Combination Therapy for Hepatocellular Carcinoma: A New Standard

March 19, 2021

Information

Liver CME Symposium | March 18, 2021

Stacey Stein, MD

ID6303

To CiteDCA Citation Guide

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.