • 12:30you can see here in the phase
  • 12:32three that there was.
  • 12:33No difference in the event free survival,
  • 12:35which was the primary endpoint.
  • 12:37No difference in the overall survival.
  • 12:40And even in the CRA there was
  • 12:42no improvement with the combo.
  • 12:44So that I think highlights why it's
  • 12:46very important we enroll patients
  • 12:48in phase three trials and not just
  • 12:51assume activity based on phase two trials.
  • 12:54How about immune checkpoint inhibition?
  • 12:56As I'm sure you know,
  • 12:57in solar tumors immune checkpoint
  • 12:59inhibition has led to very important.
  • 13:03Progress in very difficult to treat
  • 13:05tumors such as Melanoma and lung cancer.
  • 13:08Early data with immune checkpoint
  • 13:11inhibitors in MD's has not been
  • 13:14so far particularly great.
  • 13:16With this is an example of this study
  • 13:19that was conducted at several centers,
  • 13:22including Yale,
  • 13:22where we showed that there was no
  • 13:25difference by adding door volume app,
  • 13:27which is an approved PDL 1
  • 13:29inhibitor that already has.
  • 13:31Meaningful clinical activity and solid
  • 13:33tumors by adding it to a society.
  • 13:37However, there are novel.
  • 13:38I think immune checkpoint
  • 13:40inhibitors that seem to.
  • 13:42Early and early results seem to
  • 13:45have a promising clinical activity.
  • 13:47One of them is about so sabatelli map
  • 13:51works on a receptor called Team Three.
  • 13:53So term 3 basically is an inhibitory
  • 13:56receptor that is not only expressed
  • 13:59on the adaptive cells,
  • 14:01such as the T cells,
  • 14:02but also it's expressed in
  • 14:04the innate immune cells,
  • 14:06including the macrophages,
  • 14:07but also importantly on the leukemia
  • 14:11stem cells. So this is being.
  • 14:14Presented as as an immuno myeloid agent?
  • 14:17Because it leads to activation of
  • 14:20the T cells and then it immune system
  • 14:24but also it directly inhibits.
  • 14:28A loop of self renewal within the
  • 14:31leukemia stem cells by interfering with
  • 14:34the ligand called galectin 9 that binds
  • 14:37to team three on leukemia stem cells.
  • 14:39So this drug was combined with Dean
  • 14:42and Decitabine in a phase one trial.
  • 14:44You can see here the early data
  • 14:46that was presented in actually
  • 14:48in more than one ASH meeting.
  • 14:51And, uh, the CR rate was not very
  • 14:55high compared to a similar therapy.
  • 14:58However, in certain subsets like
  • 15:00TP 53 for example, the CR rate.
  • 15:04The CR was durable.
  • 15:05The median duration of response
  • 15:07was 21 months,
  • 15:08which again in a very difficult
  • 15:11field such as CP3, I think,
  • 15:13is very exciting,
  • 15:13but we are also seeing hints of
  • 15:15durability and other subsets,
  • 15:17so clearly there is also excitement
  • 15:21about this agent.
  • 15:22There is actually a randomized phase
  • 15:24two and a randomized phase three trial.
  • 15:27Both of them were open at Yale and
  • 15:29they are fully enrolled and we have
  • 15:31two other studies with this drug,
  • 15:32one in combination with oral.
  • 15:34Typo methylating agents.
  • 15:35So you can give the sidik the
  • 15:37oral decitabine with this drug,
  • 15:39and another study of a triplet
  • 15:43where is cited in with venetoclax
  • 15:47and will be given for patients
  • 15:49with high risk MD's and both of
  • 15:50those studies will open at the end.
  • 15:52Lastly,
  • 15:53the idea inhibitors this is dawn of
  • 15:57the precision era in MD's like other.
  • 16:12Malignancies in leukemia, where we do
  • 16:14it more so approved clearly and MD's,
  • 16:17but we have seen 2 presentations
  • 16:19from the French group and ash where
  • 16:22we are seeing basically activity and
  • 16:25responses within a signal for IDH 2
  • 16:28mutated MD's and I was sitting there
  • 16:30for IDH 1 mutated MD's so I think
  • 16:33this is an option clearly off label.
  • 16:35But in the absence of a clinical trial,
  • 16:38I do check for IDH mutations for patients
  • 16:40with MD's and consider using these drugs.
  • 16:43Lastly, CPX 351 or liposomal
  • 16:46daunorubicin was approved for secondary,
  • 16:49AML is also being studied in high
  • 16:52risk patients who have access plus
  • 16:54in particular and we are seeing
  • 16:56encouraging activity.
  • 16:57Again this is single ARM study.
  • 16:59Small number of patients.
  • 17:00Those are not your typical MD's patients.
  • 17:03Those are younger fit patients
  • 17:04who go to transplant.
  • 17:05So this probably does not
  • 17:07apply to most patients,
  • 17:08and this is intensive chemo,
  • 17:09so there is high risk of toxicity.
  • 17:11Those patients should be monitored
  • 17:13the same way you would consider
  • 17:15someone who is getting 7 + 3.
  • 17:17So in summary, a lot of active.
  • 17:21Instigation for new agents in MD's,
  • 17:23I think the field is clearly
  • 17:25very exciting with looking like
  • 17:29a therapeutic revolution similar
  • 17:30to what's happening in XAML,
  • 17:32and I think to continue with that
  • 17:34we need to continue to refer
  • 17:36patients for clinical trials.
  • 17:37So thank you so much.
  • 17:39This is my email.
  • 17:42Many of you have my cell as well
  • 17:44and feel free to reach out for
  • 17:46any questions about MD's or any
  • 17:48other questions you might have.
  • 17:50Thank you so much and I will move
  • 17:53to Doctor Challace who will talk
  • 17:55about acute myeloid leukemia updates.
  • 18:02I have to confirm it's just
  • 18:03presenter view or the standard view.
  • 18:09It's a present, sorry it's
  • 18:11your for you. You need
  • 18:12to. Such. How's that look good? Yeah, but.
  • 18:19So alright thanks Doctor
  • 18:21Sadanand all of you for joining.
  • 18:23I'll be reviewing some of the
  • 18:25highlights from this past meeting
  • 18:26as it relates to similar disease.
  • 18:28Akuma leukemia touching on a few that
  • 18:31caught our attention as a community we
  • 18:33can start with a retrospective analysis.
  • 18:35First, liposomal done rubison sutera
  • 18:39been or CPX 351 and hypomethylating
  • 18:42agent plus band have shown vantage
  • 18:45as frontline therapies for older
  • 18:48and we call adverse risk AML.
  • 18:50Although HMA van is approved for
  • 18:53ineligible patients who are ineligible
  • 18:55to receive intensive therapy,
  • 18:57there's an increased use of this
  • 18:59combo in older intensive therapy.
  • 19:01Eligible patients including
  • 19:02adverse risk disease.
  • 19:03Furthermore, there's no getting around the
  • 19:05fact that CPX is just pretty darn expensive,
  • 19:08and we also recently published data on
  • 19:10this and listen to classical 7 + 3,
  • 19:12but getting back to CPX and ban there
  • 19:14have been no randomized trials.
  • 19:16So the two treatments have not
  • 19:18been appropriately compared.
  • 19:19There have been a number of.
  • 19:20Retrospective analysis comparing them.
  • 19:21But as upfront therapy for
  • 19:23newly diagnosed AML.
  • 19:24But this would be the largest thus far,
  • 19:27so this was a multicenter retrospective
  • 19:30study from 4 centers northwestern,
  • 19:33Moffitt, Cornell.
  • 19:34And yeah,
  • 19:35I think Sloane,
  • 19:37presented by Pinkel Desai and included
  • 19:39211 patients treated with CPX 351 and
  • 19:43server 220 that got then you could
  • 19:45see here the overall population on
  • 19:47the left baseline characteristics.
  • 19:49The meeting ages were different between.
  • 19:51Groups as expected,
  • 19:52more adverse risk disease in the
  • 19:54HM Event group.
  • 19:55Like I mentioned,
  • 19:55there's also a trend towards being a
  • 19:58more enriched for P53 mutated disease,
  • 19:59but the CPX group was more likely
  • 20:02to have received prior HMA relevant
  • 20:04consideration given these patients
  • 20:06probably progressed from MD's.
  • 20:07The study team is also interested
  • 20:09on the right here.
  • 20:10You could see in patients aged
  • 20:1260 or 75 years,
  • 20:13which was the original
  • 20:15age group studied for CPX.
  • 20:17351 on the randomized phase three
  • 20:19and differences between groups were
  • 20:20about the same as you can see here.
  • 20:22With regards to outcomes,
  • 20:24more patients achieved CR in the CPX group,
  • 20:26but more CRI in the HMA Venn Group
  • 20:28as you would expect given the
  • 20:31continual the cyclic continuous
  • 20:32mouse oppression that's encountered
  • 20:34with phonetic lack specifically.
  • 20:36However,
  • 20:37these differences appear to offset when
  • 20:39looking at the overall or composite.
  • 20:42Rate.
  • 20:44And there was a trend towards better
  • 20:47CR CR I in the TPP related subgroup.
  • 20:50And interestingly,
  • 20:51no differences in response rates for
  • 20:54patients with prior looking to the right.
  • 20:56You can see that real free survival
  • 20:58RFS was longer than CPX group,
  • 21:00actually more than doubled but did
  • 21:02not meet statistical significance.
  • 21:03However,
  • 21:04meeting OS was better in the
  • 21:07arm at 17.3 months.
  • 21:10Among patients aged 60 to 75 years,
  • 21:12similar to the overall cohort
  • 21:14or FS was no different,
  • 21:15but neither in this case was
  • 21:17OS in multivariable analysis.
  • 21:19After adjusting for things like age,
  • 21:22Ellen Risk,
  • 21:23history of permanency and
  • 21:25importantly prior receipt of HMA,
  • 21:27there was an advantage favoring
  • 21:29CPX for with regards to
  • 21:32S in the P53. Sorry TP. 50 mutated cohort.
  • 21:35However, it should be noted that among
  • 21:38this population age 60 or 75 years.
  • 21:40The shy 50% of patients in the CPX arm
  • 21:42went to transplant compared to just 520.
  • 21:45In the ACE event or sorry HM Event group.
  • 21:48So more than double in this is
  • 21:50important because you know,
  • 21:51transplant was a significant
  • 21:53predictor of RFS and OS.
  • 21:55They conducted another MVA in patients that
  • 21:58were aged 65 years who did not receive a
  • 22:00transplant and found no difference in OS.
  • 22:02So, in conclusion, this there was a
  • 22:05significant difference favoring CPS and the
  • 22:07overall cohort and in several subgroups,
  • 22:10although in no difference in C.
  • 22:12However, this is very likely related
  • 22:14to a better rate of outlook transplant
  • 22:15in the CPX group or likely had.
  • 22:17As you'd imagine,
  • 22:18if you were morbidities and thus
  • 22:20you know CPX could still be the
  • 22:21standard for for younger fit patients,
  • 22:23even with at risk risk disease.
  • 22:26Switching gears to some clinical trial
  • 22:28updates starting with targeted agents.
  • 22:30Given the the dawn of a new era,
  • 22:32that Doctor Zaidan had appropriately
  • 22:34mentioned and specifically starting
  • 22:36with frontline trials,
  • 22:37we could talk about each one mutated disease,
  • 22:39which are found so mutations in IDH
  • 22:421 mutations are found at about 5
  • 22:44to 10% really diagnose patients.
  • 22:46Ibis Sydney is an oral IDH 1 inhibitor
  • 22:50that's FDA approved for two population,
  • 22:52specifically adults with factory
  • 22:54mutated disease and those with newly
  • 22:56diagnosed disease, but are just.
  • 22:58Older 75 years plus,
  • 23:00or if commodities that quote UN quote
  • 23:02preclude the use of intensive therapy
  • 23:04there already data from a phase.
  • 23:05One study of think it was 2425 patients
  • 23:08with newly diagnosed disease that
  • 23:10showed a favorable safety profile
  • 23:12and pretty encouraging clinical
  • 23:14activity for the combination of
  • 23:16either sitting in a society and for
  • 23:18that reason and also for the fact
  • 23:21that this trial started enrolling.
  • 23:23I think I wanna say March or April 2018,
  • 23:26before we had the valley a data.
  • 23:29This prompted a double blind randomized,
  • 23:31placebo controlled phase three study
  • 23:33where patients were randomized 1 to
  • 23:35one to receive Asia or Asia plus I've
  • 23:37acid nip with the primary endpoint.
  • 23:39As you can see in the right here
  • 23:41of event free survival,
  • 23:42which was defined as a time frame
  • 23:44randomization until treatment failure.
  • 23:48146 patients have been enrolled as
  • 23:49of this day to cut with the data.
  • 23:51Cutoff was March of 2021 and as shown here,
  • 23:54these were older patients with
  • 23:56a median age of 75 to 76 years,
  • 23:58a third with Anika performance status of two.
  • 24:01Also about 1/4 of patients had
  • 24:03defined poor risk disease.
  • 24:06In looking at responses,
  • 24:07which was not the primary end point,
  • 24:09there was a statistically significant
  • 24:11difference in CR as well as composite CRH
  • 24:14favoring the Asia plus I've Sydney more,
  • 24:16which namely demonstrated a 53% rate of CRC,
  • 24:19RH, and half of these patients
  • 24:21experienced a mutational clearance
  • 24:23which is increasingly becoming.
  • 24:25Is being recognized as a predictor
  • 24:27of a durability of response and
  • 24:29improvement in event based outcomes
  • 24:32in the intent to treat population
  • 24:34in line with the better rates of
  • 24:36response and deep response by.
  • 24:39There was a better EFS in the
  • 24:41Asia plus Ivy Sydney farm.
  • 24:42This is also translated into better
  • 24:44OS for that for that arm as well.
  • 24:46Quite striking at 24 months
  • 24:48compared with eight months.
  • 24:49As you can see here for patients
  • 24:51just getting as alone and this
  • 24:52is generally what we expect for
  • 24:54patients getting a zoumana therapy.
  • 24:56Did it come at the cost of more toxicity?
  • 24:58Not really in looking at human logic talks,
  • 25:00but perhaps a little more neutropenia.
  • 25:02Pina Nonheme talks was also about the same,
  • 25:05but the frequency of all grade
  • 25:08differentiation syndrome, but concerned with.
  • 25:09Ibis Sydney Pomona.
  • 25:10Couple other targeted agents
  • 25:12as assessed by investigators,
  • 25:13was about 14% in the combo arm,
  • 25:16compared to 8%.
  • 25:18Think 70% on the monotherapy arm,
  • 25:21although grade 3 differentiation
  • 25:23syndrome was only about 4%.
  • 25:25However, in both arms,
  • 25:26so not terribly different.
  • 25:28And looking on the right here you can
  • 25:29see these are patient reported outcomes
  • 25:31and measurements of quality of life.
  • 25:32You can see that Ivo plus Asia
  • 25:34appear to be a bit more favorable,
  • 25:37so in some there wasn't.
  • 25:40Recommendation that further enrollment
  • 25:42be prematurely discontinued given the
  • 25:44evidence of a benefit for the combination.
  • 25:46So I would say, how does this
  • 25:49translate into clinical practice?
  • 25:50In short,
  • 25:50as yet it remains to be determined for
  • 25:53the patient with ID terminated disease,
  • 25:55whether he or she is best served
  • 25:57with a so plus van or a soap.
  • 26:00I am personally aware of any
  • 26:01randomized trial at the moment,
  • 26:02but suspect that is a that is coming soon.
  • 26:06Sticking with the same theme
  • 26:08for frontline randomized trials,
  • 26:09we should discuss the LACEWING trial,
  • 26:11which was just presented by Eunice
  • 26:13Wang at the meeting and this is a
  • 26:16trial that randomized patients with
  • 26:17newly diagnosed AML and who were
  • 26:19inappropriate to receive intensive
  • 26:21therapy to either get a Cerezo plus
  • 26:24gilteritinib which is a footer
  • 26:26inhibitor that demonstrated efficacy
  • 26:28and safety and patients with ribs
  • 26:30refractory for the mutated disease and
  • 26:32what's known as the atom whole trial.
  • 26:34Similarly,
  • 26:34this trial was launched before
  • 26:36the results of the alley A.
  • 26:37Were known the primary endpoint
  • 26:39of this trial was overall
  • 26:40survival, so not FS and not or
  • 26:42more of a response based endpoint.
  • 26:45Patients were originally randomized 1 to
  • 26:47one to one either get filter written at
  • 26:50monotherapy built plus as a or as alone.
  • 26:53But due to the website it as
  • 26:55being a preferred therapy change,
  • 26:56it was modified to randomize patients 2 to
  • 26:59one to get either guiltless ASA oracea alone.
  • 27:03Baseline characteristics are shown here and
  • 27:05demonstrate that this was as expected and.
  • 27:07Older population with meaning ages 77
  • 27:09years and also a good proportion with
  • 27:11any card performance status of two
  • 27:13plus with perhaps some imbalance in
  • 27:15favor of the Asian monotherapy arm.
  • 27:17As expected, there were about 80% IT
  • 27:20mutations and similar rates of it.
  • 27:21High disease without at least from my eyes.
  • 27:24Clear imbalances.
  • 27:27It's pretty much up for this slide
  • 27:29with regards to responses CR rates,
  • 27:32not the primary endpoint,
  • 27:33which is OS like I mentioned,
  • 27:35we're somewhere between arms,
  • 27:36but the rates of CRI and CRP which
  • 27:38are less than CR response is still
  • 27:40to be clinically meaningful were
  • 27:42higher in the combination are nearly
  • 27:43three times actually for a composite
  • 27:45C area of about 58% for the combo
  • 27:48and the 26% for as a monotherapy.
  • 27:52However, it it's pretty clear
  • 27:54from this KM curve that overall
  • 27:56survival was not different between
  • 27:57arms at about nine months.
  • 27:59It should be noted, however,
  • 28:00and this was discussed at the
  • 28:02meeting and I believe it that this
  • 28:04may be explained by a couple things.
  • 28:06Subsequent email therapy was
  • 28:08received by 20% of patients on
  • 28:10guilt ASA and just shaved half of
  • 28:12patients on the ASA monotherapy arm,
  • 28:14meaning time to that next therapy
  • 28:16was a bit longer in the ASA.
  • 28:18Sorry, the combination arm.
  • 28:19It was like 8 versus 5 months.
  • 28:22So this might have influenced OS
  • 28:23in addition to the imbalance and
  • 28:25performance status that I showed
  • 28:27you earlier on the right here.
  • 28:29Looking at unplanned subgroup analysis,
  • 28:31improved overall survival with guilt
  • 28:32as it was really not observed in any.
  • 28:34Although some trans were noted for
  • 28:36patients that were more fit and
  • 28:38also here with Highet delic ratio,
  • 28:41I didn't show any adverse event data
  • 28:43here because they were largely similar
  • 28:45between arms including grade 3 plus events.
  • 28:47So in some,
  • 28:49although a negative trial
  • 28:50still an informative 1.
  • 28:52Supporting the contention that
  • 28:53a zevan as based on the alley a
  • 28:55may be the preferred combination
  • 28:57for older patients who were
  • 28:58inappropriate to receive intensive
  • 29:00therapy with mutated disease.
  • 29:01At the moment, I guess I can always change.
  • 29:06Last year I had reviewed the data for
  • 29:08Asia and McGraw map which is an anti
  • 29:10CD 47 antibody that blocks the quote.
  • 29:12Don't eat these signal on
  • 29:15macrophages and specifically.
  • 29:17Pretty robust efficacy for patients
  • 29:18that have both P fitted mutated disease
  • 29:20and wild type disease. Actually,
  • 29:22for the pilot for the mutated cohort,
  • 29:24I just over 12 months would be
  • 29:26the longest meeting OS reported
  • 29:27for that particular subgroup.
  • 29:29But like everything else,
  • 29:30this has to be combined with a zven, right?
  • 29:32But I will say there are a number
  • 29:35of preclinical studies which do
  • 29:37support synergy for this combination,
  • 29:40so this leads to the trial,
  • 29:43which was a phase 1B2 trials divide with
  • 29:46the triplet and patients with both.
  • 29:47Newly diagnosed disease but
  • 29:48restricted to P footage.
  • 29:49Mutated disease as well as factory disease.
  • 29:52Regardless of Peachtree status,
  • 29:53the latter being the only cohort
  • 29:55for the phase one portion and
  • 29:57the primary endpoint for this
  • 29:59trial was a composite rate of.
  • 30:03Here are some baseline characteristics
  • 30:05to date. I should mention that.
  • 30:10Skip that part so.
  • 30:12It's basically nothing out of the ordinary.
  • 30:15In line with what I mentioned as how
  • 30:17the kind of codes were divided up.
  • 30:18You could see that you know the ages,
  • 30:20maybe a bit younger in the mutated cohorts
  • 30:22and the rips or factories specifically,
  • 30:24then naive cohorts,
  • 30:26as you would imagine.
  • 30:27But other than that,
  • 30:29no major surprises from a baseline
  • 30:30characteristics standpoint and looking well.
  • 30:33Just go over some safety data.
  • 30:34No DLT's were observed in the Phase 1B
  • 30:37portion and the RP 2 randomized phase.
  • 30:39Two dose recommended phase two dose
  • 30:41was established at 30 milligrams
  • 30:42per kick with about a two week
  • 30:44kind of priming dose ramp up and
  • 30:46then eventually gets a bit easier
  • 30:47for the patient every two weeks.
  • 30:49Cycle 3 going forward.
  • 30:51So getting to some efficacy data.
  • 30:53Global findings first.
  • 30:54The rate of CR being based
  • 30:57on 14 patients with.
  • 30:58TP50 mutated disease with 64% double what you
  • 31:01would expect with with with a sub N alone,
  • 31:04and this has been attributed
  • 31:05to at least at the meeting.
  • 31:06A quick depth of response with
  • 31:08more than half being negative by
  • 31:10flow and a first response in less
  • 31:12than a month without really any.
  • 31:14As you can see here,
  • 31:15any early mortality and what I would
  • 31:17consider to be a reasonable time
  • 31:18to blood count recovery felt to be
  • 31:20meaningful and really landing with
  • 31:22the definition of what we call CRH.
  • 31:25Frontline treatment for wild type
  • 31:27patients was even more impressive
  • 31:30with a CR CRA of 90%.
  • 31:31Conversely, and this is,
  • 31:32you know, one of the downsides.
  • 31:33This doesn't appear to be a
  • 31:34meaningful option for patients
  • 31:35who've already been failed by vanetta
  • 31:37klax based regimen with the CRA.
  • 31:38As you can see here, based on 15 patients,
  • 31:40but still zero and only 20% rate of CRI
  • 31:43and at the bottom here you can see a 20%.
  • 31:45It gets phone numbers but 20%
  • 31:47rate of pearly mortality here.
  • 31:49Look at this plot that was
  • 31:51presented at the meeting.
  • 31:52Much of what the last slide kind of showed,
  • 31:54but also including data demonstrating that.
  • 31:56There was 100% six month OS so short
  • 31:58follow up as you could see here as well.
  • 32:00For patients that had mutated disease and
  • 32:02five of the 14 that were able to get to.
  • 32:06Some form of response.
  • 32:07We're able to get the transplants
  • 32:08about 35% of course.
  • 32:09Again short follow up,
  • 32:11so maybe more will get the transplant.
  • 32:12We'll get a better sense of the median
  • 32:14OS and see how it stacks up to 12
  • 32:16months noted for the Asian Macro Delta
  • 32:18data that I presented to you last year.
  • 32:22Frequent I share some more toxicity
  • 32:23data frequente, ease of all grades.
  • 32:26Hypokalemia, hypophosphatemia,
  • 32:27hyperbilirubinemia, about half of patients,
  • 32:29and some otherwise.
  • 32:30He talks you would expect
  • 32:32with as event itself,
  • 32:33not necessarily mad or attributable.
  • 32:35Among 17 patients that were newly diagnosed,
  • 32:39and thus TP50 mutated,
  • 32:41the median drop was just about
  • 32:431 gram per deciliter this after
  • 32:45the first dose,
  • 32:45and even lesser after the second dose.
  • 32:47So with close monitoring,
  • 32:48this anemia was manageable and the anemia,
  • 32:50which just to give a refresher.
  • 32:52There is some on target hemolytic anemia,
  • 32:54just that you know was a bit
  • 32:56troublesome early on in the trial,
  • 32:58but appears to be manageable
  • 32:59with you know no SAS,
  • 33:01no interruptions or discontinuations
  • 33:02due to this anemia specifically,
  • 33:04so this is promising and position
  • 33:06to possibly be a new standard.
  • 33:08I mean maybe a little ambitious,
  • 33:10but for frontline treatment
  • 33:11both for TP 53 mutated disease
  • 33:13and even wild type disease.
  • 33:14But of course need more data
  • 33:16and more follow up and of course
  • 33:19randomized trials to confirm this
  • 33:21added benefit they are underway.
  • 33:23One last combination and this one is
  • 33:25one that's restricted to patients
  • 33:26with RIPS or factory disease and
  • 33:28one that may have some promise for
  • 33:30patients with molecular subgroups
  • 33:31that of interest and maybe patients
  • 33:33who have been failed by better clocks
  • 33:35today to critical area of need
  • 33:36after patients are failed by then,
  • 33:37it's essentially.
  • 33:40A black hole Blackstone ever
  • 33:41metaphor you want to use.
  • 33:43This is another combination
  • 33:44that adds to as event,
  • 33:45but for which there is
  • 33:47sound clinical rationale.
  • 33:48This is a therapy that targets CD 123,
  • 33:50which is the alpha subunit of the
  • 33:52aisle 3 receptor and is overexpressed
  • 33:55on leukemic blasts Immunogen 632.
  • 33:57It's a CD123 targeting ADC comprised of
  • 34:00a high affinity anti CD 123 antibody
  • 34:03coupled to a novel DNA alkylating payload.
  • 34:08Goodsell,
  • 34:08Linedata Goodyear in PDX modeling
  • 34:11or experiments good synergy between
  • 34:13Immunogen 632 in Asia and Dwarven,
  • 34:15including being able to overcome
  • 34:17a certain resistance.
  • 34:19So For these reasons, this is a phase one.
  • 34:21Two trial of that product combined with
  • 34:22a 7 and patients with as you'd have guessed,
  • 34:25CD one or three positive AML to date.
  • 34:29The triple combo escalation
  • 34:30is consists of five cohorts,
  • 34:324 with the investigational product
  • 34:34dosed on day, seven of each cycle,
  • 34:37and one cohort where it's dosed
  • 34:38on the first day.
  • 34:39Each cycle make it a bit more
  • 34:40convenient for the patient at the
  • 34:42time of this analysis presented.
  • 34:44Obviously at the last meeting,
  • 34:4635 patients have been enrolled
  • 34:48based on characteristics are shown
  • 34:49here in meeting age was about 65,
  • 34:51so it was somewhat younger
  • 34:52population with median 2 lines or
  • 34:54prior therapy up to three,
  • 34:56so not relatively terribly pretreated,
  • 34:59but half of patients did receive
  • 35:00prior medical acts important to know
  • 35:02the talks profile was manageable,
  • 35:04and this inherently goes factory
  • 35:06population with multiplier
  • 35:07therapies become an S were.
  • 35:10Infusion related reactions.
  • 35:11About 1/3 of patients with only two
  • 35:13percent being grade 3 and otherwise
  • 35:15things you would expect with a Savannah loan.
  • 35:17One patient in the day one cohort
  • 35:21had to discontinue because of an
  • 35:23infusion reaction was considered DLT,
  • 35:24but early mortality defined it at the
  • 35:27bottom here 30 days with zero percent.
  • 35:29So my last slide among the 29
  • 35:33percent 29 patients who are valuable
  • 35:35efficacy was seen across kind
  • 35:37of all cohorts, doses and schedules.
  • 35:39The response rate was 55%.
  • 35:41And looking at the composite remission rate,
  • 35:43it's about 30%, you know,
  • 35:45with maybe higher rates in the higher
  • 35:48dose cohorts of no patients prior
  • 35:51van had good Angeliki make activity
  • 35:53as seen here on the right, waterfall
  • 35:56plot and overall response rate of 40%.
  • 35:59Other subsets of note
  • 36:00flipper mutated disease.
  • 36:01Even more striking.
  • 36:02I'll be at 9 patients,
  • 36:03but 80% rate of composite emission.
  • 36:05So in some encouraging in some molecular
  • 36:07subsets and then treated patients,
  • 36:09but certainly.
  • 36:10Like the other studies I presented
  • 36:12more data to assure these values
  • 36:14don't regress to the mean like
  • 36:15unfortunately many other similar studies.
  • 36:18That's my last slide.
  • 36:18There are a few more presentations
  • 36:20from match that I wish I could discuss,
  • 36:21but last only 15 minutes and
  • 36:23I'm sure I'm over that already,
  • 36:25so I apologize to Doctor Podolsky and
  • 36:27look forward to your questions at the end.
  • 36:32Can you unshare? Sure can.
  • 36:35Go. Still cannot share the screen.
  • 36:40Right here we go. Thank you alright,
  • 36:43so let me find my presentation here.
  • 36:53Sorry about this technical difficulty.
  • 37:17Here we go. Alright, here's my view OK?
  • 37:24Yes, OK, so this is my disclosures,
  • 37:27so I'm going to go onto the outline.
  • 37:29So I'm going to present four studies
  • 37:32which I selected based on disease.
  • 37:36Talk about devera,
  • 37:38myelofibrosis and one other
  • 37:41condition which is infrequent.
  • 37:43Myeloid lymphoid neoplasm is in
  • 37:45Affilia and FGFR 1 rearrangement,
  • 37:48so the first study I would like to
  • 37:51talk about is the study which is.
  • 37:54Lookout Trust restaurant type or PTG 300
  • 37:59and its control of human grade levels
  • 38:01in patients with polycythemia Vera.
  • 38:05So the rationale for the study is.
  • 38:09Which is looking at Hillside and medic.
  • 38:13Right is the fact that in patients with
  • 38:17polycythemia Vera iron is necessary
  • 38:19to make red blood cells in the marrow,
  • 38:21which is affected by Jack.
  • 38:22Two V 617 FM PM.
  • 38:26So as you can see on the left,
  • 38:28ferroportin is the main transporter
  • 38:30of the iron from outside,
  • 38:33from inside the macrophage to the
  • 38:35circulation and then delivered by
  • 38:37transparent to the bone marrow
  • 38:39which is utilized to make excessive
  • 38:41amounts of red blood cells by Jack.
  • 38:432 mutated. Red blood cell precursors.
  • 38:46So the hepcidin as well as
  • 38:49restricted which is hepcidin.
  • 38:51Medical shut down the gates ferroportin
  • 38:54and decreases the amount of iron
  • 38:58which is available for transparent
  • 39:00to transport to the bone marrow
  • 39:02so it's kind of shutting down the
  • 39:04door but perhaps not the window.
  • 39:06A little bit of line is available
  • 39:08and the idea is that there is no
  • 39:11iron deficiency state which is
  • 39:12otherwise created by phlebotomies
  • 39:14by therapeutic phlebotomies.
  • 39:16Leading to decreased quality of life of
  • 39:18this patients due to tissue and efficiency.
  • 39:20So this is a phase two trial over spare
  • 39:23type in patients requiring phlebotomy.
  • 39:27Patients with PD diagnosis based
  • 39:29on 2016 W criteria were included.
  • 39:31At least three phlebotomies in the
  • 39:34last six months were necessary.
  • 39:35Patients were treated with or without sector.
  • 39:39Reductive therapy and therapy,
  • 39:40so the primary endpoint was proportion of
  • 39:43patients in randomized withdrawal period.
  • 39:45Who schematic rate is maintained.
  • 39:46Without the need for phlebotomy,
  • 39:49the secondary endpoints is the
  • 39:51response of 29 weeks.
  • 39:53Absence of liberty eligibility,
  • 39:54and that's what I'm going to
  • 39:55talk about today,
  • 39:56as well as total symptom score
  • 39:58for those patients who are
  • 40:01receiving treatment register type.
  • 40:03The idea is that symptoms will get
  • 40:05better while they're receiving this
  • 40:07treatment because planning deficiency state,
  • 40:09which is otherwise present in patients
  • 40:11treated with therapeutic phlebotomies,
  • 40:13will be gone,
  • 40:15so the study.
  • 40:17As the three parts,
  • 40:19the first one is those findings
  • 40:21part that 28 weeks,
  • 40:22then there is blinded withdrawal and
  • 40:24then open label part is part three,
  • 40:26so we're talking about 63 patients
  • 40:29currently enrolled enrollment
  • 40:31between October 2019 and May 2021,
  • 40:33and patients were treated up to 18
  • 40:36months between 8:00 and 92 weeks.
  • 40:38So you can see here that initial
  • 40:42period is describing six months
  • 40:45preceding the first dose of the drug.
  • 40:47Yeah,
  • 40:48and patients are getting phlebotomy
  • 40:49is that by you can see this by red
  • 40:52triangles right after those there
  • 40:53are very few red triangles,
  • 40:56so this is going to be for optimization.
  • 40:57That's what we looking for.
  • 41:0184% of patients did not require 14%
  • 41:05required one and only 2% required 2
  • 41:08phlebotomists so very significant we self
  • 41:12eliminating phlebotomies in almost all
  • 41:14of the patients within the 1st 28 weeks.
  • 41:18Treatment, so this was actually true for
  • 41:20both patients who received such a reductive
  • 41:22therapy and who didn't on the left.
  • 41:2431 patients who didn't require center
  • 41:27adaptive therapy on the right 30 put
  • 41:29in two patients who did so from the
  • 41:32standpoint of assessment of symptoms.
  • 41:36Scoring system was used weekly and
  • 41:39you can see on the left at baseline
  • 41:42the score as well as the score
  • 41:45after 2020 weeks of therapy.
  • 41:47So there is significant reduction of
  • 41:49treatment out of symptoms with this
  • 41:52treatment and specifically 1/3 of patients
  • 41:55reported at least 40% reduction of
  • 41:57symptoms based on MPN soft TSS at 28 weeks.
  • 42:01So it is the drug is effective at the
  • 42:04eliminating the need of phlebotomy.
  • 42:06This is a continuous injection which
  • 42:09patients self inject once a week.
  • 42:11So from the standpoint Bruce of
  • 42:13X to summarize,
  • 42:14basically the main side effect
  • 42:17was injection reaction.
  • 42:1920% of patients and it was transient
  • 42:22and did not require discontinuation.
  • 42:26In summary,
  • 42:26research type war that PTG 300 is hepcidin,
  • 42:32mimetic subcutaneously injected
  • 42:33for PV patients,
  • 42:35leading to elimination of therapeutic
  • 42:38phlebotomy needs of majority of patients
  • 42:41within the 1st 28 weeks of treatment.
  • 42:43Also,
  • 42:43reversing iron deficiency,
  • 42:45which was evident by increasing MCV
  • 42:48MHC and 13 of those patients that was
  • 42:51positive impact on PV related symptoms,
  • 42:53perhaps because of.
  • 42:56Negating some of the iron deficiency
  • 42:58related to therapeutic phlebotomies,
  • 43:00it was safe and well tolerated without
  • 43:03grade 3-4 adverse events and we are
  • 43:05planning to open phase three randomized
  • 43:08control study at Yale for this patients.
  • 43:11So the second study is for my
  • 43:14love fibrosis patients and it's
  • 43:16gone collaborative wanna therapy
  • 43:18for patients with myelofibrosis?
  • 43:19This is update of ongoing study.
  • 43:22I presented this study last year so
  • 43:27it uses it utilizes this knowledge
  • 43:30that promo domain and extra terminal
  • 43:34domain proteins promote myelofibrosis.
  • 43:37You can see the activation of NF
  • 43:40Kappa B targeted genes leading to
  • 43:43increased inflammatory response.
  • 43:44Aberrant,
  • 43:45or through a differentiation
  • 43:47and aberrant megakaryocytic
  • 43:48differentiation manifestations.
  • 43:49So far my love fibrosis,
  • 43:52inflammatory response causes systemic
  • 43:54symptoms as well as cytopenias,
  • 43:57including an email from both.
  • 43:59Cytopenia conceit can be seen in my life.
  • 44:01I prove this difference,
  • 44:02so collaboration is the subject of
  • 44:05this study, also known as CPI 0610,
  • 44:07which is a first in class selective oral,
  • 44:11small local inhibitor,
  • 44:12bit bad proteins.
  • 44:14Got it modifies the expression of
  • 44:16genes and Bolton Kappa B signaling.
  • 44:19Decreasing the cytokines.
  • 44:21Also promoting erythrocyte
  • 44:23differentiation and normalizing
  • 44:25megakaryocytic differentiation.
  • 44:27So that's the background for this study.
  • 44:30The study is currently ongoing.
  • 44:32It's manifest trial,
  • 44:33global study and at this pace to trial.
  • 44:36So there are three arms and the arm.
  • 44:40I'm going to focus on this
  • 44:43patients who are receiving.
  • 44:44A collaborative and second
  • 44:46line so they were previously
  • 44:48treated with rock solid nib
  • 44:50or were not able to take Luke Slim
  • 44:52for some reason so the dosing is
  • 44:54it's an oral drug so this is given
  • 44:57to its one one week off schedule and
  • 44:59there are two cohorts in this arm.
  • 45:02One part of the study,
  • 45:03one of them is transfusion dependent cohort,
  • 45:0636 out of 60 patients accrued and
  • 45:08there's ongoing enrollment and the
  • 45:102nd cohort cohort one be finished.
  • 45:13Enrollment 50 patients. So the.
  • 45:15Primary endpoint for transfusion
  • 45:16Dependent Court court is transfusion,
  • 45:18independence for patients and one cohort 1B.
  • 45:22It's it's splenic volume response,
  • 45:2635% reduction spleen volume.
  • 45:27So the patients were enrolled
  • 45:30were either Ching knowledgeable,
  • 45:32jacked to intolerant,
  • 45:33and the biggest group is jacked
  • 45:34to refractory resistant patients.
  • 45:3656% this is a group of patients
  • 45:39with poor outcomes.
  • 45:40Median survival is about 14 months,
  • 45:42so the SDR 35 response at week 20.
  • 45:46War was a primary endpoint for
  • 45:48group 1D which is non transfusion
  • 45:50dependent cohort and it was 18%.
  • 45:53Most of the patients had
  • 45:55some splenic response,
  • 45:5618% had reduction by 35%.
  • 45:59So the symptom reduction by 50% at
  • 46:05the end of the 24 week period was
  • 46:07observed in 20% among all study
  • 46:10participants transfusion dependent and
  • 46:11not transfusion dependent participants.
  • 46:13Finally the group 1B.
  • 46:17Primary endpoint the transfusion
  • 46:19dependence converting to transfusion
  • 46:21independence occurred in 16% of
  • 46:24patients overall in the whole
  • 46:26population there was observed
  • 46:27improvement in hemoglobin levels.
  • 46:30As you can see on the right hand side
  • 46:32and among transfusion independent patients,
  • 46:3438% had improved hemoglobin
  • 46:36level by 1.5 grams per deciliter.
  • 46:39At the end of the 2424 week period.
  • 46:42So there are some exploratory
  • 46:44endpoints including evolutional.
  • 46:46Fibrosis in the marrow,
  • 46:48and about quarter of patients
  • 46:51had improvement,
  • 46:52including about 6.7% of patients
  • 46:54who had improvement by two grades
  • 46:57of Milo fibrosis in the .0.
  • 46:59Improvement in fibrosis correlated
  • 47:01with improvement in hemoglobin levels,
  • 47:04so the side effects are summarized
  • 47:06on this slide.
  • 47:08For the sake of time,
  • 47:1019% of patients reported adverse events
  • 47:12which led 2 collaborative discontinuation.
  • 47:15Most of the side effects were great.
  • 47:18One and two.
  • 47:19So, in conclusion,
  • 47:21this is manifest on one looking
  • 47:24at 64 patients planned enrollment,
  • 47:26110 patients,
  • 47:27there was a decent reduction of
  • 47:30the spleen volume among transfusion
  • 47:32dependent patients,
  • 47:34and there was an improvement in hemoglobin,
  • 47:36including among patients who are
  • 47:38transfusion dependent and the 16% of
  • 47:41them became transfusion independent.
  • 47:43Marrow fibrosis and I didn't
  • 47:44present this data.
  • 47:45Plasma cytokines decrease suggested
  • 47:47potential disease modification by
  • 47:52majority of the most common treatment.
  • 47:54Emergent adverse events were low grade
  • 47:56and we are planning to participate in
  • 47:58manifest 2 study randomized phase.
  • 48:01Three study,
  • 48:02double blinded between
  • 48:06CPI 0610 and looks lit new versus
  • 48:08placebo and looks lit nip at Yale.
  • 48:10So the next step is and this is
  • 48:13about the symbol of the drug which
  • 48:16was recently approved for patients
  • 48:18with CML as a third line treatment.
  • 48:21People who were enrolled in the study
  • 48:25received at least two TCR's and the
  • 48:28presentation I'm focusing on today is
  • 48:31update of what was previously presented.
  • 48:34So this is the drug which is in
  • 48:38which hits BCR ABL on core protein.
  • 48:41Activity specifically targeting
  • 48:43able marstall pocket.
  • 48:45It's a different way of inhibiting BCR ABL,
  • 48:48as you can see, even with key for one point,
  • 48:509 mutation.
  • 48:50Weighty people get this changed,
  • 48:52and regular guys cannot attach a synonym,
  • 48:56was able to inhibit people
  • 48:58one kinase activity.
  • 49:01Study is a phase three trial
  • 49:04which randomizes patients.
  • 49:06Between pursuit net 500 milligrams once
  • 49:08a day and a 740 milligrams twice a day.
  • 49:11Once again,
  • 49:12there's a patients who were previously
  • 49:14treated for chronic phase CML with
  • 49:16at least two different keys and the
  • 49:20initial presentation at previous ASH
  • 49:24meeting looked at primary endpoint,
  • 49:27which is major molecular response
  • 49:29at 24 weeks.
  • 49:31This presentation updates
  • 49:33the results by expanding.
  • 49:36Observation period for additional
  • 49:387 1/2 months.
  • 49:40So basically in 19.2 months
  • 49:42from randomization period.
  • 49:44So the key secondary endpoint is Mr
  • 49:48rated 96 weeks is not presented yet,
  • 49:50so this is the first.
  • 49:53Presentation in 20 Dash 2020,
  • 49:56which was also the data was
  • 49:58also published in Blood.
  • 50:00Last year,
  • 50:01so the synonym was better than pursuit
  • 50:03nip from the standard primary endpoint,
  • 50:06which is major molecular
  • 50:08response at 24 weeks by 12.2%.
  • 50:11So the updated 48 week results
  • 50:15continue to show the higher
  • 50:18major molecular response rate.
  • 50:20So basically at one year is 29.3% which
  • 50:24is 16% higher than with pursuit nip.
  • 50:26Also the reduction of desirable
  • 50:28transcript to less than one.
  • 50:30Or something blood is seen more
  • 50:32frequently in a semi warm 42%
  • 50:34versus 19% more than double.
  • 50:37So the deep responses are also better
  • 50:39in a synonym as you can see on our
  • 50:424.57 point 6 versus 1.3% and Mr.
  • 50:45410.8 versus 3.9% when compared to episode.
  • 50:49So we're all adverse events that
  • 50:53were less common in patients
  • 50:56with severe then with mood dip.
  • 50:59So nevertheless pretty much
  • 51:00everyone had some kind of adversity.
  • 51:02But adverse events leading to
  • 51:05discontinuation again less frequent in
  • 51:07a similar treating patients treated patients,
  • 51:10so this is the most common all
  • 51:13great adverse events as seen
  • 51:14in more than 20% of patients.
  • 51:16You can see that a synonym is better
  • 51:18than other than cytopenia switch.
  • 51:20I seen more frequently among patients
  • 51:22who are treated with a similar,
  • 51:24but this was transient fact at
  • 51:26the beginning of treatment,
  • 51:27usually related to the disease itself
  • 51:29rather than to the treatment so.
  • 51:32Adverse arterial occlusive events
  • 51:37that were comparable in both groups,
  • 51:38but it is challenging to say
  • 51:40what would happen to the certain
  • 51:42patients because they were observed
  • 51:43a lot less than a similar patient.
  • 51:45So, in conclusion, this is the first
  • 51:48control study comparing tiki for resistant,
  • 51:50intolerant patients using
  • 51:52first and class specific drug,
  • 51:54which is specifically targeting
  • 51:56able one restoril pocket.
  • 51:57Superior efficacy was demonstrated
  • 51:59for synonym against BOSUTINIB, and.
  • 52:02More patients remain the treatment
  • 52:04at the end of 48 week period,
  • 52:06so it has favorable safety profile.
  • 52:08Now this is the drug which is available as a
  • 52:10standard of care option for our CML patients,
  • 52:12particularly with resistant with
  • 52:15resistance and influence to two
  • 52:17TK eyes or more so finally, the.
  • 52:22They got me up for patients with the
  • 52:25nominee and rearrangement of GFR one.
  • 52:27So just to map that this is one
  • 52:29of the myeloid malignancies.
  • 52:32We spoke about MPN's pH
  • 52:33positive and negative so far,
  • 52:34but this is the myeloid lymphoid
  • 52:36neoplasm with is an affiliate affiliates.
  • 52:39Hallmark feature of this group of
  • 52:41malignancies myeloid malignancies.
  • 52:42I'm going to focus on this particular one,
  • 52:44which is, I mean,
  • 52:45all of them are not very common,
  • 52:47but nevertheless it's an
  • 52:49interesting disease which is.
  • 52:51I'm due to translocation of eight P.
  • 52:5411 leading to constitutive
  • 52:56activation of FGFR,
  • 52:58one that's 16 known partners.
  • 53:00Chronic phase of this disease
  • 53:02may present as MPNMDS or MDSMPN.
  • 53:04That's why it is important to
  • 53:05check if patient has is an
  • 53:07affiliate for this rearrangement,
  • 53:08usually treated with hydroxyurea and keys,
  • 53:11including non selective
  • 53:13ponatinib and might historian.
  • 53:1550% of patients are in blast phase after
  • 53:1712 months and meeting all survival
  • 53:19and unfortunately only nine months
  • 53:20without stem cell transplant one term.
  • 53:22Oceans are possible with transplants.
  • 53:24Las Vegas may present as a
  • 53:27MLTOB cell and mix phenotype.
  • 53:29Acute leukemia once again important
  • 53:31test to do to select this patients
  • 53:34and there is treatment with
  • 53:37specific induction chemotherapy,
  • 53:38perhaps with the tiki with one year survival,
  • 53:40one with 30%.
  • 53:41Those who achieve CR will abduction,
  • 53:43Kima have superior survival obviously,
  • 53:46and long term remissions are
  • 53:47reported with transplanted patients.
  • 53:49So this disease is rare.
  • 53:52And also not very good to have because
  • 53:54of lack of specific treatments
  • 53:56as well as poor outcomes with
  • 53:58available therapy at perhaps other
  • 54:00than transplant which is available
  • 54:02for limited number of patients.
  • 54:04So is this drug which is currently
  • 54:06approved by FDA as well as in some
  • 54:09other countries for patients with
  • 54:11cholangiocarcinoma previously treated
  • 54:13and respected locally advanced it
  • 54:15was FGFR 2 fusion and rearrangements.
  • 54:17The drug inhibits FGFR 1/3 and that
  • 54:20led to its study in this flight.
  • 54:23Two or three trial.
  • 54:25So this is a swimmer sport showing
  • 54:28ongoing responses for majority
  • 54:30of patients with chronic phase.
  • 54:32There are 18 of them and then there is.
  • 54:34This is the 13 patients with blast phase.
  • 54:38Unfortunately less responses here.
  • 54:39A lot of patients,
  • 54:41especially in the black box who died
  • 54:43from this disease in the blast based.
  • 54:45Nevertheless,
  • 54:46some were breached to allogeneic stem
  • 54:48cell transplant. So in conclusion.
  • 54:52Is the first therapy to demonstrate
  • 54:54durable and high rates of CR&CCYR
  • 54:56in this group of patients.
  • 54:59Previously, these patients were
  • 55:01treated with other treatments.
  • 55:03Majority of them progressed,
  • 55:04including intensive chemotherapy and
  • 55:06chemotherapeutic stem cell transplant.
  • 55:08Kaplan Meier median duration of CR
  • 55:10and overall response have not been
  • 55:12reached in those treated with Pamela
  • 55:14Gardner clinical and cytogenetic.
  • 55:15Responses were less frequent in
  • 55:17and durable and blood space,
  • 55:19but nevertheless some patients
  • 55:20were able to breach too.
  • 55:21Collagen in stem cell transplant.
  • 55:23See if there were no surprises and
  • 55:25safety profiles and die of this
  • 55:27treatment consistent with Jeff
  • 55:29Gordon condition and this may be a
  • 55:31good option for long term treatment
  • 55:33for patients with Melanie with FGFR
  • 55:35rearrangement ineligible for transplant
  • 55:37or facilitate bridging tool transplant.
  • 55:40Thank you.
  • 55:43Thank you Doctor Badasci
  • 55:44thank you Doctor Cialis.
  • 55:45Great comprehensive presentations and.
  • 55:49We are going to take a few questions
  • 55:51from the audience if any has,
  • 55:53so please feel free if you want
  • 55:55to type your question or if you
  • 55:57want to ask directly, you can.
  • 56:00I think Lenny can mute you
  • 56:02and you can ask the question.
  • 56:04I'm gonna actually start one question
  • 56:06for Doctor Sheraz where we are waiting
  • 56:09so Rory treatment of AML historical.
  • 56:147 + 3 or really not much aside from that,
  • 56:20so can you walk us through your
  • 56:22thinking of the different options
  • 56:23for a patient that potentially could
  • 56:25be seen in any of the care centers.
  • 56:2874 year old male. Walks with a cane,
  • 56:33but otherwise in good shape.
  • 56:34Who comes with acute myeloid
  • 56:37leukemia outpatient?
  • 56:41And the patient has a flip 3
  • 56:44mutation and mutation which we can
  • 56:46see certainly in some patients.
  • 56:48So how do you work through the
  • 56:51different treatment options as you
  • 56:52consider what to do with this patient?
  • 56:56Well, I could think my practices
  • 56:58is fairly evidence based with some
  • 57:00rare exceptions, and you know,
  • 57:02I'd say this is a double edged sword.
  • 57:04I mean, it's very fortunate that the field
  • 57:05is moving very quickly with novel agents,
  • 57:07novel combinations with.
  • 57:08You know a recent preference
  • 57:11for randomized trials,
  • 57:12but by the time a trial is launched,
  • 57:14let alone completed,
  • 57:15maybe the reference standard,
  • 57:16the comparator arm is obsolete, so.
  • 57:19At the moment,
  • 57:20you know a 74 year old is,
  • 57:22you know, age isn't all ages,
  • 57:25more of an imperfect surrogate
  • 57:26for other patient specific
  • 57:27factors like end organ reserve.
  • 57:29And I'd say maybe I put a bit
  • 57:32more emphasis on the disease
  • 57:34biology and with two troubling
  • 57:36mutations and intensive therapy
  • 57:38appropriate eligible candidate.
  • 57:40I mean,
  • 57:40I would probably say this is a patient
  • 57:42that probably would be treated with
  • 57:44an intensive backbone plus midostaurin
  • 57:46you didn't give me a fits it high or.
  • 57:50But I think we can all agree
  • 57:52this is probably a patient best
  • 57:53served with that triplet regimen.
  • 57:55You know at the patient was not intensive,
  • 57:56they would be eligible in the clinic.
  • 57:58You know, you know,
  • 57:59eyes in the beholder.
  • 58:00Then it's a it's dealers choice.
  • 58:02As event is probably still appropriate
  • 58:04just based on the Lacewing data,
  • 58:06you know that Eunice Wang had
  • 58:08presented and until we have a
  • 58:11randomized trial looking at sequencing.
  • 58:13Just flip three.
  • 58:14I think the question is still unanswered,
  • 58:16but it's hard to stray from
  • 58:17what we know from the belly.
  • 58:18I think as of them still be the
  • 58:20standard if the patient is need to
  • 58:22not be intensive therapy appropriate
  • 58:23and maybe in the next couple of
  • 58:25years you might have a randomized
  • 58:27trial that looks at that and maybe
  • 58:28a seven could be superior to even
  • 58:30classical intensive therapy,
  • 58:31but at the moment that's the
  • 58:33dichotomy I would say.
  • 58:37Perfect so clearly a lot of options
  • 58:39for this patient. This patient
  • 58:40could go with his even potentially.
  • 58:43Some patients can still do IDH 2 monotherapy
  • 58:47could be aids with IDH 2 inhibitor could be.
  • 58:5210 + 3 could be 7 + 3 with middle story and
  • 58:54you still could consider transparent or not.
  • 58:56So clearly many many different options.
  • 58:58And clearly the best option
  • 58:59is always a clinical trial,
  • 59:00which we always encourage.
  • 59:02So I'm pretty sure you know in the care
  • 59:05centers these patients are seen all the
  • 59:07time and I encourage people even if the
  • 59:09patient does not want to come to the
  • 59:11main campus or cannot travel to call
  • 59:14one of us and go through some of the
  • 59:17potential options that we have Nikolai.
  • 59:21So fibrosis things are also clearly changing
  • 59:24issue that some of the clinical trials
  • 59:26that are in progress but currently 4.
  • 59:29Doctors in.
  • 59:30In practice,
  • 59:30one of the most common I think tough
  • 59:33situations is patients with myelofibrosis
  • 59:35who are on rock solid and anemic.
  • 59:39So the patient basically
  • 59:41has controlled spleen.
  • 59:42They are not having constitutional
  • 59:44symptoms but they are needing
  • 59:45transfusions and they are on.
  • 59:49Let's say 20 milligram P opyd.
  • 59:53Now we have a drug approved that we
  • 59:57have a drug nib and there's another
  • 60:00drug in front of the FDA molet nib.
  • 01:00:02And you know a bunch of other things,
  • 01:00:04he says androgens and potentially.
  • 01:00:09So how do you think about these
  • 01:00:11different options as you approach
  • 01:00:12your patient like this?
  • 01:00:14So from the standpoint
  • 01:00:15of FDA approved therapy,
  • 01:00:17we have right now for awhile and
  • 01:00:19looks like name is obviously
  • 01:00:21dominating the market since 2011,
  • 01:00:23so I think that was approved for
  • 01:00:25similar group of patients from 2019
  • 01:00:27and usually considered as a second
  • 01:00:29line for those patients who are
  • 01:00:31not satisfied with that rock solid.
  • 01:00:33Networx limp is not working
  • 01:00:36anymore with variable results,
  • 01:00:37So what we have approval is.
  • 01:00:40A grid Neb out on the 1st of March
  • 01:00:42was FDA approved for patients
  • 01:00:43who have low platelet count so
  • 01:00:45called cited piknic Milo fibrosis
  • 01:00:47and perhaps this drug can be used
  • 01:00:49not only for patients who have
  • 01:00:51platelet count less than 50 so,
  • 01:00:53but maybe between 50 and 100 because
  • 01:00:56effective dose sometimes is not
  • 01:00:58feasible for this group of patients.
  • 01:01:00So none of these drugs address anemia
  • 01:01:03sore from momentum study which was
  • 01:01:05just presented that you know the data
  • 01:01:08was presented as a company release,
  • 01:01:09so there's no publication about
  • 01:01:11that at the end of January.
  • 01:01:12So this drug is geared towards
  • 01:01:16patients with anemia,
  • 01:01:18who are progressing after sliding.
  • 01:01:21Now this was a randomized
  • 01:01:23study against Danazol,
  • 01:01:25which you argue may not be the
  • 01:01:26best randomization strategy.
  • 01:01:27So there is some improvement in
  • 01:01:29patients who have anemia there,
  • 01:01:30but the drug is for symptom control,
  • 01:01:32more just for anemia.
  • 01:01:33Fix the patient you were talking
  • 01:01:35about at the beginning.
  • 01:01:36Looks solid, treated, patient with anemia.
  • 01:01:38There is a there is a study called
  • 01:01:41Independents trial looking at luspatercept.
  • 01:01:42This group of patients we know that
  • 01:01:45was part of Sept is approved for
  • 01:01:47MDS with doing Super Blast right so
  • 01:01:49and perhaps some people can get it
  • 01:01:51off label to treat these patients,
  • 01:01:53but I think it is a little premature.
  • 01:01:54We have to see how this results
  • 01:01:56are going to bend out.
  • 01:01:59So what would you do
  • 01:02:01so you know, for patients who first
  • 01:02:03of all don't give up slip to patients
  • 01:02:06whose main problem is an email, right?
  • 01:02:08So because an email becomes worse,
  • 01:02:10is the drug to fix the symptoms,
  • 01:02:12and some patients would be happy to
  • 01:02:15take crooks because they have bad
  • 01:02:17symptoms and receive transfusions
  • 01:02:19because their quality of life,
  • 01:02:20even though transfusions may be a little
  • 01:02:22bit more frequent, becomes better.
  • 01:02:24So we can sometimes try to give
  • 01:02:27everything like Derby Poitin 150 weekly
  • 01:02:29or 300 weekly to those patients.
  • 01:02:32In conjunction with within those
  • 01:02:34country intuitive.
  • 01:02:35Because rooks,
  • 01:02:35lithium is Jack stat pathway
  • 01:02:37inhibitor and worth reporting
  • 01:02:38actually activates that pathway,
  • 01:02:40but Bruce Lipton was not there 24/7,
  • 01:02:42so we allow some hematopoiesis in between.
  • 01:02:45So by doing that and some of the patients
  • 01:02:47may have less transfusion requirement,
  • 01:02:49so it's either supportive,
  • 01:02:51care with transfusions or trying to give
  • 01:02:53darbepoetin to those patients who need
  • 01:02:56or trying to decrease the looks lit nap,
  • 01:02:59which of course is a you know may lead to.
  • 01:03:02Reoccurrence of some of the symptoms
  • 01:03:04and worsening of symptomatology
  • 01:03:06in those patients.
  • 01:03:07So no perfect solution to this
  • 01:03:08group of patients at this time.
  • 01:03:12Would you consider adding danazol also or
  • 01:03:15so danazol would be one of the options
  • 01:03:17with Retropulsion doesn't work with
  • 01:03:19overall response rate of about 20%,
  • 01:03:21which may last up to two years.
  • 01:03:23Again, monitoring of liver function,
  • 01:03:25test PSA and man would be important
  • 01:03:26for this group of patients.
  • 01:03:28Yes, this is the second line
  • 01:03:29option for an email management.
  • 01:03:31Can I ask you a question?
  • 01:03:33So because we have to move
  • 01:03:34to the tumor board.
  • 01:03:35I just have this question so if
  • 01:03:36there is no clinical trial and your
  • 01:03:38patience and your patient with MD's
  • 01:03:40high risk MD's didn't respond to HMA,
  • 01:03:43would you try to do off label addition
  • 01:03:46of donetta clocks two weeks on,
  • 01:03:47two weeks off to this patient?
  • 01:03:49If you can get it covered by the insurance?
  • 01:03:51No clinical trial available.
  • 01:03:55Yeah, so that's again like the
  • 01:03:57dilemma we have with those patients
  • 01:03:58because we don't have anything that's
  • 01:04:00FDA approved for those patients,
  • 01:04:02so I would consider it.
  • 01:04:03However, I would, you know,
  • 01:04:05be very clear with the patient about
  • 01:04:07the limitations of this being off
  • 01:04:09label and we don't have a lot of data.
  • 01:04:11I do think it's quite a suppressive regimen,
  • 01:04:14so for some patients you have to expect
  • 01:04:17that they are going to need to come
  • 01:04:19three times a week to the clinic,
  • 01:04:21need frequent transitions they will
  • 01:04:23need to be on prophylactic antibiotics.
  • 01:04:25So I consider it more in the setting
  • 01:04:28where I'm thinking about bridging
  • 01:04:30the patient to a transplant.
  • 01:04:31If the patient does not have
  • 01:04:34a transplant option.
  • 01:04:36Think about it,
  • 01:04:37but not as strongly,
  • 01:04:38except in situations where the
  • 01:04:40patient is in relatively good shape.
  • 01:04:42The problem is that many of those
  • 01:04:44patients are very old and they
  • 01:04:46have a lot of comorbidities and
  • 01:04:48therefore supportive care could be.
  • 01:04:51Also, I think appropriate in some patients,
  • 01:04:54but just take one last question because I
  • 01:04:56see it from doctor to doctor Szeles about.
  • 01:05:00Why do you think there was no
  • 01:05:02overall survival advantage with
  • 01:05:03his guilt compared to.
  • 01:05:055% Neb with guilt in in in the agile.
  • 01:05:12I actually answered in the trap,
  • 01:05:13but I guess in brief I mean there
  • 01:05:15were some imbalances between the
  • 01:05:16groups were only talking about the
  • 01:05:18you know the Lacewing trial which
  • 01:05:20which is the gold ribbon trial.
  • 01:05:22More patients on the ASA monotherapy
  • 01:05:24arm were able to proceed to subsequent
  • 01:05:26therapy which of course could influence
  • 01:05:29any OS for that group as well.
  • 01:05:31I think it was more.
  • 01:05:31I think it was like 40 versus 20%.
  • 01:05:33It was almost double and there is
  • 01:05:35also about a four month difference
  • 01:05:37in time to next therapy.
  • 01:05:39So patients who already committed
  • 01:05:41so that could probably.
  • 01:05:42You know, explain some of that.
  • 01:05:44There were also.
  • 01:05:45There was also striking imbalance
  • 01:05:46in the performance status,
  • 01:05:48which is more of a surrogate for frailty,
  • 01:05:50which is again debated itself,
  • 01:05:52but more patients on the ASIC guilt
  • 01:05:54arm were just higher performance
  • 01:05:56status you talked to was I
  • 01:05:58think I wanna say 30% wallpaper
  • 01:06:00so you know I thought the second
  • 01:06:02line treatment with guilt in those
  • 01:06:03who were treated with ASA you know
  • 01:06:05so would be also the main reason
  • 01:06:07why there was no at the end of all
  • 01:06:09survival difference in this too.
  • 01:06:10And they were, you know.
  • 01:06:11So it's just very difficult
  • 01:06:12to show overall survival.
  • 01:06:16Yeah, I think with all of
  • 01:06:17these trials I you know, I,
  • 01:06:19I think doing this postmortem is,
  • 01:06:22you know, a good thinking exercise.
  • 01:06:24But at the end of the day,
  • 01:06:25all of this should be thought
  • 01:06:26before the trial and what we
  • 01:06:28have is what we need to go with.
  • 01:06:29So thank you so much. Again,
  • 01:06:31if anybody has any additional questions,
  • 01:06:33feel free to send us an
  • 01:06:36email or call any of us.
  • 01:06:37Thank you so much and I think
  • 01:06:39we have the tumor board. Yes,
  • 01:06:40tumor board please.