Combination Therapy for Hepatocellular Carcinoma: A New Standard

Transcript

• 00:00OK, so you know if you instant.
• 00:05We will be starting.
• 00:09So this is the server.
• 00:14Seminar on the liver.
• 00:16Tumor lecture we've launched in January
• 00:20and today we will have FaceTime to.
• 00:23The medical treatment of HCC.
• 00:28I remind you that this is part
• 00:30of our liver cancer program
• 00:32and it takes a village to treat
• 00:35the patient with liver cancer.
• 00:37You see, on the left all the different
• 00:41approaches that needs to be considered
• 00:43when we discuss the patient and
• 00:46and on the right part of the people
• 00:49that takes part to our program.
• 00:51Between surgeons,
• 00:52interventional is the medical
• 00:54oncologist at geologies pathologist,
• 00:56and so on and so forth.
• 00:58And in the two prior seminars,
• 01:02we have the Doctor Billingslea from
• 01:07Service Surgical oncology Ann Dr.
• 01:10Model from interventional radiology today.
• 01:14We will have Stacy,
• 01:16which is a format of just so
• 01:19that to remind you very briefly
• 01:21how the program works.
• 01:23We have a a comment intake line and
• 01:26the patient is seeing in in the liver
• 01:30cancer clinic and then discuss the
• 01:32tumor board where everybody participate.
• 01:36You see here on all the discipline
• 01:39that take part to our discussion
• 01:41and then a treatment is.
• 01:44Is discussed among us an and
• 01:46the patient is referred for the
• 01:48treatment and and the follow up.
• 01:50So today I am very happy to
• 01:53present Doctor Spacetime.
• 01:54Stacy is is a very valued member of our
• 01:58program. She had this battle studies.
• 02:01I looked gassed in New York she got
• 02:04the ND in the University University
• 02:07and then a master in science.
• 02:10She did her residency in the Montefiore
• 02:13Medical Center in New York City and
• 02:17your college fellowship are and where you?
• 02:20She donyale in 2010.
• 02:22And she's now associate professor
• 02:24of internal medicine ecology.
• 02:27She has leadership positions at the
• 02:30Center for Gas, intestinal cancer,
• 02:32and she's a member of our steering
• 02:35committee of our Liver Cancer program,
• 02:37and she is one of the person that actually.
• 02:43Give us their guidelines through
• 02:46her activity in the effort
• 02:49Ability Cancer panel ansehen.
• 02:51In addition, Stacy is one of the really
• 02:56few medical oncologist who are expert
• 02:59in the treatment of liver cancer,
• 03:03which is a particularly difficult
• 03:06condition to to treat because of the
• 03:10combined liver and an ecology diseases.
• 03:13And in addition to that,
• 03:15she has the time to be the.
• 03:18Principal investigator or one of the Co.
• 03:21Investigator in about 30 different clinical
• 03:24trials and it's really impressive.
• 03:27And so without further ado,
• 03:30let me share my screen Anne and
• 03:33let Stacy begin his lecture.
• 03:46OK great. Can you see it now?
• 03:49Yep OK perfect.
• 03:50Alright thanks Mario for the introduction,
• 03:53so I'm really excited to be talking
• 03:55to you about combination therapy
• 03:57for HCC and you know,
• 04:00I usually start talks by giving a
• 04:02lot of background information and
• 04:04really explaining why this is such a
• 04:08multidisciplinary disease to treat.
• 04:09But this group is well aware of that,
• 04:13and so I'm going to jump right
• 04:16into really thinking about the
• 04:18medical oncology piece of.
• 04:20Of treatment and so you know,
• 04:22I like to start with looking at the BC
• 04:24else staging system because I think this
• 04:26really shows kind of where things were,
• 04:29you know,
• 04:29and then thinking about where
• 04:31things are and then really thinking
• 04:33more broadly about where things
• 04:35are going in the feature.
• 04:36So we'll come back to this slide later.
• 04:39But you know also,
• 04:40I feel like this reflects the
• 04:42time when I came to Yale 10
• 04:44years ago and it was really a
• 04:46transplant conference at the time,
• 04:48not a liver tumor board.
• 04:50But I went to weekly and I kind of sat in
• 04:53the back of the room right out of fellowship.
• 04:56And when someone kind of
• 04:58came off the transplant list,
• 05:00you know someone would look back
• 05:02at me in the in the corner and say,
• 05:05do you want to see this patient
• 05:07and put them on Seraphim?
• 05:08And so I feel like the story that I
• 05:11could present today is kind of all
• 05:13the new treatment options really come
• 05:15in parallel with my experience and
• 05:17kind of growth here in this field.
• 05:20So you know,
• 05:21really seraphim's been the one drug
• 05:23that's been around for awhile and
• 05:25now we have different treatment
• 05:27options and we're kind of, you know,
• 05:29sandwich done after the cure
• 05:31it if intent therapies,
• 05:32right?
• 05:33And then the local regional therapies for the
• 05:35Child Pugh for the for the BCLCB patients.
• 05:38And so you know,
• 05:39I think.
• 05:40Also,
• 05:40although this staging system isn't perfect,
• 05:43it really reflects right?
• 05:44The you know the importance of thinking of
• 05:46the underlying liver function of the patient,
• 05:49their performance status and.
• 05:50The tumor characteristics and so starting
• 05:53at the beginning here with the sharp study,
• 05:55which I'm sure everyone is
• 05:56familiar with rates,
• 05:57so this goes back to 2008 and this
• 06:00was the first study to show a survival
• 06:02benefit of a systemic therapy in HCC.
• 06:05So other drugs like doxorubicin
• 06:06had been used in the past,
• 06:08but they had ever never actually
• 06:10been shown in a randomized child
• 06:12to show a survival benefit.
• 06:13So in this study you could see that
• 06:16Seraphim was actually randomized to placebo,
• 06:18right?
• 06:18Which is unusual for a first
• 06:20line systemic therapy option.
• 06:22An in this study we saw an overall
• 06:24survival benefit going from 7.9
• 06:26months with placebo to 10.7
• 06:28months and so based on this data,
• 06:30this became the new standard of
• 06:32care option and you could see also
• 06:34that there was a time to radiologic
• 06:37progression on this on this drug
• 06:39and just remember,
• 06:40you know Seraphim, right?
• 06:42It's not chemotherapy in the exact
• 06:44strict sense of the term rate,
• 06:46but it's a it's a TKI and multi
• 06:48tyrosine kinase inhibitor,
• 06:49and because of that you know it's
• 06:51really targeting multiple pathways.
• 06:53It's kind of a dirty.
• 06:55Drug and you know they're not.
• 06:58Although their oral and they're taken daily,
• 07:01and they may not have some of the
• 07:04more serious side effects that
• 07:06some chemotherapy drugs have.
• 07:09They do have a lot of great two toxicities
• 07:12that often affect our patients like fatigue.
• 07:16Sometimes decreased appetite,
• 07:17hand foot, skin reaction,
• 07:19diarrhea, right?
• 07:20Which are definitely important in the
• 07:23management of these of these patients still.
• 07:26Stay on therapy and I'm just going
• 07:28to focus now on first line therapy
• 07:30and then we could talk more about.
• 07:32The second line therapy option so Lynn
• 07:35van if another tyrosine kinase inhibitor,
• 07:37was the next drug that had a positive
• 07:40result in a first line study,
• 07:42and so this study is actually powered
• 07:44to look for either superiority
• 07:46or non inferiority to Seraphim.
• 07:48And this is the reflect study and I'm
• 07:51just going to manage mention for this study.
• 07:54Some of the criteria and then you could
• 07:57see that really all of the systemic
• 08:00therapy studies in HTC kind of follow.
• 08:02Pretty closely this standard
• 08:04criteria so you know patients
• 08:07have to have measurable lesions.
• 08:09BBC else stage B or C.
• 08:12Usually child Pugh a disease.
• 08:14Some studies may have included
• 08:17some patients with B7 disease,
• 08:19but most are primarily child Pugh.
• 08:22A good performance status of zero or one,
• 08:26and then you know usual parameters
• 08:29for adequate organ function.
• 08:32They excluded patients that had,
• 08:34you know more more advanced
• 08:36disease like Portal,
• 08:37vein invasion and then they
• 08:39were stratified by region,
• 08:41whether they had Macrovascular
• 08:43invasion or extrahepatic spread
• 08:45and E COGS status and they were
• 08:48randomized one to one to live at nib,
• 08:51which you know most patients received
• 08:53the 12 milligram dose to start,
• 08:56or saraf nib and the primary
• 08:58endpoint was overall survival
• 09:00with multiple secondary endpoints.
• 09:02And you could see that basically
• 09:04you know they didn't show that it
• 09:07was superior and the lines cross a
• 09:09few times but it was non inferior
• 09:11so the median overall survival
• 09:13is very similar between the two.
• 09:15But the reason why many people would
• 09:17consider this a better option for
• 09:20first line therapy for patients who
• 09:22are going to start therapy on a TKI is
• 09:24that even though the survival was similar,
• 09:27the progression free survival was better.
• 09:29Although the study was not powered.
• 09:31You know to have this as
• 09:33the primary endpoint.
• 09:34And if you look at the bottom,
• 09:36the overall response rate,
• 09:38which 9% to me is high for seraphon.
• 09:41But it was up to 24% with
• 09:43the Lynn Vatanen arm.
• 09:44And so you know you could argue without
• 09:47the benefit of overall survival.
• 09:49Whether there really is a
• 09:50benefit of having a response.
• 09:52But I think most most people
• 09:54that take care of
• 09:56these patients would think that.
• 09:58Potentially having a response.
• 10:01May help with better symptom
• 10:04you know symptom management.
• 10:07And this just showed a subset analysis
• 10:09looking at multiple different groups
• 10:12that in all the groups in the
• 10:14subset they favored linv at NAB.
• 10:17And so so now moving to immune therapy.
• 10:23So obviously this is an exciting
• 10:25area for HCC and there's multiple
• 10:27ways rate that we could think about.
• 10:31You know using immune therapy
• 10:33for different targets.
• 10:34Immune therapy was a little
• 10:36bit late in the game to HCC,
• 10:39I think largely because before
• 10:41there were drug approvals,
• 10:43it seemed like a risky choice to give
• 10:46to patients who had either hepatitis
• 10:48B or C or were at higher risk,
• 10:52potentially for D compensation.
• 10:54If they had autoimmune.
• 10:55Effects to the liver,
• 10:57and so these studies weren't really
• 10:59started until they already had FDA
• 11:01approval for other indications and
• 11:03out of the concern for potential
• 11:06viral reactivation.
• 11:07These initial studies in the
• 11:09Phase one setting separated the
• 11:11patients out into a hepatitis C
• 11:13Group A hepatitis B group,
• 11:15and then you see they had some patients
• 11:18who have progressed on sorafenib.
• 11:20But then there's also this fourth group
• 11:23of some patients who actually we're
• 11:25getting this as first line therapy.
• 11:28And what you could see?
• 11:30You know on these on these patient bars
• 11:33is that the four groups are pretty
• 11:35much superimposable on each other,
• 11:37and so you know there were many
• 11:40patients that were on treatment
• 11:42for at least a year and they were
• 11:45pretty similar across the groups.
• 11:47And this just shows on the left
• 11:50the spider plots,
• 11:51so anything that goes below the 30%
• 11:53response there on the bottom was at
• 11:55least a partial response and you
• 11:57could see that those are pretty
• 11:59similar across the groups and then
• 12:01on the right is just another form of
• 12:03looking at the data in a waterfall
• 12:05plot and you could see from the red
• 12:08dotted line going across the bottom.
• 12:10All the patients that went below that
• 12:12had had at least a partial response
• 12:14to the drug and basically the four
• 12:17graphs are. Very similar and so.
• 12:19Based on this data,
• 12:21the FDA approved Nuvola MAB with
• 12:24the conditional approval that there
• 12:26would be randomized data in the future,
• 12:29but this allowed patients to have
• 12:32access to immune therapy for HCC,
• 12:35an in a similar study.
• 12:37The keynote 224 study very similar design.
• 12:40This looked at pembrolizumab and
• 12:42they separated the patients out in
• 12:45a similar fashion with hepatitis B,
• 12:48hepatitis C, and uninfected group.
• 12:51And you could see again that in in
• 12:53you know this waterfall plot that
• 12:56there were responses in all of the
• 12:59groups and that they were pretty
• 13:01similar in distribution.
• 13:03And so again they got a very similar
• 13:06FDA approval that was conditional
• 13:08on having future randomized data
• 13:10and so now we get to more exciting
• 13:13data rate of thinking of combination
• 13:15therapy in the first line.
• 13:17And so this study looked at a
• 13:20combination of atisa
• 13:22Les Mab. With bevacizumab of veg
• 13:24F inhibitor and what's interesting
• 13:27is that bevacizumab had been
• 13:29looked at in HCC before in a small
• 13:32couple small phase two studies,
• 13:34and there was a response rate.
• 13:37They weren't randomized to show a clear,
• 13:40you know, survival benefit,
• 13:41but there was a signal that there was
• 13:45clearly benefit of giving anti VEGF therapy,
• 13:48but there was never approval for
• 13:50or an application for approval.
• 13:53You know for the drug.
• 13:55So before this berbasis map was not an
• 13:58approved drug for each CC and you know,
• 14:01it's interesting to think about why there
• 14:04is potentially synergy between these two
• 14:06drugs as opposed to an additive benefit,
• 14:09but it seems like Bevis is.
• 14:11Mab does normalize the tumor vasculature?
• 14:13An actually allows for
• 14:15more T cell infiltration,
• 14:16and so this is the phase one study.
• 14:20This is the Geo 30140 study that
• 14:22looked at several arms of which.
• 14:25HTC was one of the arms on the study,
• 14:28and so these were the other arms that
• 14:31that we also had open here are may
• 14:34was for unresectable advanced HCC.
• 14:37They did include some B7 patients
• 14:40on the study.
• 14:41To have measurable disease rate very
• 14:46similar eligibility criteria and.
• 14:49The primary endpoint here,
• 14:51because it was a phase one study
• 14:53with safety and tolerability,
• 14:55safety and tolerability and then
• 14:58looking at the overall response
• 15:01rate by resist 1.1 there's also.
• 15:03Duration of response progression.
• 15:05Free response time to radio graphic
• 15:08progression and then they also looked
• 15:10at modified resist criteria and
• 15:13overall survival so this looks at the
• 15:16baseline demographics of this study.
• 15:18So in total there were 103
• 15:21patients on the Phase one study,
• 15:23predominantly male,
• 15:24which is the HTC population that
• 15:27we see about half the patients were
• 15:30in Asia and the other 40% were in.
• 15:34Japan or the US patients were
• 15:36split between E kog performance,
• 15:38status of zero and one and the majority
• 15:41of the patients had child Pugh A5
• 15:44disease with 20% ASICS and you could
• 15:47see there were only six patients that
• 15:50wound up in rolling with B7 disease.
• 15:53About half the patients had hepatitis B,
• 15:56reflecting the you know mostly the
• 15:58Asian population that enrolled 30% with
• 16:00hepatitis C and another 20% more nonviral.
• 16:03The majority of the patients
• 16:05had extrahepatic spread.
• 16:06About half had Macrovascular invasion.
• 16:09And so when you think of those two as
• 16:11being kind of high risk characteristics,
• 16:14right,
• 16:15about 90% of the patients had one or both,
• 16:18and then they also looked at AFP
• 16:21to see if that was potentially a.
• 16:25You know show different responses and
• 16:28that was about half with less than 400 AFP.
• 16:31About half the patients had prior taste
• 16:34and about a third had prior radiotherapy,
• 16:38and this Spider plot shows the
• 16:40responses to treatment and you could
• 16:43see that the green lines or the
• 16:46patients who had either a partial
• 16:48or complete response to treatment.
• 16:51Then there were many patients in blue,
• 16:54it's stable disease than the red.
• 16:57The red bars show progressive disease,
• 16:59so you could see that for
• 17:01the patients you know,
• 17:02they often had a good response.
• 17:04Kind of starting pretty early into
• 17:06treatment and many of the patients
• 17:08had a quite sustained response.
• 17:10So if you look at the Disease
• 17:13Control rate, there were.
• 17:15There were many responders and there
• 17:17were many that lasted a significant
• 17:20amount of time with the progression free
• 17:22survival of 15 months and the median,
• 17:25overall survival had been
• 17:26reached at the time.
• 17:28When you know this was
• 17:29considered a positive study.
• 17:31So based on this Phase,
• 17:33one data that I am brave 150
• 17:35study was designed and this is
• 17:37a randomized study then to look
• 17:40at the combination of a tease.
• 17:42Oh Bevause was given in the Phase
• 17:45one study randomized to Seraphim.
• 17:47Which at the time when this was started,
• 17:49it was still the standard of care
• 17:52and it was randomized 2 to one and
• 17:55again with the same stratifications.
• 17:57And so the I am brave 150 study was
• 18:01published back in June and based on
• 18:04that data, there was FDA approval.
• 18:06I'm actually showing you here.
• 18:08The updated overall survival and
• 18:10progression free survival data
• 18:12that was presented at the GI
• 18:15ASCO meeting in January.
• 18:16So this is newer,
• 18:18newer data and you know you could
• 18:21see here that the overall survival.
• 18:25The median overall survival
• 18:26for Seraphim was 13.4 months,
• 18:28so as these studies go on in time,
• 18:32the median overall survival for this
• 18:34rafina Barb keeps getting better,
• 18:36reflecting that most patients are
• 18:38going on to at least second line
• 18:40therapy and the median overall
• 18:42survival for the combination
• 18:44was an impressive 19.2 months,
• 18:46so this is really the best data
• 18:49that we have so far for first
• 18:52line therapy for HCC and you
• 18:54could see the progression free.
• 18:57The.
• 18:59The PFS data for Steven it was 4.3 months,
• 19:02and for that is above arms 6.9 and
• 19:04you could see that there's a nice
• 19:06separation of the curves at six months,
• 19:0912 months going out to 18 months
• 19:12and on for both the OS and PFS.
• 19:15And looking at responses to,
• 19:17they looked at resist 1.1 and modified
• 19:20resist and the confirmed overall
• 19:22response rate for Seraphim is now 11%,
• 19:25which seems to also keep going
• 19:28up for Seraphim data,
• 19:29which I find interesting,
• 19:31but I'm not sure how to explain
• 19:35that and then.
• 19:36The response rate was an
• 19:38impressive 30% for the A tease.
• 19:40Oh Bev combination and you know the
• 19:42response rates are always a little bit
• 19:45higher when their looked at by modified
• 19:47resist as opposed to resist 1.1 and
• 19:50so we saw some complete responses.
• 19:54Several partial responses.
• 19:55Many patients with stable disease,
• 19:57and so when you look at the
• 19:59overall Disease Control.
• 20:00Rates it's an impressive.
• 20:03It's an impressive 74% and so the
• 20:07median duration of response for
• 20:10Seraphim was 14.9 and four that
• 20:14is above combination 18.1 and,
• 20:17importantly,
• 20:18you know,
• 20:19looking at the adverse events
• 20:22for for the combination.
• 20:24So there was some decreased appetite fatigue,
• 20:29pyrexia rash. Hypertension,
• 20:30which is mostly from the bevacizumab which
• 20:34we know from you know, veg F inhibition.
• 20:37We see this and it's easily treatable with
• 20:41with blood pressure medication, you know.
• 20:44Importantly, there is a lot of interest in
• 20:47looking at bleeding events in these patients
• 20:50because we are giving bevacizumab and the
• 20:54variceal hemorrhage rate was very low.
• 20:57Upper GI hemorrhage rate also low,
• 21:00and so now comparing the safety
• 21:02data between Saraf and amenities.
• 21:05Oh Bev. So not surprisingly,
• 21:07of course we see more.
• 21:10More grade one into diarrhea.
• 21:13It's Arafa nib and less with a tease.
• 21:16Oh Bev hand foot skin reaction,
• 21:18really exclusively with Saraf nib decreased
• 21:21appetite in both groups hypertension
• 21:23and we see that in Seraphim also.
• 21:25Of course, because there's
• 21:28partial veg F inhibition there.
• 21:31Some infusion related reactions,
• 21:32some proteinuria which we see also
• 21:35with veg F inhibition an are used
• 21:37to checking blood pressure at every
• 21:39visit and checking your Infor for
• 21:42protein as we do with bevacizumab.
• 21:44Another disease groups.
• 21:45And importantly,
• 21:46you know for the phase one and phase three
• 21:49study all patients had to have an EGD
• 21:52within six months of initiating therapy,
• 21:54so you know.
• 21:55Now we think of really doing that
• 21:57exclusively for the patients
• 21:59who have underlying cirrhosis.
• 22:01But for the studies they didn't.
• 22:03Distinguish between patients who
• 22:05did or did not have cirrhosis,
• 22:07so all patients had an EGD within
• 22:09six months of starting therapy and
• 22:12they had to have verisys treated
• 22:14according to local standard of care,
• 22:16and so importantly,
• 22:17looking at the upper GI bleeding rate
• 22:20in the combination versus Seraphim.
• 22:22EBIT increased from 4.5% in Strafford,
• 22:24up to 7% with a tease.
• 22:27Oh bed,
• 22:27which is considered safe and also
• 22:30importantly thinking about quality of life.
• 22:32All patients filled out.
• 22:33Patient reported outcomes on this
• 22:36study and patients reported a
• 22:38significantly better quality of life
• 22:40with a time to clinical deterioration.
• 22:43Much improved from 3.6 months on
• 22:45Seraphim to 11.2 months on a tease.
• 22:48Oh Bev,
• 22:49so not only are we seeing increases in
• 22:52survival and progression free survival,
• 22:55but we're actually seeing patients
• 22:57reporting that they feel like they
• 23:01have a better quality of life for
• 23:04significantly more months on this regimen.
• 23:07So you know, based on this data,
• 23:09this now is.
• 23:10So it is so Bev is the first line
• 23:13preferred option for patients who
• 23:15are considered good countenance
• 23:17for for the regiment.
• 23:19And this was really a game
• 23:21changer in the field.
• 23:23So so thinking about combination therapy,
• 23:25right?
• 23:26This is really the gold standard now,
• 23:28but will go through some emerging data.
• 23:31So I wanted to go back first and
• 23:34think about now the second line.
• 23:37You know the second line data that we have,
• 23:40so again,
• 23:41you know the initial studies were
• 23:43with tyrosine kinase inhibitors.
• 23:45So these studies were designed when Saraf
• 23:48and it was the only drug approved and.
• 23:52They were randomized to placebo and
• 23:55so in this study the celestial study
• 23:58patients were randomized 2 to one to
• 24:01khabbaz antonym or to placebo
• 24:03with similar stratifications.
• 24:05And based on this study,
• 24:07the progression free survival
• 24:09increased from about two months to 5.2.
• 24:12There was a very low response rate with
• 24:15cabozantinib that we often see with
• 24:18tyrosine kinase inhibitors, you know.
• 24:20And so very few partial responses.
• 24:22It was mostly stable disease that was seen,
• 24:26but there was an overall survival
• 24:28benefit of another two months.
• 24:30You know which is interesting.
• 24:32So is there something really different?
• 24:35About the pathways targeted with cabins,
• 24:37antonym or would just staying on any TKI
• 24:40kind of post progression still give you some.
• 24:44You know some survival benefit,
• 24:46but this was positive data.
• 24:48There were also mentioned some patients
• 24:51who received this in the third line on
• 24:54the study and then a similar design.
• 24:57The resource study looked at red graph nib
• 25:00versus placebo and very similar design
• 25:03of primary endpoint of overall survival.
• 25:06And you can see here that there
• 25:08was a survival benefit of again
• 25:10about a two month benefit here.
• 25:12This is the progression free survival curves
• 25:14and the probability of progression here.
• 25:16And if you look at all the
• 25:18subgroups that favored by graphene,
• 25:20if also so cab is answered have
• 25:22been red graph,
• 25:23and if we're both approved
• 25:24in the second line,
• 25:26you know for those who have
• 25:28experience with using these drugs,
• 25:29I would say I think that
• 25:32overall cabins antonym.
• 25:34Is probably better tolerated
• 25:36than than Reg Raffa nib.
• 25:40But a similar kind of TKI side effects,
• 25:43and then to mention you know other
• 25:46other data in the veg F area,
• 25:49so ramucirumab,
• 25:50another veg F inhibitor,
• 25:51was looked at in the REACH study
• 25:54where they looked at this in
• 25:56the second line versus placebo,
• 25:58and the study was a negative study.
• 26:01But in subset analysis there seemed
• 26:04to be a benefit in the patients who
• 26:07had an AFP level of greater than 400.
• 26:10So they went back and design the reach
• 26:13two study and so using similar criteria.
• 26:16But for this study they only included
• 26:19patients who had a baseline AFP level
• 26:21of greater than 400 and they were
• 26:24randomized 2 to one to ramucirumab
• 26:26or placebo and that study did show
• 26:29a survival benefit and then if you
• 26:32pull the data from this study plus
• 26:35the patients who had an AFP of over
• 26:38400 from the first reach study,
• 26:40you see that there was.
• 26:42Clearly, uh,
• 26:43you know positive benefit again in
• 26:46the same range of a couple of months.
• 26:49So for patients with an AFP level of
• 26:52over 400 for second line therapy,
• 26:55this is another potential option.
• 26:58So now thinking of you know.
• 27:00So I mentioned before that nivolumab
• 27:03and pembrolizumab were both approved
• 27:05as conditional approvals pending
• 27:07randomized data.
• 27:08So the two companies took different
• 27:11approaches in thinking about randomized.
• 27:13Studies this Checkmate 459 study
• 27:15looks at nivolumab versus rap native
• 27:18sorafenib as first line treatment and
• 27:20so again looks at similar patient population.
• 27:23They looked at primary endpoints
• 27:25of time to progression and
• 27:27overall survival and secondary
• 27:29endpoints of response rate
• 27:31and progression free survival.
• 27:33An you know the study did not meet
• 27:36its primary endpoint so you could
• 27:38see that the lines really cross.
• 27:41There's a little bit of
• 27:43separation at the end.
• 27:45You know, it's interesting
• 27:47because we know that there is
• 27:49a percent of patients right in
• 27:51about the 18% range that responds
• 27:54to pembrolizumab and nivolumab,
• 27:55and so you know you could argue the
• 27:58subtleties of the statistical analysis
• 28:00of the study of how it maybe could
• 28:04have met the primary endpoint if
• 28:06it had been designed differently,
• 28:08but it was a negative study,
• 28:10and similarly,
• 28:11you know the Pember Lizum app study.
• 28:14They actually went for the second
• 28:16line indication.
• 28:17And randomized to best supportive care,
• 28:19which seems to be a very low bar.
• 28:22Knowing again that we see, you know,
• 28:24usually about an 18% response rate.
• 28:26With pembrolizumab they randomized
• 28:28over 400 patients to Pembroke Plus
• 28:30best supportive care versus placebo.
• 28:32Plus best supportive care,
• 28:33but they split the primary endpoint and
• 28:36so even though these P values are very low,
• 28:38they actually did not meet
• 28:40the threshold for the study,
• 28:42and so I think one could argue that
• 28:44if the study had been designed a
• 28:47little bit differently with maybe just
• 28:49one primary endpoint and the other.
• 28:51As a secondary endpoint,
• 28:53it may have been positive,
• 28:55but basically both of these
• 28:56studies turned out to be negative,
• 28:59and it remains to be determined
• 29:01what the FDA will do with this data,
• 29:04so they may or may not continue to
• 29:06have an indication as as a single
• 29:09agent therapy in HCC so will probably
• 29:12know more later this year about that,
• 29:15but I think you know really.
• 29:17Excitingly though,
• 29:18you know there's a lot more combination
• 29:21therapy that's being looked at.
• 29:23And so you know,
• 29:25there's there's several studies,
• 29:26so one is the LEAP 02 study looking at
• 29:29lens at an IM plus Pember lizum app
• 29:33versus Limbaugh and their balloon.
• 29:35And so this is looking at a combination
• 29:38of right so so PD one inhibition plus a TKI.
• 29:42So this is the Keynote 524 study
• 29:45was the Phase 1B study and that
• 29:48data is already been presented.
• 29:50There was an overall response rate of.
• 29:5336% but I just caution you that when the
• 29:56Phase one data was initially presented,
• 29:59the response rate.
• 30:00You know from the beginning was very high,
• 30:03even higher than this,
• 30:05and so you know as you get randomized data,
• 30:08the response rate often comes down
• 30:10so you know the final data for
• 30:13this may not be as high as this,
• 30:15'cause often the patient selection for
• 30:17the Phase one study is very selective.
• 30:20An in the Phase one study they had a
• 30:23median overall survival of 2022 months
• 30:25and that was about 100 patients.
• 30:27And so I think it will be really
• 30:30interesting to see the combination
• 30:32data for this.
• 30:33You know,
• 30:34and then you could really kind
• 30:36of think about right?
• 30:38Which patient might be best suited
• 30:40for which combination therapy,
• 30:42and similarly the Cosmic 312 study
• 30:44is looking at cabins antonym plus
• 30:46atezolizumab versus rafanan, so again,
• 30:48you know another tyrosine kinase
• 30:50inhibitor plus plus PD one inhibitor and
• 30:53you know we know right cab is antonym
• 30:56is active in second line therapy.
• 30:58And as I mentioned there were some
• 31:01patients that had been treated as.
• 31:03Third line therapy.
• 31:05So this I think this is a
• 31:08promising combination also and
• 31:10then the other two studies.
• 31:13Look at the combination of with
• 31:15a CTL A4 antibody right and so we
• 31:19know from other diseases you know,
• 31:21adding a CTL A4 antibody often increases
• 31:24response rate in immune therapy,
• 31:26but also increases the immune
• 31:28related adverse events,
• 31:29and so the check mate and I have
• 31:32some slides to show you from this,
• 31:35But the check Mate 040 study,
• 31:37which was the 1B study that I showed
• 31:40you the single agent data for.
• 31:43Also had a small arm that looked
• 31:46at the combination of it Bluma,
• 31:48Mebane,
• 31:49nivolumab and so their response rate
• 31:51was up to 32% there with an impressive
• 31:54median overall survival of over 20 months.
• 31:57And so this study is looking at the
• 32:00combination of niveau nippy versus Seraphim,
• 32:02Berlin,
• 32:03Baton IB in the first line,
• 32:05and then another combination again of PD.
• 32:08One inhibition with a CTL A4 antibody is
• 32:11the durvalumab and tremelimumab study.
• 32:13And so this is the Himalayas study that
• 32:17I'll show you the study design for.
• 32:19As you know so far has showed a
• 32:23response rate of 24% and the median
• 32:26overall survival of 19 months with the
• 32:29with one of the arms of this study.
• 32:32So you know.
• 32:33There will be a lot of data coming
• 32:36which will be exciting to see
• 32:39the final data and then I think
• 32:42there's a lot to debate about which
• 32:45patients are best suited.
• 32:47You know,
• 32:47really kind of peacing out who responded,
• 32:50what the adverse events were.
• 32:52You know?
• 32:52What were the difference in side
• 32:54effects of who might be a better
• 32:57candidate for addition with the
• 32:59CTA for antibody versus bevacizumab
• 33:01versus a tyrosine kinase inhibitor?
• 33:03And those will be exciting.
• 33:05Discussions to have just to show
• 33:07you this is the Himalaya design,
• 33:10so the development plus Tremelimumab
• 33:12as first line therapy and they
• 33:15used a couple of different arms
• 33:17of tremelimumab dosing so you know
• 33:20in the other disease groups where
• 33:22there's been approval for CTA
• 33:24for combination like in Melanoma.
• 33:26Typically the patients get four
• 33:29cycles with the combination and
• 33:31then go on to the single agent
• 33:33drug of Nuvola MAB by itself.
• 33:36So in this study they did a
• 33:38couple of different regimens.
• 33:39One where there were four doses
• 33:41of tremelimumab and also looking
• 33:42at different doses.
• 33:43Then there was also a small cohort
• 33:45that looked at just one dose
• 33:47of tremelimumab to start,
• 33:48and that one actually seemed to have.
• 33:52More responses, but less toxicity,
• 33:54and so it'll be interesting to
• 33:56see in the end
• 33:57if that's the arm that really is the
• 34:00best one to move forward to within HCC,
• 34:03and this is to show you the group I
• 34:06mentioned from the Phase one study
• 34:08from the Checkmate 040 study of the
• 34:11combination of Nivolumab and IP,
• 34:13aluminum AB and so they used again.
• 34:15You know a few different dosing
• 34:17schemes for the patients,
• 34:19and it looks like you know
• 34:21for HCC the winner was really.
• 34:23Than evil one it be 3 arm that
• 34:26had the best overall survival and
• 34:29so that's sort of these colors
• 34:32came out different on this one,
• 34:35but basically it's it's this dosing
• 34:37here of the four doses and then they
• 34:41continue with just nuvola MAB alone.
• 34:43And you know, so lots of so.
• 34:46Lots of good questions.
• 34:48Kind of thinking about,
• 34:50you know the combination data and.
• 34:56I think the biggest ones you
• 34:58know right now, right eye for me.
• 35:00Two of the biggest questions to really
• 35:03think about our how do we sequence
• 35:05after tease Alisme Heaven Bevis is mad,
• 35:08so if that's the first line option
• 35:10then what do we do in second line?
• 35:13Do we restart with a tyrosine kinase
• 35:16inhibitor like Lynn Fat and if
• 35:18so go to a first line and kind of
• 35:20start through the you know the first
• 35:23slide into the second line again.
• 35:25Or do we think about going
• 35:27into combination immunotherapy?
• 35:28You know we have.
• 35:29It be anevo,
• 35:30now approved as a second line regimen,
• 35:33and then do we use another TKI and
• 35:36the third line?
• 35:37You know, I think about and I mean,
• 35:40obviously you know this is relatively new,
• 35:42'cause we've only had approval of
• 35:44the regimen since June,
• 35:46and so depending on how long
• 35:48someone's on the regimen,
• 35:50I think that could potentially help guide
• 35:52you know what what you would want to do next.
• 35:56So if someone really,
• 35:57I think progressives quickly through a tease.
• 36:00Oh, Bev.
• 36:01I don't know that going to a
• 36:03combination immune therapy you
• 36:05know regimen would be the best,
• 36:07but perhaps if someone responds
• 36:09and then eventually progresses,
• 36:10you may want to think about
• 36:13combination immune therapy.
• 36:15And.
• 36:17For the patients that tolerate
• 36:19a tyrosine kinase inhibitor and
• 36:21maybe have good control or decrease
• 36:24in AFP initially,
• 36:25I think it's very reasonable to go
• 36:27to another tyrosine kinase inhibitor.
• 36:30You know,
• 36:30maybe for patients that really
• 36:33did not tolerate a TKI well,
• 36:35even at reduced dose,
• 36:36and they have a high AFP that
• 36:39maybe a group that I would think
• 36:42more about ramucirumab in.
• 36:45I think another big question to think about,
• 36:47you know, for treating these patients,
• 36:50is that all of the clinical child
• 36:52data that you know that I presented
• 36:54here really only reflects the child Pugh,
• 36:57a population and maybe a couple of B7's.
• 37:00And you know,
• 37:01as we know,
• 37:02the majority of the patients that
• 37:04were actually treating in our
• 37:06practice have child Pugh B disease
• 37:08and so the question then is what
• 37:10is safe to give those patients?
• 37:12And as the data that we are seeing.
• 37:15From the trial really,
• 37:17is it really applicable to these patients?
• 37:19So as a tease?
• 37:21Oh,
• 37:21and Bev safe in the child Pugh B patients.
• 37:24Well,
• 37:25I think we're going to have a
• 37:27lot of data from that soon.
• 37:29You know,
• 37:30as patients are being treated
• 37:31out in the community,
• 37:33you know with approval now and
• 37:35you know patients with child PB
• 37:37disease or being treated regularly.
• 37:39My hope is that at least everyone's
• 37:41getting endoscopies so that we're not
• 37:44seeing higher incidence of GI bleeding.
• 37:46But that's certainly.
• 37:48A concern that I have.
• 37:51An you know which tyrosine
• 37:53kinase inhibitors you know.
• 37:54We're better to give.
• 37:55We have a lot of data for Saraf
• 37:58and if in Child Pugh B disease,
• 38:00so there was a Gideon registry
• 38:02that included a lot
• 38:03of data for patients with child
• 38:05PB and even somewhat see disease
• 38:07which basically showed that patients
• 38:08would see disease barely or on the
• 38:11drug for any length of time and
• 38:13don't seem to be on it long enough
• 38:15to really get any benefit from it.
• 38:18We do have some child Pugh B
• 38:20data now with Lynn VAT nib.
• 38:22Um, and we do have some data with
• 38:25with cabins antonym you know.
• 38:27Overall I would say it seems to
• 38:29me that these patients really
• 38:30wind up with more dose reductions,
• 38:33which is what the data suggests below.
• 38:35None of these were randomized studies right,
• 38:38but just you know more observation.
• 38:40ULL and I think the really when we
• 38:42think about the combination data
• 38:44from the slide I showed before
• 38:46right of thinking of you know,
• 38:48are we adding a see TL A4 antibody,
• 38:51a tyrosine kinase or Beves ISM AB?
• 38:53I think it's going to be really important
• 38:56to have data in those groups later
• 38:59with Child Pugh B patients because
• 39:01it may turn out that one combination
• 39:04is clearly better in that group,
• 39:07or at least you know safer.
• 39:09And so I think having that data
• 39:12after we have the initial trial data
• 39:15is going to be really important.
• 39:18So you know one thing that I
• 39:21haven't mentioned at all,
• 39:22which we usually spend a lot of
• 39:24time in other oncology talks.
• 39:26Thinking about right is
• 39:28molecular directed therapy.
• 39:29And so I just wanted to mention,
• 39:31you know,
• 39:32I think that this is a this is a big issue,
• 39:36right?
• 39:36So we're only talking about mostly tyrosine
• 39:39kinase inhibitors and then immune therapy.
• 39:41So we really have no biomarker.
• 39:43You know we have we have ramucirumab
• 39:45with a higher AFP,
• 39:46although I wouldn't necessarily call that a.
• 39:49No marker, you know,
• 39:51and even for the immune therapy
• 39:53responses in many diseases,
• 39:55you see that there is clear
• 39:58correlation with PDL one status and.
• 40:00So a lot of drug approvals are based on
• 40:03the CPS scores that we get from our path
• 40:07ologist an those multiple studies do not.
• 40:10There does not seem to be
• 40:13any correlation for HTC,
• 40:14which makes it harder for us to know
• 40:17which patients are more likely to respond.
• 40:20You know,
• 40:21there have been studies with
• 40:23met amplification.
• 40:24There's some studies looking
• 40:25at chromosome remodeling,
• 40:27which will be interesting to see right,
• 40:29but so far we have.
• 40:31No molecular directed therapy
• 40:33we are aware of course of the
• 40:35mutational landscape of HCC,
• 40:37you know,
• 40:38but unfortunately right the ones
• 40:39on the top there,
• 40:41we don't have any drugs for and
• 40:43the drugs that we do have for the
• 40:46targets at the bottom of the slide,
• 40:49right or very uncommon in HCC.
• 40:52I have sequence in patients this year,
• 40:55especially ones that had no underlying
• 40:58cirrhosis and this kind of confusing
• 41:00why they developed HCC and we found
• 41:02a couple of Baraka carriers which
• 41:05have not been well described in
• 41:07the literature as thinking about
• 41:09HCC's abraco related disease.
• 41:11And we've seen some back one mutations,
• 41:14so I think it's you know it's interesting
• 41:16to find these select patients,
• 41:19although it's not clear that they
• 41:21necessarily, you know, respond better to.
• 41:24PARP inhibitors or that there's really
• 41:26necessarily other targeted therapy for them,
• 41:28but I think you know the more patients
• 41:31that we sequence and do testing on.
• 41:33We may. You know, we may find more.
• 41:36And of course you know a lot
• 41:38of the patients with HCC get
• 41:40treated in the absence of biopsy,
• 41:42which is really unique to
• 41:44this to this disease.
• 41:45And so going back to the
• 41:47BC else staging system.
• 41:49So I think this is an important slide to
• 41:52kind of circle circle back to right so?
• 41:55You know, thinking of the narrow role
• 41:57where oncology could fall kind of
• 41:59just in this advanced stage C group,
• 42:02you know we've now accumulated rates
• 42:04several different drugs in this category,
• 42:06so adding into seref and if now
• 42:08we have a tease.
• 42:09Oh, and Bev approved in the first line.
• 42:12Also Lynn VAT and approved
• 42:14in the first line cabins,
• 42:15antonym burgraff and IMMA ramucirumab
• 42:17approved in the second line.
• 42:19Also it be niveau right and then we
• 42:21have pen Bruen Niveau still kind of
• 42:24conditionally approved a single agent drugs.
• 42:26But I think those will be largely
• 42:28replaced soon by the multiple combination
• 42:30studies of data that's going to come out,
• 42:33and so we've really added a
• 42:36lot in this category here,
• 42:37but I think that even more importantly,
• 42:40right now we need to kind of
• 42:42think of the whole, you know,
• 42:44the whole staging system he ran.
• 42:46Really say now that we finally
• 42:49have more effective therapies.
• 42:50You know, in my mind,
• 42:52combination doesn't just mean
• 42:53combination of two systemic therapies,
• 42:55but it's really combination of.
• 42:57All the modalities that we
• 42:59use in this disease,
• 43:01with potentially systemic therapy,
• 43:02and so you know,
• 43:04there's a lot of interest now.
• 43:07I'm thinking of Advent therapy,
• 43:09thinking of combination
• 43:10therapy with local therapy.
• 43:13This study is that it weren't
• 43:15done in the past.
• 43:17You know,
• 43:18looked at Saraf,
• 43:19and it's so there was an adjutant fit study
• 43:22that looked at Seraphim after reception.
• 43:24That study was negative,
• 43:26but as far as I know,
• 43:28I don't think there's a tyrosine
• 43:30kinase inhibitor approved in any
• 43:32diseases adjutant therapy because,
• 43:34you know,
• 43:35when you think of the mechanism of action.
• 43:38I don't think it's actually really
• 43:40illuminating microscopic disease,
• 43:41and so it's not surprising.
• 43:44I guess in retrospect that
• 43:45it wasn't a positive study.
• 43:47There was also the first study that
• 43:50I that I opened when I came here
• 43:52was the E Card 1208 study which was
• 43:55looking at the role of adding saraf
• 43:58number placebo to sequential tastes.
• 44:00And you know,
• 44:01I think it's interesting 'cause going back.
• 44:03You know,
• 44:04to almost 10 years ago now
• 44:06you know doing this study.
• 44:08It accrued really poorly across the country,
• 44:10and so the study never finished.
• 44:13Accrual and it,
• 44:14kind of.
• 44:14Ended halfway through the data somehow
• 44:17is still not published from it.
• 44:19There was another study in the UK
• 44:22that looked at a similar question
• 44:25in a smaller way, but you know,
• 44:27I think partially why it didn't accrue
• 44:30well was because there wasn't the
• 44:33kind of multidisciplinary groups that
• 44:35were able to do studies together.
• 44:37Because this study really required a
• 44:40relationship with interventional radiology
• 44:42that allowed everyone to work together,
• 44:44an really approach the patients.
• 44:46Before they moved on to systemic
• 44:48therapy to get them interested
• 44:50in the study and work together.
• 44:52Which is why I think we're in such
• 44:56a different place now in 2021 that
• 44:58I think we have the ability at Yale,
• 45:02as do other centers to really do
• 45:04multidisciplinary studies like
• 45:05the AGEMENT study,
• 45:07and like the combination with
• 45:09local therapy study.
• 45:10And so I'm excited to really think
• 45:12about what the role is for combination
• 45:15therapy in this intermediate stage.
• 45:18You know group and so I just wanted
• 45:20to mention a couple of studies
• 45:23that we have open now at Yale.
• 45:25So one of them is the Keynote 937 study.
• 45:28So this study is looking at Agilent
• 45:31Pember Lizum app versus placebo.
• 45:33So for patients that have had a complete
• 45:35radiologic response after surgical
• 45:37resection or local ablation of HCC,
• 45:39they're planning to enroll
• 45:41close to 1000 patients.
• 45:44In one to one randomization September,
• 45:46Liz, member,
• 45:47placebo,
• 45:48which would be for one year and then
• 45:52they'll be followed for survival
• 45:55with primary objectives of of.
• 45:57Re recurrence free survival in an
• 45:59overall survival and also safety and
• 46:01patient reported outcomes will be collected,
• 46:04so I think this is an interesting study.
• 46:06This is not the only adjutant study,
• 46:09you know.
• 46:10There's other companies that are
• 46:11doing kind of similar design.
• 46:13Similar design studies,
• 46:14so I think this will be interesting.
• 46:17And then I wanted to mention that
• 46:19we also have a study open of the
• 46:22safety and efficacy of live at
• 46:24and it was Pember Lizum app.
• 46:26So one of the.
• 46:28Doublet regimens that's being
• 46:29looked at in the advanced setting.
• 46:32That's a typo there versus placebo
• 46:34in combination with tastes
• 46:36and David Mann office.
• 46:37The Pi of this study here at Yale,
• 46:40and we have the primary
• 46:42outcomes of progression,
• 46:43free survival and overall survival,
• 46:45and then multiple secondary outcomes
• 46:47that will be looked at by resist
• 46:501.1 and by the modified resist.
• 46:52And so I think you know,
• 46:54and again, there's other studies in
• 46:57combination with tastes and why 90.
• 46:59That are in development or, you know,
• 47:03recently started in the country.
• 47:05And I think this will give us really
• 47:10interesting information to see you know,
• 47:12are these patients kind of better
• 47:15off by getting systemic therapy
• 47:18earlier in the algorithm and.
• 47:23We also are planning to open the
• 47:26Morpheus HCC study so this is,
• 47:28uh, so Genentech has this platform
• 47:31called Morpheus where it allows them
• 47:33to do a bunch of small protocols.
• 47:36Kind of that can cycle into the
• 47:38trial as there's new combinations
• 47:40that look potentially interesting.
• 47:42So the competitor the comparator arm in
• 47:45this study is the combination of a tease.
• 47:48Oh and Bev.
• 47:49So all patients get that and then
• 47:52right now the experimental stage one.
• 47:55Looks at a drug added called to
• 47:58Raghuram AB and then the other one
• 48:00is totalism AB and there's actually
• 48:03going to be 2 new arms opening soon
• 48:05which I can tell you more about.
• 48:08Once once we have those open this
• 48:11study we don't have open yet,
• 48:13but once the two new arms open
• 48:15will will be opening the study.
• 48:18Hopefully in the next couple of months.
• 48:20So this will be a good first
• 48:24line systemic therapy.
• 48:25Option for our patients.
• 48:29And so you know,
• 48:31I just wanted to mention,
• 48:33as Mario,
• 48:33you know,
• 48:34was discussing in the introduction
• 48:36that this disease really requires
• 48:38multidisciplinary care.
• 48:39I really enjoy meeting with my
• 48:41colleagues every Thursday at
• 48:43our at our liver tumor board.
• 48:45And, you know,
• 48:46I think we have great discussions
• 48:48on the patients because even
• 48:50though there are guidelines,
• 48:52they really are just guidelines and
• 48:54and there never a replacement for
• 48:56the real discussion that happens,
• 48:59you know, centered.
• 49:00For each patient, and so you know,
• 49:02I think as we have more systemic
• 49:05therapy options, we have to think about,
• 49:08you know the role for that and how
• 49:11that affects the other modalities
• 49:13of treatment that we're giving
• 49:15and how best to sequence things.
• 49:18And it's been really great for me
• 49:21over the last 10 years to have
• 49:23such a great team to work with,
• 49:26and also to see so much growth
• 49:29and new treatment options.
• 49:31For our patients,
• 49:32so with that I'll end in leave
• 49:35some room for questions.
• 49:38Thank you.
• 49:44Fuller's courses then at Andrew.
• 49:47Very successful 10 years in which
• 49:51we saw everything changing so we
• 49:54have already a few questions one.
• 49:58Is a. From Doctor Rohit Gupta and
• 50:02the question is would you stop at
• 50:06ease or Bev completely if they do
• 50:10have very cell bleed on treatment?
• 50:15Yeah, you know that's that's a good question.
• 50:17I mean, so I guess the question then
• 50:20is you know if they could be so.
• 50:22I mean, hopefully the risk is very low.
• 50:25'cause if we're selecting the right patients,
• 50:27then hopefully they shouldn't have a bleed.
• 50:29And so I guess the question then you
• 50:31know if someone bleeds where they on
• 50:33anticoagulation do they need to be on
• 50:36an anticoagulation and could they be
• 50:38banded and then be considered back?
• 50:39Kind of in a low risk population you know.
• 50:42I will mention that there was another arm
• 50:45on the study from the Phase one study so.
• 50:48After the arm A was positive,
• 50:50the combination the FDA asked for data
• 50:52for single agent at Easel is a map,
• 50:55so there was another arm on the Phase
• 50:57one study that looked at the combination
• 51:00versus a tease oh alone and you really
• 51:02don't get the same responses with a tease.
• 51:05Oh alone.
• 51:06So I think if you could you would
• 51:08try to continue the you know the
• 51:11combination if if you were able to,
• 51:13you know bans them or you know put
• 51:15them back in a lower risk category.
• 51:18I haven't had that.
• 51:19I haven't been in that situation yet,
• 51:21but I think I think it's something
• 51:23that you know. If we could, we would.
• 51:25We would try to get them back on systemic
• 51:28therapy if they were responding.
• 51:30So
• 51:30let let me ask you a question in this regard,
• 51:34but so outside of a try,
• 51:36we're probably you will have to
• 51:38have a certain month of leeway.
• 51:41You know you probably need
• 51:43to have a recent endoscopy,
• 51:45but we we do have a very well
• 51:48detailed guidelines, so you know what,
• 51:50how many times the patient should undergo,
• 51:53but it's still in the Earth in the
• 51:56Oscar people, very sick screening,
• 51:58you know where they are in.
• 52:01A beta blocker there.
• 52:02Nothing but the blocker, so it's it's
• 52:05a pretty well a detailed protocol.
• 52:08In order for you to put the patient
• 52:11in a in one of such a treatment.
• 52:15What do you need?
• 52:17I mean, do you need somebody who
• 52:19has already done at an endoscopy?
• 52:21Azie anhyzer prophylaxis?
• 52:22Or do you need to have something?
• 52:25A more recent and what are the
• 52:27mechanism of breathing in that case?
• 52:30Yeah, so I mean you know the truth is right.
• 52:33So we treat a lot of other
• 52:35cancers like colon cancer.
• 52:36Bevacizumab is a staple of therapy, you know.
• 52:38Unfortunately we just see bleeding sometimes.
• 52:40You know we see bleeding from the
• 52:42tumor or we just see you know we
• 52:44see other causes of bleeding.
• 52:45So it's not only variceal bleed,
• 52:47you know there was a patient on the study
• 52:49that just had like a abdominal hemorrhage.
• 52:52So you know.
• 52:52So there's always a risk with Bevis
• 52:54ISM AB and let you know when patients
• 52:56are on anticoagulation, right?
• 52:58You have to think about that too
• 53:00if you think they might be having
• 53:02a surgical procedure, right? So?
• 53:03You know there's more thought around that,
• 53:06but but overall you know if they've
• 53:08had an endoscopy.
• 53:09Even if it was a little bit out
• 53:11of six months, but I,
• 53:12but they have a hepatologist following them,
• 53:14who thinks that their risk is low.
• 53:16You know, I think right whenever
• 53:18whenever patients are not on a trial,
• 53:20I think there's always a little bit
• 53:22more leeway kind of discussion,
• 53:24you know,
• 53:24and thinking about each patient,
• 53:26I just think that you know it would
• 53:28be a mistake.
• 53:29I think for an oncologist to treat a patient
• 53:32like this without any hepatology input.
• 53:34You know,
• 53:34and so I think if you at least have the
• 53:37hepatology input of someone familiar
• 53:38with this with this data to really say,
• 53:41I think this patient is low risk even
• 53:43if you didn't do it exactly in the
• 53:45timeframe that was required on the child.
• 53:47I think that's that's fine,
• 53:49you know.
• 53:51Another question,
• 53:51thank you for your answer,
• 53:53and there's another question
• 53:55from Leshan why Japan is excluded
• 53:57and food Japan and US together.
• 53:58Any specific missing?
• 53:59Yeah, I don't know.
• 54:01You know I have a feeling that was
• 54:04more based on how the company
• 54:06was opening the study.
• 54:07Because you're right,
• 54:08I'm not really sure I saw that
• 54:11I saw that also in the trial
• 54:13design and I I don't have a good.
• 54:15I don't have a good answer for that,
• 54:18but I think it probably has
• 54:20to do with where the company
• 54:22is located and how they set.
• 54:25We set up the child because I
• 54:26don't think that there really
• 54:28is a separate signature.
• 54:30OK, more questions so.