Center for Gastrointestinal Cancers CME Series: Gastric Cancers

June 22, 2022

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June 21, 2022 | Presentations by: Drs. Jill Lacy, Dan Boffa, and Marie Robert

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00:00Our group tonight for this CME event.
00:04Sponsored by our Center for
00:07Gastrointestinal cancers here at
00:08Smilow Cancer Hospital in Neoma Haven
00:11Hospital and Yale School of Medicine,
00:13so we're delighted that you
00:16took some time out from.
00:18I know it is a busy time of
00:19year for many to join us.
00:21This evening we're going to be focusing
00:25in on gastroesophageal cancers.
00:28We have three talks tonight.
00:31It will give about 30 minutes
00:33to each with some time in each
00:36session for some questions,
00:37and we'll try to leave some time at
00:40the end for questions as well in
00:42terms of the order of the talks,
00:45we're going to start with Doctor Baffa,
00:46then move on to Doctor Robert
00:48and then myself.
00:50I am doctor Lacey by way of introduction and
00:52I will introduce myself again at the end.
00:56So we're going to,
00:57without further ado,
00:58get started and Doctor Baffa is
01:01going to kick this off this evening.
01:06Doctor Baffa is a colleague that
01:08I work with very closely.
01:10He is professor and chief of the
01:13Division of Thoracic Surgery here
01:15at the Yale School of Medicine
01:18and Cancer Center,
01:19and he is going to be speaking to us
01:22tonight about the impact of recent.
01:25Trials on systemic therapy before
01:28and after esophagectomy.
01:32Thank you very much and again,
01:34thank you to everybody who is joining
01:38either live or after the fact and
01:41I will tell you that I'm a fast
01:44talker and I always give short talks.
01:48So if you feel like you did
01:50not get your moneys worth,
01:51I don't know what to tell you,
01:53but I I will. My e-mail is
01:59daniel.boffa@yale.edu and if
02:00there's anything I say that.
02:02Is unclear or you want to talk more about,
02:04please don't hesitate to reach out to me.
02:07So I have a couple of disclosures, so the.
02:12I'm going to talk 1st about preoperative
02:15therapy and then I will talk about post
02:18operative therapy in patients that have
02:21what is perceived to be resectable,
02:24esophago gastric cancer.
02:26So there was a study,
02:30the CLG B8 O eight O 3 trial that was
02:35pet guided therapy in the preoperative
02:38setting in terms of which chemoradiation
02:42cocktail to be administered.
02:45So this is this is a really
02:48interesting study in my opinion.
02:50I was fortunate enough to
02:53be involved in this.
02:55And I think it's understanding
02:56a little bit of the background.
02:58I think it was a cleverly designed study.
03:00I don't know that it was a huge,
03:02really impactful study,
03:03but I think the study design
03:05was pretty interesting.
03:07So the the fundamental principle that this
03:10was based on is that if you give induction,
03:13chemotherapy,
03:14and radiation,
03:16about 25% of people will sterilize the cancer
03:21within the surgically removed specimen.
03:24But that means that three out of four.
03:25Patients actually have some form of
03:28resistance to that neoadjuvant treatment.
03:31And we know that the best
03:33prognosis is in patients who have
03:35a pathologic complete response,
03:36and so it doesn't take much to connect
03:39those dots that if we can increase the
03:41path CR rate that there's a potential
03:43that we could make people live longer.
03:45And.
03:47Different chemotherapies have been used
03:50for esophageal and gastric carcinoma
03:52and there is potentially a different
03:55mechanism of resistance and so just
03:58because somebody's resistant to one
04:00may not mean they're resistant to both.
04:02So the question is what if
04:04you changed chemotherapy?
04:05If there was a way to know it wasn't working,
04:08could you change it during the neoadjuvant
04:10course to something that's more effective?
04:12So these are the two common
04:15regimens carboplatinum,
04:16paclitaxel and oxaliplatin.
04:19And five FU,
04:21and so they actually do both
04:25have platinum backbones,
04:27but they're they do have different
04:31mechanisms of resistance and so.
04:34This is sort of the founding principle
04:37that if you give a chemotherapy regimen,
04:40we're just going to call regimen a.
04:43And you assess mid treatment pet and if
04:47they don't reduce the Max SUV's by 35%.
04:51So go from 5:50 and a half if they
04:55don't have at least that much
04:58of a response and you keep going
05:01with the same regimen,
05:03then the chance of you having
05:07a pathologic complete response.
05:09Is quite low.
05:13Sorry,
05:13one second here.
05:17It seemed to have. There we go.
05:18It's it's only 5%.
05:21However, if you are giving 1 regimen and
05:25you notice that there's no pet response,
05:27but change to a different chemotherapy
05:31regimen for the chemo radiation phase,
05:34the null hypothesis is that we can take
05:37this 5% path CR rate and bump it up to 20%.
05:41So that was the foundation
05:43for the CL GB study,
05:44and so this was in adenocarcinoma patients,
05:47was a phase two trial they had
05:49to at least be clinical stage T.
05:52To and or have lymph node metastases now.
05:57One thing that's just really
05:59important is you could get into
06:01this trial being a T2 and zero.
06:03That was the the minority of the
06:05patients and I would say this study was
06:08not powered to look at that subgroup.
06:10So just because a group is in a trial
06:12does not mean the trial findings
06:15universally apply to every small subgroup.
06:17I think that's important, and that's
06:20I think been misinterpreted and that.
06:22The patients had have a distal,
06:23esophageal, or GE junction cancer,
06:27and again, as I mentioned,
06:28they would get chemo.
06:29There would be an early pet assessment and
06:32if they had a response you would keep going.
06:36If you didn't,
06:38you would change to another chemo
06:41form of chemo radiation and then
06:44have an esophagectomy and about
06:463/4 of the patients in both arms
06:49went on to have an esophagectomy,
06:51so there's certainly was some fallout.
06:54Between induction and moving
06:56on to Esophagectomy,
06:59and again the primary endpoint
07:01of this study was path CR.
07:03In the patients who were
07:05deemed non responders.
07:06So again,
07:07that's that group we thought would have
07:09a 5% path CR rate and so could we bump
07:12that up by changing the chemotherapy so.
07:16Green is starting with full Fox,
07:19but responding and continuing with full Fox.
07:24The the yellow is starting with folfox,
07:27but then changing the carboplatin paclitaxel
07:30blue is starting with Carbo Taxol,
07:33and if you continue in blue
07:36then you were responder.
07:37If you did not respond,
07:38then you changed a full box.
07:41So if you look at the path
07:43CR rate in the responders,
07:45there's a pretty big difference.
07:46So of the people that got folfox,
07:49these are adenocarcinomas.
07:50If you started with Folfox and you
07:54responded and that was 73 out of
07:57129 were responders and you kept
07:59going the path CR rate was 40%,
08:01so that's pretty good.
08:02So that's higher than that
08:0425% historical number.
08:07If you started with carboplatin,
08:09paclitaxel, and you responded and kept
08:12going with Carbo Taxol, you're past CR.
08:15It was 14%.
08:16That's pretty darn low,
08:18and I'm going to give you some context
08:20in terms of other recent trials.
08:23Now, the non responders.
08:24Now this is the group we
08:26were trying to bump up from.
08:285% so if you started green,
08:31if you started folfox,
08:32you were deemed a non responder
08:35and changed the path CR 8.
08:3718% so that's pretty darn close to 20%.
08:41And however, if you were a
08:43non responder to carboplatin,
08:45paclitaxel, and you switched,
08:47you actually got 20%,
08:49so this was actually.
08:53This actually met criteria for both arms,
08:55so this was actually a positive study.
08:57Again, because we were expecting a 5%
09:00path CR rate from historical data and
09:04both of these were significantly higher
09:06than what we would have anticipated.
09:08So I'm just some stats from CL GB 80803.
09:13The complete resection rate.
09:14So granted 3 out of four patients that
09:17started in each arm went on to get
09:20into Sophie Ectomy the path CR that
09:22the complete resection rate was 94%.
09:24That's pretty good.
09:25That's that's pretty average.
09:27The mortality rate.
09:28This is the 90 day mortality rate is 3.3%.
09:32That's quite low,
09:33so in the French and German trials though,
09:35they had double digit 30 day mortality.
09:39So this is quite low.
09:40Usually the 90 day mortality
09:42mortality is twice the 30 day
09:44mortality and so this is quite low.
09:46Five or six started with
09:49Carboplatinum paclitaxel,
09:50so that's I think that's just a statistical.
09:52I think that's just an aberration,
09:54but maybe a light signal and the five year
09:57survival for this study was about 45%.
10:00So if you look at the difference
10:04between responders and non responders.
10:07So again, how did people do based
10:09on whether they respond to that?
10:11Early pet, the responders,
10:13as you might think,
10:15would have had a better outcome.
10:1949% five year survival versus 39% and
10:22the median survival was almost twice as long.
10:25Now if you look at the
10:27different treatment groups,
10:29so the red is full fox.
10:33The dash is responder the the
10:36solid line is the nonresponder,
10:38so you can see those are the those
10:41are wider than the blue lines,
10:43which are the people that started
10:47with carboplatinum paclitaxel.
10:49So here's how I put this study
10:52together so that that if you the
10:54path CR was more likely if you
10:56started with full fox of all the
10:59patients that started with full Fox,
11:01they were more likely to have a path CR.
11:04So when you combine an average
11:06this out 31% versus 14% in the
11:10carboplatinum paclitaxel group,
11:12Now this is a bit odd because sorry,
11:16the in the cross trial which was.
11:19Carboplatinum, paclitaxel,
11:20the all the way through the
11:23paths CR8 was 29%.
11:25So something's funny in that 14%.
11:27So it's hard to know what to make of that.
11:30But at least in the in this study
11:33there was a difference based on
11:35whether you started with folfox
11:37or carboplatinum paclitaxel.
11:39But paths yard does not tell the
11:41story because when you actually
11:43look at the overall survival,
11:45this is the five year overall survival.
11:48The the.
11:49The mustard and there's probably
11:51a fancy name for that color.
11:54Maybe no, I forget what you call that color,
11:58but brownish yellow, the.
12:03They're both around 4142%,
12:06and if you look at the Greens,
12:08the full fox patients,
12:10they're all in the same ballpark,
12:12so I don't think if anything
12:14you know we were.
12:15We were expecting this this carboplatin
12:18group, which went all the way
12:20through without a Pats CR of 14%.
12:22They still had a 44 percent five
12:26year survival, so path CR definitely
12:29does not tell the whole story.
12:32Now the other question is this study.
12:34The biggest part of this study was a pivot,
12:36meaning if you use a pet to change
12:39what you're going to give people,
12:42does that help you know?
12:43So these were two common chemotherapy
12:46regimens used with radiation
12:48that there was a pivot in place.
12:50So with this pivot,
12:51did we make anything better?
12:53So overall, the five year survival
12:56in this study was about 45%,
12:58so the pivot gets you about 45%.
13:01However, the cross trial,
13:04it's pretty much the same,
13:05and there that was carboplatinum
13:07paclitaxel all the way through,
13:08so it's hard for me to say that
13:11using PET to guide your therapy,
13:13at least in this context,
13:16that it really changed the overall survival.
13:19Now that that doesn't mean that
13:21there's never a role for this,
13:23but it does mean pivoting
13:25between these two regimens,
13:27carboplatin and paclitaxel, and full fox.
13:32Using trying to mimic this and thinking
13:34you're going to make people live longer.
13:37I think that's that's a hard sell.
13:39So what are the take home messages
13:41that the pet does predict?
13:43Resistance?
13:43So I think that of the non responders in
13:46general they had lower response rates.
13:49So if there was a better pivot,
13:52potentially this this there is potential
13:55for pet early pet response to predict
13:59overall response to chemo radiation.
14:03I think that this adds to a signal.
14:06Now, again,
14:06this is a very soft call,
14:08and and Jill I'd love to
14:09get your feedback on this,
14:11but I think this adds to a signal that
14:13if you have a squamous cell carcinoma
14:16that that really carboplatinum
14:17paclitaxel makes the most sense
14:19and so this is the cross study.
14:22Again,
14:22this is I'm just saying it adds to a signal.
14:24I'm not saying that this is an
14:27absolute but this is the the the
14:31squamous cell that got chemoradiation.
14:33And squamous cell that got surgery only.
14:35And you could see how wide apart those
14:38bars are. The lighter Gray bars.
14:41Those are the adenocarcinoma with
14:43and without induction therapy.
14:46So I think this is pretty impressive
14:49that with squamous cell the induction
14:52carboplatinum paclitaxel really
14:53does have a profound widening.
14:56I think this adds to a signal
14:59that full Fox is better with AD.
15:01No that compared to.
15:06Carboplatin,
15:06paclitaxel,
15:07there are studies like protect
15:10fourteen O2 that are going to compare
15:14different induction regimens,
15:16but I think this adds to that signal.
15:18So why do I say that?
15:19So if you look at the full fox,
15:23the people that started with full
15:26Fox the the lines are just more
15:29separated based on response,
15:31and so I think it does a better
15:33job stratifying people that are
15:35going to respond and not respond.
15:37So again,
15:37that's not telling you prognostically,
15:39it's just saying if the whole point of
15:41this study is to be able to separate
15:43responders and non responders,
15:44it's the the pet format.
15:47Seems to be better with folfox.
15:49The blue lines are people that
15:51started with carboplatinum paclitaxel.
15:54This is the cross study and if
15:58you this is the forest which
16:01basically looks at unplanned,
16:02these are unplanned subset
16:04analysis from the cross study.
16:07This is old now, but if you actually look
16:10at by the Histology and and to be clear,
16:13the majority of these patients
16:15were adenocarcinoma patients,
16:16it actually was not statistically
16:19significant in the ADNO group.
16:21Clearly the mortality reduction.
16:24Is less impressive in adeno
16:27versus squamous cell, so again,
16:29I'm not saying it's wrong to give
16:32carboplatinum paclitaxel to adno,
16:35but I do believe this the the CGB study
16:38adds to a signal that in adno full
16:41fox is actually a better way to go.
16:44So now I'm going to pivot to
16:47postoperative therapy and I'm going to
16:49talk just briefly about checkmates 577,
16:51and this was giving nivolumab
16:54after completely resected,
16:55so they had negative margins.
16:59Esophageal cancer that had
17:03some residual disease.
17:05They were not anybody.
17:06That was anything other than a
17:08pathologic complete responder.
17:10So this this they accrued between 16 and 19,
17:15a lot of different centers.
17:17They had to be clinical stage two or three.
17:20They received induction chemo
17:23radiation with two common backbones
17:26of chemo that was platinum based.
17:29They again they had to have
17:32a complete resection.
17:33No positive margins and then they
17:36were randomized whether or not to
17:39start between one and four months
17:41after the complete resection,
17:43and again they had to have some residual
17:45disease in the pathologic or specimen,
17:48so it could not be a a a complete
17:52pathologic response. And so.
17:56It was nivolumab for four months.
18:01That was given every two weeks and
18:03then it became monthly after that and
18:06it continued either to progression
18:08or if it was terminated for toxicity
18:12or patients got to a year and again.
18:15This was designed for disease free
18:18survival and so this just highlights
18:22where the patients came from the.
18:27About 40% were from Europe.
18:3160% were esophageal and 40%
18:34were gastroesophageal junction.
18:3871% were adenocarcinoma.
18:40Now the the PDL 1 count so was
18:46about 16% were PDL 1 positive.
18:49Now that's different.
18:50Something Doctor Robert is going
18:52to talk about which is a which
18:56is a complete positive score.
18:59A composite positive score which is a
19:02different and in just to be clear in a
19:05post hoc analysis the that score was.
19:07Positive in about 57% had five
19:10or more percent cells positive,
19:12so this looks like there was
19:14very little PDL one.
19:15But actually when you use the.
19:18The composite score it's actually was higher.
19:25So the. So this was well tolerated so the
19:33there were no grade 5 adverse events.
19:38About 1/3 of patients had any
19:40three or four adverse events.
19:42It was actually pretty similar between
19:44the placebo and then the volume Nob arm.
19:46This continued treatment.
19:49Was 9% in the Nomad and 3%
19:53in the placebo group. Umm?
19:58The sorry, so when we look at disease
20:03free survival, the blue line is the
20:05nivolumab arm and the red line is placebo.
20:08So you can see there was a really
20:10significant difference in the disease.
20:12Free survival if you look at the median
20:15disease free survival in the nivolumab group,
20:19it was basically twice that
20:21of the placebo group.
20:24When you look by Histology so.
20:28The the the the blue lines are
20:32the patients who got nivolumab.
20:36The red lines are the placebo groups and when
20:40you actually just break it down by Histology.
20:44So if you look at adenocarcinoma,
20:46the median disease free survival
20:48was 19 versus 11 months.
20:50And when you look at
20:51squamous it was actually 29,
20:53almost 30 months versus 11 months.
20:57Which is something we've seen
20:59before where there seems to be a
21:02little bit more activity in the
21:04squamous cell patients and again,
21:0570% of the patients in the
21:08study were actually adino.
21:09When you look at the forest plot again,
21:11these are all unplanned subset analysis.
21:15When you look at Adno versus Swain,
21:18they were both significant.
21:21Adno was flirting with a non
21:25significance but was significant.
21:28When you look at PDL one,
21:30so the people that had PDL 1 less than
21:33one now granted this is probably just
21:36a power analysis but the people with
21:40PDL 1 less than one it was significant
21:43but they had 600 patients versus the
21:46patients who were greater than one
21:48and these are tumor cell PDL one.
21:50It's it actually was not significant.
21:53That doesn't necessarily make sense,
21:55but I think it's got to be a power issue.
21:58And interestingly,
22:00if you the people who had node
22:05positive pathologic specimens,
22:07they seem to do a little bit
22:09better and have a bigger impact.
22:10The people that were no negative.
22:12Actually it did not reach significance.
22:14And again these are unplanned
22:16subset analysis.
22:17So it's I don't think these
22:19should be practice changing,
22:21but should inspire future
22:24deliberation and future trials.
22:27And if you were really on the fence.
22:29As to what should somebody get
22:31immunotherapy if they were in a group
22:33where there really wasn't significance,
22:35I think you can.
22:37That's one perspective to consider.
22:40Older patients we've seen this before in
22:44different immunotherapy adjuvant trials.
22:47the IT was not significant,
22:49although it was a.
22:50A hazard ratio less than one and this
22:53very well may have been a power issue,
22:56but again, if you had an older
22:58patient and you were on the fence,
23:00you know I think you could.
23:02You can consider that the
23:04impact might be less,
23:05and if you're her two positive.
23:10This was a very small group.
23:11There were only 63 patients so I don't
23:14know how much stock to put into this,
23:17but just something to think about.
23:19So there are a couple of there's
23:21a bunch of ongoing studies.
23:23These are a couple interesting ones,
23:25which is flot versus Cisplatinum 5 FU and
23:30in patients that have resectable gastric
23:34and GE junction cancer,
23:36getting adjuvant Pembroke
23:38versus placebo and then keynote.
23:41975, which is for either people
23:44who are have unresectable disease
23:46or don't want esophagectomy,
23:48which I don't know why anybody
23:50wouldn't want an esophagectomy I
23:52giving definitive chemoradiation
23:53again with a one of the common
23:57backbones and then Pembroke or
23:59not so a lot of information.
24:02I appreciate your time.
24:04So this was a a chemotherapy talk
24:06by a non chemotherapy ologist
24:08so take it for what it's worth.
24:11But again,
24:12thank you for your your attention.
24:17Dan, thank you. That was great.
24:19Really nice review of
24:21some very very important.
24:23Studies, one of which is clearly
24:25practice changing adjuvant neevo
24:27huge advance in the field and
24:29advance that we've been waiting for
24:30for I think a couple of decades,
24:32so really exciting to have the adjuvant
24:35therapy option with the volume
24:37up in these patients we are happy
24:40to take questions in this format.
24:43It's in the chat box so please put
24:46any questions in that you may have.
24:50Dan, if I may, I have. I have a couple
24:53of for for you, so the C LGB study.
24:59Left us hanging with a lot
25:01of unanswered questions.
25:03And and wish A wish list for maybe
25:04how they had designed the study.
25:06But one just your opinion on
25:09the the question of induction,
25:11chemo versus prior to chemo radiotherapy.
25:15There's been no study that's compared
25:17adding induction chemo priority if
25:20therapy versus just chemoradiotherapy
25:21followed by esophagectomy.
25:24It's from a pragmatic perspective.
25:26We find it useful to start
25:28with induction, chemo,
25:29because often dysphagia resolves rapidly,
25:31so we do it pretty routinely,
25:33and I think based on the study you reviewed,
25:36we have shifted towards full
25:38Fox in the adenocarcinomas.
25:42Do do you have an opinion?
25:44I'll just I will just ask for
25:45your opinion on whether you think
25:47induction chemotherapy is important.
25:49The survival statistics from
25:50that study were impressive.
25:51I think better than prior studies.
25:54Could that in part be due to the induction.
25:58The inclusion of induction, chemo?
25:59Or do you think it just has
26:01more to do with maybe full Fox
26:02in the adenocarcinoma subset?
26:05So, so the fact that there were that that
26:09you know roughly 1/4 of patients did
26:13not get an esophagectomy could be that.
26:17You know, anytime there's attrition
26:19that could be could be appropriate.
26:22Patient selection patients progress and they
26:25avoided a surgery that didn't help them.
26:28I think in my experience there are
26:32definitely patients who achieved a a
26:35superior nutritional status and had a
26:38they were better surgical candidates,
26:40ultimately because they got induction,
26:42chemo and then moved on to chemo radiation
26:45instead of just getting hammered right away.
26:48Clearly there also had patients that
26:50got so much chemo by the time they
26:52got to the operating room they were.
26:54So they just really didn't.
26:55They distorted, never recovered.
26:57And it and it increased the risk.
26:59And so one thing I love about Connecticut,
27:04I've practiced in a couple of
27:06different places.
27:07The medical oncologists have been really
27:09engaged and just say you know and I and
27:11been really open to this conversation.
27:13And often, you know,
27:14there's no scientific way of doing this,
27:16but but a gestalt of are they?
27:20What's the regimen that's going to really
27:21get them to take advantage of all modalities?
27:24And so I do think if they're
27:26obstructive and then nutritions.
27:28An issue trying to optimize them,
27:31I think in our experience the
27:33induction chemo is very effective.
27:36But I do think there are people who
27:40just get so debilitated from all
27:43of the induction to try to to to
27:45identify those people so that they
27:48don't miss out on an opportunity
27:50of a curative and resection.
27:54I have a question before we let Dan go,
27:59I don't know how close to this part
28:01of the data that you might be,
28:04but in the trial with Nivolumab did anyone
28:08have to withdraw due to immune related
28:12adverse events from the checkpoint?
28:15Or was there a significant?
28:17Was there any incidents or could
28:19you talk about that at all?
28:22Great question and and I'm gonna.
28:24I'm Jill is going to know exactly
28:27what I'm talking about here,
28:29but we so. So in the trial,
28:33discontinuation of therapy was about
28:3510 percent 910% and and I would say. I,
28:40I think that is an overly optimistic number.
28:44We've now had the advantage of seeing people
28:48on on nivolumab after Esophagectomy and
28:50I I don't think it's a walk in the park.
28:54I think it's tolerated,
28:56but I think it does. You know?
28:58Unlike because we've because I
28:59do a lot of lung cancer and we
29:02give a ton of immunotherapy.
29:03I personally think it is a it is a
29:06real thing to go through immunotherapy.
29:10After off Ectomy and I would guess
29:14that that more than 10% of people
29:18have a hard time with it.
29:20But but Joe, what?
29:21What is your sense of that?
29:25This is a learning curve for all
29:26of us because this is very new,
29:28so I I think we don't have vast
29:31experience yet in that study I
29:33think was about 10% discontinuation
29:34for treatment related areas,
29:36and I would imagine that most of
29:38those were felt to be immune related.
29:40So I mean, I think in general we
29:41think Nevo is a well tolerated drug,
29:43a single agent with a low incidence
29:46of serious immune related AE,
29:48but I think you're right, Dan.
29:49This is a new patient population.
29:51We've not done this before in large numbers,
29:52so I think to be continued,
29:55we'll we'll have to see how it plays out.
29:57Just one final question,
29:58and maybe this is the lead in for
30:01Marie's talk you you you showed
30:02some of the information about
30:04PDL 1 scoring in this study?
30:06Was that done in the post treatment
30:08Pathologic specimen stand?
30:10Do you know off the top of your head?
30:12Yeah, that's a great question, I don't know.
30:15Because, you know, going to,
30:18I think educate us all about some
30:20of the challenges with PDL one,
30:22but I think 1 issue is that.
30:26We don't really have a.
30:27I don't think a clear understanding of
30:29what we would see with PDL 1 scoring
30:32pretreatment and then post chemoradiotherapy,
30:34but you have to imagine it's
30:36going to affect the results.
30:37So all right, Dan,
30:39thank you very much.
30:40That was really a great review
30:43of really important studies.
30:44So we're going to move on to our second talk.
30:47We're going to shift directions now and
30:50take a very deep dive into immunotherapy.
30:53And as I think, most of you know,
30:55in the last two years we have
30:57heard a lot about immunotherapy
31:00and gastroesophageal cancers.
31:02And we are deploying it quite regularly
31:04now in the first line setting.
31:07And there's a lot of chatter about.
31:10How do we use PDL one as a
31:14predictive biomarker in choosing
31:15an patients for immunotherapy in
31:17the first line setting and beyond.
31:20And Marie is going to shed some
31:22light on that very confusing topic.
31:25And then with that backdrop then I will
31:27then review some of the more recent studies.
31:30So Marie Doctor Robert,
31:32another wonderful colleague of mine that
31:35I get to work with on a regular basis.
31:37Is professor of pathology,
31:39medicine,
31:39and human and translational immunology here.
31:42And she directs our GI pathology program and,
31:45very importantly and relevant to her topic.
31:48Tonight she is Co leading an important
31:52international study on interobserver
31:54agreement in PDL one CPS scoring
31:58and gastric cancer, so Marie.
32:00Thank you.
32:02Thank you so much, Jill.
32:04And I'm still smiling despite
32:07being on doing that study.
32:10OK, so I think you can see my screen.
32:14Well, I'm delighted to be here with you
32:18today in person and those watching later on.
32:20And I want to thank Doctor Lacey for the
32:24invitation and Doctor Boffa for sharing the.
32:28Virtual podium this evening.
32:31I hope that I will only spend about 20
32:35maximum 25 minutes discussing really the
32:38inside baseball nitty gritty in the weeds.
32:43What does it mean to score a
32:46PD1 immunohistochemical stain
32:48in gastric cancer and this would
32:50apply to other tumors as well,
32:53and so the subtitle is the challenges and
32:56interpretation and how for a clinician,
32:58how should one decipher the report?
33:00These are my disclosures.
33:02So by way of outline,
33:04I'm just going to spend a moment just
33:06second on things you already know,
33:08way better than me.
33:09The rationale for blocking PD one
33:11receptors on immune cells in cancer.
33:14Spend the bulk of the time talking about.
33:18An overview of the development of the
33:22PO1 immunohistochemical stain as a
33:25companion or complementary diagnostic
33:27for the use of checkpoint inhibitors,
33:30and we're really going to look very,
33:33very intensely at how Pedial Wednesdays
33:35are interpreted at the microscope,
33:38and I will show you examples and
33:40ask you to do this with me.
33:43And in doing so, I hope to.
33:47Sort of.
33:48Unveil the challenges in applying
33:51the scoring criteria that are
33:53recommended by the Agilent Dako
33:56group for two are proportions.
33:59Score what we're really about today.
34:01The combined positive score and all of that
34:04is about scoring tumor cells in immune cells.
34:07And this will get to the question
34:10of Interobserver agreement and
34:12reproducibility of results.
34:13Finally, I'll hope to help decipher reports,
34:17at least the Yale reports and.
34:20Touch on what I think would be,
34:22I think what everyone thinks who does
34:24this for a living is what would be great.
34:27A future directions.
34:29So this is the tried and true example.
34:33There's a cartoon.
34:34There are many.
34:35This happens to be photos from the Agilent
34:38Vehicle Training manual for pathologists.
34:41I, just to remind everyone what are we?
34:43What are we standing here?
34:44What are we talking about?
34:45So PDL one and also PDL 2 Stanford
34:49Program cell death ligand.
34:51So the ligand is the thing
34:53sticking out of the cell.
34:55On the membrane and it's expressed
34:58normally in normal cells,
35:00normal immune cells,
35:02epithelial cells,
35:03fibroblasts and endothelial cells
35:05and the ligate.
35:07The the receptor for this to the PD
35:09one which is the program cell death
35:12receptor is expressed on the surface of.
35:15Inflammatory cells CD 4 positive and CD
35:178 positive T cells natural killer cells,
35:20B cells,
35:22macrophages,
35:22and dendritic cells and in health.
35:26The purpose of the PD one ligand
35:30is to bind to a T cell receptor
35:35and and and tell it I'm OK.
35:38This is me.
35:39This is you stop and cease and desist friend.
35:43And this prevents autoimmunity.
35:48Interesting when that breaks down not just
35:50because of drugs but from other diseases.
35:53The then you can get bad autoimmunity.
35:57It is one of the mechanisms actually.
35:59As a side point is there's the
36:01CLA 4 deficiency that can lead
36:02to severe colitis, for example.
36:05But in tumor growth,
36:08some tumor cells develop the ability
36:11and mimic normal cells by up regulating
36:14PD1 ligand on their membranes,
36:17and then they trick the cytotoxic T
36:20cell which binds via the PD1 receptor
36:23and it activates the cytotoxic T cell
36:25which is supposed to recognize this as
36:27something that doesn't belong and kill
36:30it and so you all know this very very
36:32well and therefore the the rationale behind.
36:36Anti PD One therapy is to give an
36:40antibody that will bind instead of
36:42the PD one ligand on a tumor cell
36:45will block these receptors and allow
36:47these cells to then not to say,
36:50hey, you're not me,
36:51you're not self and and attack.
36:53That's the rationale.
36:57So. I'm trying to put my pictures somewhere.
37:03This led to this these the discoveries
37:05about this, the wonderful science,
37:07some of a lot of which done it, Yale.
37:11The development led to the development
37:13of immunohistochemical PDL.
37:15One stain as a companion or companion
37:17meaning companion diagnostic means.
37:19If you don't have this result you
37:21can't give the drug or complementary.
37:23We want to know the result,
37:24but either way we'll still
37:26use the drug diagnostic,
37:27so immunohistochemical stains
37:30if you don't know, they're very.
37:31I think you all do.
37:33These are these are a series of
37:36antibodies linked together to identify
37:38a molecule on a formalin fixed,
37:40or it could be frozen,
37:42fixed piece of human tissue or any
37:45tissue that is in mostly in this setting.
37:48Formalin fixed and paraffin
37:50embedded and cut onto a slide.
37:52And this is the of course on the
37:54manual they show beautiful stain.
37:56This is an example of a PD.
37:58One stain on a cancer and you see
38:02the brown is positive stain and
38:04it's outlining the cell membrane,
38:06so it's membranous, strong,
38:08membranous staining.
38:09If anyone looks at her too immunostains,
38:12it's very similar when it's this strong,
38:14it's similar to what up 3 plus positive
38:16her two stain would look like strong
38:19member to staining on tumor cells.
38:21OK,
38:21but that's the manual.
38:22And then there's real life so,
38:25but this development,
38:26I was very successful and LED
38:29to in 2015 the Deco,
38:31which is bought by Agilent few years later.
38:37Firm DX anti PD122C3 assay which
38:40was first developed and FDA
38:42approved for lung cancer in 2017.
38:45The combined positive score
38:47I'll be defining all of this.
38:49Was FDA approved for gastric and GJ
38:52had no person Noma after phase two?
38:55Keynote 59 trial.
38:59So Agilent or Dayco developed
39:02and and but this this.
39:05This approval was based on pathologist at
39:08Merck and I'll talk about this in a moment.
39:11The the scoring, the the the putting
39:14together of combined positive score.
39:16What was it? How to do it was done in
39:19the confines of a single company Merck.
39:22And and the FDA approved their methodology.
39:26That's how that got going.
39:27That's how CPS came to be as a requirement.
39:31Was not tested outside of that.
39:34It's important to know that so,
39:36but nonetheless,
39:37Agilent then developed training
39:39modules for work and day pathologists
39:42like myself and others to to
39:45train and learn how to look at.
39:49Video 1 stains and produce these scores from
39:52the methods developed in house at Merck.
39:55I will just mention that now
39:56there are multiple antibodies.
39:57I purposefully mentioned the specific
40:00antibody 22 C three because that's
40:02the one that was approved by the
40:04FDA for this purpose and with CPS
40:07score and also TPS and inland.
40:09There are multiple antibodies available
40:11and at Yale we use the E1L 3N.
40:17Antibody that has been shown to have a
40:21homology and to work equally well as 22C3,
40:25and there's also 28 eight SP 142.
40:28Many proof of concept studies since
40:30I was not involved in those I
40:33feel I can brag for my colleagues.
40:35We're actually performed by Yale Smilow
40:38and pathology department faculty,
40:40and so it's a nice legacy of progress.
40:47But I think it's important
40:49is so so.
40:52Those of us who look at this stain
40:55on a daily basis have come to,
40:57I would say almost universally,
40:59across the United States.
41:00In any case, and opinions are
41:02slightly different in Europe from the
41:05pathologist with whom I interact with.
41:09That what we are having trouble.
41:12With reproducibility and with
41:14frankly performing the stain as it
41:17is laid out in the in the guidelines,
41:19I just like to share this with you.
41:21We do it, we we we do our very best.
41:25We follow the guidelines but I would
41:27like you to know about some concerns.
41:31About relying on this immunostain
41:33because I think we can move on,
41:35hopefully in the not so far
41:37future to something else,
41:38so it starts back from 2017 at ASCO.
41:41This presentation by Merck about
41:43the development of the combined
41:45positive score for the evaluation
41:47of PD one and solid tumors.
41:49Using this antibody and what they
41:51discussed is that they had an
41:54interobserver agreement amongst
41:56their pathologists of 88%,
41:58which sounds pretty good further.
42:00For a cut off of of Cpia score of 1,
42:05about 57% of the gastric cancers in
42:08their hands had a positive score.
42:11I've seen in in the literature
42:13and I would say in our hands it's
42:15somewhere more between 30 and 50%,
42:18but that's what they found.
42:20So that's interesting that in their
42:23hands they got an 88% agreement.
42:25As at a cutoff of 1. But what what?
42:30There are a few questions that this
42:32raises once we get into start doing
42:34this as we've been doing for some years now,
42:37there's not much data on agreement
42:38at other cut offs,
42:40nor at what if and what if the
42:43case will come,
42:44which it may be coming that oncologists
42:46would like to have an exact value,
42:49not a cut off,
42:50like greater than one greater
42:51than five greater than 10.
42:52But was it 8 or 45?
42:56And and I've heard I'm in discussions
42:58now with with.
42:59Gynecology here at Yale about what
43:01we should be providing and this
43:04is because the indications keep
43:05changing and there's new protocols
43:07and wonderful opportunities for
43:09patients to be treated with these
43:12medicines that may or may not depend
43:15upon certain criteria of MCPS.
43:18And I'm just very curious.
43:20I think we have the answer and
43:21we ask this question.
43:22How does agreement on combined
43:25positive score differ?
43:26From agreement on tumor proportion score,
43:29which is simply the percent of
43:30positive tumor cells over the
43:32total number of tumor cells,
43:33simple straight percentage and the
43:35hint is you're not surprised by this.
43:37You already know is that pathologists
43:40agree much better on TPS.
43:43If you have 10 pathologists look at
43:47the same sample then they would on CPS.
43:50We're going to go into why?
43:52But the the other you know concepts
43:54to to put out here is when when one
43:57puts out in an abstract that hey,
43:59this works and there's great
44:02interobserver agreement, well.
44:03What was your training methodology
44:06in this specific setting and what is
44:09the training methodology in the the
44:12rest of the world and in practicing medicine?
44:14In fact,
44:16the methodology is voluntary.
44:18It the rigor varies widely,
44:20there's no requirement that that
44:22it's not registered with the
44:24FDA that we've done our training or not.
44:27This is honor system,
44:27so we've all done it all the graphologists
44:29if you all have gone through the training,
44:31but there's no requirement that
44:33you repeated every year.
44:34What about drift over time after training,
44:36so it's there's a lot of questions.
44:39And the unfortunate fact that we
44:41seem to notice is that many samples.
44:45Hover near the cutoff so when it's
44:48negative we're all in agreement.
44:50When it's wildly positive,
44:52and clearly you know.
44:541020, etcetera score that's easy
44:56because you're way above any cut off.
44:58But we do have many samples that
45:00hover near a CPS cutoff of 1.
45:03And I know new cut offs of five are coming.
45:06I'm just going to highlight here.
45:07This is the manual that we use,
45:09and I'm going to show some figures and and
45:13language from this from the Agilent Deco.
45:16This is what we read and is a gorgeous
45:18picture of PD one standings pristine
45:20and I'm also going to use material
45:23from a book written by friends of Mine,
45:26Sunil,
45:26Bobby and George Kumar predicted biomarkers
45:29in oncology and this is an excellent.
45:32Treatise of the topic.
45:36This is not to get into the test
45:40tube and pipette phase of things,
45:43but it is important that we all remember
45:46that in any test that's done in a
45:49laboratory there are called there's
45:51a quality assurance aspect and this
45:54is they they in in the and kumars
45:56book they talk about the predictive
45:59biomarker quality assurance cycle,
46:01and I think it's important to know that
46:03when you're taking a sample from a patient.
46:06Usually in this setting it's an
46:08endoscopic mucosal biopsy that
46:10undergoes tissue processing,
46:11first in formalin and through
46:13a series of solutions.
46:14In the regular Histology laboratory
46:16that have to be controlled.
46:18It's put into paraffin, cut into sections,
46:22and then that's the tissue processing.
46:24The pre analytic phase.
46:25Then there's sustaining the
46:27analytic phase that has.
46:28There has to be QC and quality assurance of
46:32both the controls and the test tissue sample.
46:35And then there's post analytic.
46:37That's the interpretation,
46:39scoring and reporting.
46:40So what kind of QC can we really apply?
46:43And that's a question to pose
46:46yourself when I take you through this.
46:48All of this leads to.
46:49No matter what.
46:52A decision for a patient.
46:54So think about compare this if you will
46:57as I go through what goes into this.
47:00The result of a CPS score,
47:03for example,
47:04compared to a chemistry test of
47:06a blood test in the lab and and
47:10what kinds of decisions might be
47:12made and how that's done.
47:15I won't walk through all this side,
47:17but but just to say those people
47:19who do just know that at the
47:21back of a test like this one and
47:24and hopefully every other one.
47:26Is a whole are people who understand.
47:29What needs to go into the pre
47:32analytic analytic and post analytic?
47:34Quality checks such that there
47:36are things that would indicators
47:38of unacceptable results that would cause us
47:40to pause and not report that and start over.
47:43I just want to highlight one here.
47:45Quality of tissue morphology.
47:49So the tissue morphology in a biopsy.
47:53Is is sort of decided by things that are
47:57out of our hands that they're sample.
48:00How much tumor is in it versus
48:02normal benign or incites?
48:04You crush artifact from the biopsy,
48:07forceps, necrosis,
48:08thermal injury if caught early was
48:11used in obtaining the specimen,
48:13so we have no control over
48:15this and we we don't.
48:17We try very hard not to ask folks
48:18to go back and get more samples and
48:21put patients through procedures.
48:22We deal with what?
48:23We have by and large and do the best we can,
48:26but it's something to know about,
48:28so these are some statements from the.
48:31Agilent Manual and this is the the most
48:35important equation that we are are
48:37living by for gastric and GJ cancer.
48:40So what is the combined positive score?
48:42It is as you know the number.
48:45Of Pedial 1 staining tumor cells,
48:49lymphocytes and macrophages over divided
48:51by the total number of viable tumor cells,
48:56and then we multiply that times 100 so
48:58you can see that we we ought to be,
49:00you know,
49:00shouldn't be too hard to get to
49:02something greater than one because
49:03we're multiplying by 100.
49:04So they they want us to get to 1.
49:08So let's take some definitions now for PDL 1,
49:11scorning tumor cell.
49:13OK, well, what is that?
49:15Well, it sounds pretty obvious,
49:16but there are some caveats.
49:19Not inside you, not dysplasia or carcinoma,
49:22incites you and in the esophageal cancer
49:24or gastric cancer coming from a backward,
49:27often a dysplastic background on
49:29top and the superficial mucosa
49:31that is not to be counted,
49:32and that is to be distinguished
49:35from the invasive self coming right
49:37off of that inside your component.
49:40That's very challenging at times.
49:43Areas of necrosis are to be avoided
49:45and one must have a minimum of 100
49:48viable tumor cells in the sample.
49:51To to perform the stain.
49:54What is an immune cell for the purposes
49:57of this for CPS it's consists only
50:00of lymphocytes and macrophages,
50:01plasma cells and neutrophils
50:03are not to be counted.
50:05Those are very common cells in the mucosa,
50:07especially plasma cells,
50:08fibroblasts and endothelial cells which
50:10are not inflammatory cells but are other
50:12stromal cells are not to be counted.
50:14All of these things can pick up stain.
50:18All of them can pick up a PD.
50:20One stain can be positive.
50:23So we already said what 2 reports and CPS is.
50:26I want to just point that outside
50:28of the GE of the GE junction and
50:31gastric cancer in the GI tract,
50:33we're doing PD one on many things
50:36and there because CPS or TPS
50:38have not been codified.
50:40We report simply the percent immune
50:42cells and percent tumor cells staining,
50:45and we'll talk about that
50:46when we get to reports, OK?
50:48Fine,
50:48so that's those are our marching orders.
50:51How do we do it?
50:51Well,
50:52the minimum of 100 cells we
50:54look at various magnifications.
50:56This is important if the specimen includes
50:58more than one biopsy in the in the jar,
51:01which it always does.
51:03And we put all that on one slide,
51:05all the tissue on the slide
51:06needs to be evaluated.
51:07Generate a single CPS score.
51:11And if we're doing it on a resection,
51:12the entire every single tumor cell,
51:15every immune cell should be evaluated.
51:17And that's when in tumor.
51:19We have a lot of of a little table
51:22of dos and don'ts include and don't
51:25include in the numerator and denominator.
51:28For immune cells.
51:32And specifically, what are we grading?
51:35Well, for tumor cells we're
51:37looking at membranous staining,
51:38only not cytoplasmic.
51:39And we are to count a cell as
51:43positive if it has any partial.
51:46Or complete linear membrane staining.
51:48So half the cell or the whole cell.
51:50Any part of the cell any
51:52membrane is staining.
51:53Of greater than one plus intensity.
51:57So what's interesting is
51:58that this is not defined.
51:59This is a completely subjective
52:011 + 2 + 3 plus partial complete.
52:06And for the immune cell lymphocyte
52:09or macrophage membranous staining
52:12and cytoplasmic staining count,
52:14again with with any basically
52:16any amount of staining.
52:17You're to count that cell.
52:19So let's go through now and see how to
52:22do this with some real world samples.
52:24Here's a biopsy set of biopsies
52:26all in one jar,
52:31123456789, ten eleven you know 12 ish.
52:34Biopsy fragments of various sizes.
52:37I can tell at this magnification that
52:39they basically all came all have tumor
52:41in them is very generous endoscopist,
52:43so we're meant to do an immunostain and
52:46count every single one of these pieces.
52:48So let's see how that's done.
52:50This is one piece at a
52:53slightly higher magnification.
52:54The bigger poofy cells are tumor cells.
52:57The small purple dots are inflammatory cells.
53:02Here it is at higher magnification.
53:04These are tumor cells the the bigger cells,
53:06they're bigger nuclei, a little bit paler,
53:09and the smaller purple dots are immune cells,
53:13so I just want you to know
53:15the oncologist watching.
53:17There is no ocular micrometer or
53:21software to do this counting.
53:23We are literally at a microscope
53:26with maybe an arrow.
53:28Basically, guesstimating estimating
53:29that that the numbers of denominator
53:33how many tumor cells are here.
53:35So that is what I want to communicate
53:38to you about the precision.
53:40How do we do this?
53:40Some people do a gestalt.
53:43I do a counting guesstimate
53:45and on the training in in the
53:47online training with a guide,
53:50someone teaching us how to
53:51train at Agilent at Dayco.
53:53That's as good as they had to offer.
53:55That's what we are meant to do,
53:57so I will count off 100 cells by hand,
54:0212345 at the microscope with the fellow.
54:05Count to 100 and then I do this.
54:07I don't want to scare you,
54:08but that's what we do.
54:10203 hundred, 405 hundred 600.
54:13Literally,
54:13this is what we have to work with.
54:16There is nothing better.
54:20Then when we put side by
54:21side as I've done here,
54:23the tumor cells a high power view of
54:25the tumor cells with some immune cells.
54:27I would just like to point out that some
54:30of these immune cells are plasma cells,
54:32and we're not to count plasma cells,
54:34only lymphocytes and macrophages.
54:36The the macrophages are always quite
54:38hard to recognize and distinguish from
54:40a fibroblast or endothelial cell.
54:42This is the PDL one stain in this example.
54:45So we get a sense.
54:47Here's a Member in this staining,
54:49probably a tumor cell, so that's one.
54:52There are some other cells with some
54:54membrane and I'm not sure what this one is,
54:56but you know,
54:56chances are it's meant to be counted.
54:59That's two and we're getting into
55:00some things here that have a lot of
55:02stain that's very dark where it's
55:04hard to distinguish what cell type
55:05it is and how many cells are here.
55:08So this is what is challenging
55:10when you get big clumps like this,
55:12there's a lot of standing here.
55:14This is this is here's that same vessel.
55:16It's stuff here.
55:17It's probably immune cells,
55:18and some of them are lymphocytes,
55:20some are not. So we do the best we can.
55:25In this example, there's some pretty,
55:28you know, honeycomb pretty clear cut,
55:30membranous tumor staining.
55:31And we could probably could certainly
55:33get to cut offs where we're helped a
55:36lot by the fact that we are only for
55:38the most part giving a cut off of less
55:40than or greater than one not an exact number.
55:42So one can guess that this degree of
55:45staining and then your time timing
55:47that by 100 the equation we're
55:49going to get to greater than one.
55:51So I think this saves us.
55:52But if we're going to get to cut off some 5.
55:54And and exact numbers.
55:56It's different.
55:57In this example, the tumor cells are are
56:00here and these are this very nice example,
56:03because these are all lymphocytes.
56:05Morphologically,
56:05I feel pretty comfortable about that.
56:08And the PDL one stain in this area
56:10anyway shows negative tumor staining,
56:13but lots of lymphocytes staining,
56:15so even if I'm not sure it's really
56:17impossible to count how many are positive,
56:19but one can do their best with this
56:22sort of an estimate and get to a score.
56:25In terms of a cutoff of greater less
56:28than one. Couple more examples.
56:29I want to show this is a biopsy,
56:31which is real life biopsy with the usual.
56:34Sometimes we get folds in the slide etcetera.
56:36In the section there's a lot of
56:39insights you display Asia here.
56:41This is not cancer, that's dysplasia.
56:43This is cancer. There is some cancer here.
56:46This probably is cancer.
56:48These three glands.
56:49Then there's some inside you.
56:51So when you. Pivot to the PDL.
56:53One stain one has to be.
56:55It's challenging to count only
56:57what we think is invasive cancer,
56:59not dysplasia.
57:00And only the immune cells around the cancer,
57:03not the immune cells around the dysplasia.
57:06So these are just some of the challenges.
57:08In this example, these again are tumor cells.
57:12And there's some stroma around this is
57:14the PDL one stain and there is some
57:16positive staining and this is cytoplasmic,
57:19not membranous.
57:19So if this is a tumor cell,
57:21it is not to be counted.
57:23Here's some membranous staining,
57:24probably a tumor cell.
57:26But there's some other staining that
57:28is cytoplasmic here and there and
57:30I don't know what the cells are.
57:32I don't know. I can't tell morphologically.
57:35Even going back and forth
57:36are those lymphocytes.
57:37These are actually smooth
57:38muscle cells with a faint stain.
57:40So it it does. Get quite challenging.
57:44Finally,
57:44we're asked this is a metastatic
57:46colon cancer to the liver.
57:48Just the concept of.
57:50How much material there can be?
57:53This is only about 1/5 of the
57:55tumor on the slide,
57:57and here we're counting just percent
58:00tumor and percent immune cells and making
58:03them very specific point on this slide.
58:06There's not a lot of.
58:07There's almost no tumor cell staining here,
58:09but you can see some faint brown even at this
58:11magnification surrounding some of the cancer,
58:15and there these are immune cells
58:16and a lot of these are lymphocytes,
58:18others are neutrophils.
58:20And this is the PDL one stain.
58:22This is a vessel that's staining
58:24and there is some cytoplasmic
58:25staining of variety of things.
58:27Not sure what all these cells are,
58:28but you know we we would do our best but
58:31the the other point about this is that.
58:34When we're giving.
58:35A PDL one CPS score.
58:37We just have to guesstimate the
58:39number of positive tumor and the
58:41number of positive immune cells.
58:43We don't have to give the denominator
58:45of what is the total immune cell count
58:48and you can imagine how challenging
58:50it would be for us to try to count
58:53the immune cells in in any section,
58:55let alone a large section.
58:57So percent immune cell is is really
59:00quite challenging to feel good about.
59:04So in summary.
59:05I think I'm being the bearer of
59:08of not very comforting news here.
59:11This is our reality in every academic
59:14pathologist with whom I've ever
59:16spoken across numerous centers is in
59:18complete agreement with this and we are.
59:20We are really rattling the
59:22cage for something better.
59:24So in summary,
59:25there are the challenges with PDL 1 scoring.
59:28Are in the denominator.
59:29You know,
59:30recognizing tumor cells from stroma,
59:33cautery and other artifacts,
59:34faint staining and in the immune
59:37cells it's really hard to distinguish
59:40the limbs and macros from other
59:42cells and a variety of other things.
59:45The agreement at cut offs is, I think,
59:48already can be quite challenging,
59:49but reproducibility for exact scores.
59:52Should that be be requested,
59:56would I would expect that to be
59:58even less agreements and I'm saying,
60:00well, I think it's an 8.
01:00:01Well, I think it's a 25, you know.
01:00:03So I think that would be troublesome.
01:00:06And Jill mentioned something that I
01:00:08think there's basically no data on.
01:00:11What about the variability within the tumor?
01:00:15Even even in a single tumor within
01:00:18biopsy fragments or within a resection.
01:00:21And what about?
01:00:22Should we do a primary or a metastasis?
01:00:24Pre or post therapy?
01:00:26So those are really valid questions.
01:00:29Uh, almost done.
01:00:30Just how to decipher report.
01:00:32OK, we're giving it our best shot.
01:00:34We do this test every day and we
01:00:36will continue to do so as requested
01:00:39until something better comes along.
01:00:41But at Yale, in any case,
01:00:42our reports, I think,
01:00:44can probably be somewhat confusing,
01:00:46and I'm sorry if that's the case.
01:00:48We try to give for gastric and GGJ
01:00:51a score based upon the cutoff of 1
01:00:55and say it's positive or negative.
01:00:58And what the what?
01:01:00The equation consists of?
01:01:04In, in, and in isopropyl that cut
01:01:06off his ten etcetera depends on
01:01:08the organ system elsewhere in the
01:01:11GI tract we when asked to do this.
01:01:15Since there's no cutoff agreement,
01:01:16one just gives the.
01:01:18The percent of immune cells and
01:01:20percent of tumor cells staining,
01:01:23albeit the challenges that I,
01:01:25despite the challenges that I've mentioned.
01:01:29And I just want to make a point
01:01:31here that while you can impute.
01:01:33A tumor proportion score from
01:01:35this information because the the
01:01:37percent of tumor cells is TPS.
01:01:40That is what TPS is.
01:01:42But you can't impute a CPS should
01:01:44you want to from this, because.
01:01:46The CPS is just the absolute
01:01:49number of positive immune cells.
01:01:51It is nothing to do with the
01:01:53denominator of the total number of
01:01:55immune cells staining at any intensity,
01:01:57so you can't add these together or
01:01:59in some way figure out you're not
01:02:01getting the number of immune cells,
01:02:03which is what you need.
01:02:04The absolute number,
01:02:05which is what you need for a CPS.
01:02:07You're getting the percent of
01:02:09immune cells stain.
01:02:13Future directions we would be thrilled to
01:02:19get as quickly as possible to automation with
01:02:23artificial intelligence and other software,
01:02:26and I think this is coming to remove the
01:02:29subjective interpretation from this process.
01:02:32I'm always comforted to hear from
01:02:34Jill that if if one needs to treat a
01:02:37patient with a checkpoint inhibitor,
01:02:39it is possible to do so regardless.
01:02:42Of what the score is,
01:02:44but we still feel quite a burden that
01:02:46we may be giving a result that is,
01:02:50is not could potentially not be accurate
01:02:53about a cutoff that you're counting on,
01:02:56and therefore the the sort of the hope
01:02:59given to the patient about a response.
01:03:02We would like that to be real.
01:03:05But it does beg the question.
01:03:07Are there situations where PD one stain?
01:03:09It may not be needed to treat,
01:03:11and if that's the case,
01:03:12be great not to ask for it.
01:03:15Further,
01:03:15in addition to what I I think you know,
01:03:18and I have to mention,
01:03:19Dave Rim always in a talk like
01:03:21this for all the wonderful work
01:03:22that he and his lab have done.
01:03:24And I he has a quantitative pathology
01:03:27laboratory yield that I hope will,
01:03:29I assume is working very hard
01:03:31on on getting to automation.
01:03:33But in in fact there's other
01:03:35research and Kurt Shelper in our
01:03:37department with Leaping Chen.
01:03:38Of course they recently
01:03:40published in Cell in 2019.
01:03:42They're digging even deeper,
01:03:44you know,
01:03:44because after all there are those.
01:03:46Folks with checkpoint inhibitors
01:03:47who don't respond and he's there,
01:03:49the group is getting into other discoveries
01:03:53of other potential important molecules.
01:03:57Such as fibrogenic like fibrinogen
01:04:00like protein and its interaction
01:04:03with lymphocyte activation gene 3.
01:04:06So that's very exciting,
01:04:07and hopefully they'll be more things.
01:04:09I just wanted to share some references that
01:04:12I referred to in this talk and thank you.
01:04:16I hope it's not too alarming,
01:04:19but I it's a great opportunity for
01:04:23pathologist to share what's really
01:04:25going on behind that CPS clip.
01:04:28Thank you.
01:04:31Summary that was awesome and maybe
01:04:35a little alarming. I'm sorry.
01:04:37Thank you for clarification.
01:04:38There was a question in the chat box which
01:04:41I think you preemptively answered about.
01:04:43There must be scanning software and
01:04:44artificial intelligence that can do this.
01:04:46This just seems like such an
01:04:47onerous burden on you all.
01:04:49And at the end of the day, as you said,
01:04:51it's not really as quantitative as
01:04:52we all think it might be when we
01:04:54look at forest plots with cut offs.
01:04:56So it looks like that is something
01:04:58that's in the works, and I
01:04:59think people. I know people are
01:05:02working on this and and it I agree
01:05:06with the person asking the question.
01:05:09There will be a better way.
01:05:11All right, well I will
01:05:13carry on and thank you.
01:05:14That really lays the foundation for my talk.
01:05:18And now we're going to talk about how
01:05:20we use this information in making very
01:05:23important decisions for our patients.
01:05:28So we can all see my screen.
01:05:32So I'm Jill Lacey.
01:05:33I'm a medical oncologist at the Yale School
01:05:35of Medicine and Smilow Cancer Center.
01:05:38I'm involved in caring for patients with
01:05:41gastrointestinal cancers and do have a
01:05:43strong interest in gastroesophageal cancers.
01:05:46So my topic tonight is,
01:05:49is it time for chemo immunotherapy
01:05:51for all of our patients,
01:05:53or should we slow down, put the brakes on?
01:05:56Not so fast. And here are my.
01:05:59Conflicts, so I'm going to be focusing
01:06:02solely on first line treatment,
01:06:05not second line and beyond,
01:06:07and the role of immunotherapy
01:06:09in the first line treatment of
01:06:12metastatic gastroesophageal cancers.
01:06:14I'm going to review the data
01:06:17for chemoimmunotherapy,
01:06:18and when I say chemoimmunotherapy here,
01:06:20I'm talking about a standard
01:06:22chemotherapy doublet with or without
01:06:25an immune checkpoint inhibitor.
01:06:27And all the studies have been with.
01:06:29PD1 inhibitors to date.
01:06:30I'm going to talk about the
01:06:31data in squamous cell carcinoma
01:06:33and the data in adenocarcinoma,
01:06:35which is different.
01:06:36Then I'm going to review some of
01:06:39the data for chemotherapy free
01:06:40immunotherapy in the first line setting.
01:06:43We've heard a lot about the controversy
01:06:45surrounding PDL ones predictive biomarker,
01:06:47so I will just highlight those and
01:06:51then I will have some conclusions of
01:06:53my own and some of the questions and
01:06:56future directions that we are facing.
01:06:59So.
01:07:04Enhancing
01:07:07did you click on your talk?
01:07:08I had. There you go
01:07:09there you go. OK, so immune.
01:07:12Checkpoint inhibitors.
01:07:13I think as many know in gastroesophageal
01:07:16cancers have really had a checkered history.
01:07:19Had some pretty inconsistent
01:07:21and conflicting results.
01:07:22Certainly in the second and third line
01:07:24setting and also in the first line setting.
01:07:26There are many reasons for this.
01:07:28This is really a
01:07:29heterogeneous group of tumors.
01:07:30In every respect we've just heard
01:07:32about the imperfections of PDL one,
01:07:34and yet we are continue to.
01:07:36Use it to make to design studies
01:07:38and to make treatment decisions and
01:07:40then of course the trial designs.
01:07:43Any trial design is never perfect
01:07:44and I think there have been a lot of
01:07:46imperfections in in the ways that the
01:07:48studies have have have been designed.
01:07:50You know,
01:07:50in large part baked into the
01:07:52cake and for pragmatic reasons.
01:07:53But that said,
01:07:55I think in the first line setting
01:07:57some consistent and reproducible
01:08:00data have emerged,
01:08:02especially in squamous cell carcinomas.
01:08:06As I said,
01:08:06I'm focusing on the first line setting
01:08:08at present in the United States,
01:08:10we have FDA approvals for two iOS in
01:08:13the second line setting and beyond,
01:08:15both in squamous cell carcinomas
01:08:17of the esophagus,
01:08:19one with pembrolizumab with the
01:08:21PDL 1 score is 10% or greater.
01:08:24That's CPS and neevo PDL 1 agnostic,
01:08:27so I'm going to talk now about the
01:08:31data in squamous cell carcinoma.
01:08:33So I just need to remind you as we go
01:08:36through this that when we talk about
01:08:39esophageal cancer so often historically,
01:08:41the studies have included both
01:08:44squamous cell and adenocarcinoma.
01:08:46So mixed Histology studies
01:08:47really based on the anatomy,
01:08:49but in reality these are
01:08:51very different diseases.
01:08:52Many differences as are highlighted here
01:08:55and actually not that many similarities,
01:08:58symptoms, overarching treatment algorithms
01:09:01and and prognosis, and I think.
01:09:04What's really emerged is that, yes,
01:09:06these are very different diseases.
01:09:08This is from the tumor profiling and
01:09:12molecular analysis that we're seeing with
01:09:15esophageal squamous and adenocarcinoma.
01:09:17So the squamous subtype really
01:09:19resembles from A at a molecular level,
01:09:22and a genomic profiling level,
01:09:24squamous cell carcinomas
01:09:25of other organ sites.
01:09:27Whereas adenocarcinomas of the esophagus
01:09:30resemble the chromosomal instability subtype.
01:09:34The four subtypes of gastric cancer.
01:09:36The chromosomal instability
01:09:37subtype of gastric cancer.
01:09:39So really there's no biologic
01:09:42or scientific rationale,
01:09:43I think at this point in clinical
01:09:46trials for combining squamous
01:09:48and adeno esophageal cancers.
01:09:50It's a maybe a pragmatic reason,
01:09:52but not really a biological reason.
01:09:53And I think if that's important to keep
01:09:56in mind as we look at some of this data.
01:09:59So turning now to squamous cell carcinomas.
01:10:01This is remarkable.
01:10:02There have been in the last two years 5
01:10:06completed published large randomized phase.
01:10:08Three trials of chemotherapy
01:10:10doublets versus a chemotherapy
01:10:12doublet plus a PD1 inhibitor,
01:10:14and they are listed here,
01:10:16and these studies have all shown really
01:10:18a consistent improvement in overall
01:10:20survival with the addition of a.
01:10:22I'm sorry that is PD1 inhibitor to
01:10:25chemotherapy remarkable consistency
01:10:26and two of these studies have
01:10:28led to FDA approvals
01:10:29in the United States in
01:10:31squamous cell carcinoma.
01:10:32I'm going to focus in on Checkmate 648.
01:10:35This is the largest study by far,
01:10:37and this is the study that led
01:10:39to the FDA approval of Nevo with
01:10:42chemo and squamous cell carcinomas.
01:10:44I think you've seen the study design
01:10:46is this was a three arm study
01:10:49with chemotherapy, fluorouracil,
01:10:50cisplatinum as a control against
01:10:53chemo plus Nevo and then a third
01:10:56arm without chemo of Nevo.
01:10:58Plus Skippy and the results are
01:11:01highlighted in this somewhat.
01:11:03Disease slide,
01:11:04so in terms of the overall survival,
01:11:08there was a benefit in both the PDL
01:11:12one TPS 1% or greater population,
01:11:14which was their first primary endpoint
01:11:16about a six month improvement in survival.
01:11:19Truly a stunning result with a hazard
01:11:22ratio of .54 and also improved
01:11:25progression free survival and response rate.
01:11:27This is really dramatic data for this
01:11:30very difficult disease and again major.
01:11:33Events in the field.
01:11:34Also there was benefit in terms
01:11:36of survival for all randomized
01:11:39patients of about two 2 1/2 months
01:11:41with a hazard ratio .74.
01:11:45And of course everyone is interested
01:11:47in the subset analysis that
01:11:49are often flawed small numbers.
01:11:50But if you look at the subsets here,
01:11:53I think what jumps out is that
01:11:56almost all subsets benefited.
01:11:58Interestingly, females and it's a small set.
01:12:01A number of patients in squamous
01:12:02there did not appear to be a benefit
01:12:05that's been seen in other studies,
01:12:06and importantly,
01:12:07that very important biomarker that
01:12:09we're all now relying on PDL one.
01:12:12And so that's that's blown up
01:12:14here on this slide.
01:12:15And so if you look at CPS first.
01:12:18The only group that did not appear
01:12:20to benefit in terms of hazard ratio
01:12:22less than one was a CPS less than one,
01:12:25and that was only 9% of the patient,
01:12:27so all the others were.
01:12:29The hazard ratio was was less than one.
01:12:32If you look at TPS,
01:12:34this is interesting in the
01:12:36group less than one.
01:12:38There did not appear to be a
01:12:40benefit and and by TPS less than
01:12:41one is about half the patient,
01:12:43so the data is a little bit,
01:12:45I think hard director head around, but.
01:12:48In the CPS less than one,
01:12:50there was a higher response rate.
01:12:52There was longer response duration,
01:12:54and it's possible that a survival survival
01:12:57benefit may emerge with longer follow-up.
01:13:00So in the other studies, just to run through,
01:13:02you know what these look like.
01:13:05Three of them conducted in Asia,
01:13:06three global.
01:13:07These are all big studies.
01:13:09Keynote 590 stands out in that it was a
01:13:11mixed Histology study of adenosquamous.
01:13:14The 2/3 of them being squamous.
01:13:17Different PD1 inhibitors were
01:13:18used in each of these studies.
01:13:21Different chemotherapy backbones were used,
01:13:23although most were cisplatinum,
01:13:25based with either 5 or fewer
01:13:27CARBO paclitaxel.
01:13:28Different PDL,
01:13:30one cut points for primary analysis,
01:13:34different assays.
01:13:35But what's remarkable is the
01:13:38similarity in survival benefit in
01:13:41all of these studies of a couple of
01:13:44months with quite similar hazard ratios.
01:13:47Jupiter 06 being most impressive,
01:13:50so this is a very consistent finding
01:13:52and I think that really drives
01:13:54home the point of the value PD 1
01:13:56inhibitors and squamous cell cancers.
01:13:58And for those of you that like Kaplan
01:14:01Meier plots, those are depicted
01:14:03graphically here for these studies.
01:14:05Now how does PDL 1 fit into this?
01:14:08So again we're getting conflicting results.
01:14:11I reviewed the PDL one story with 648
01:14:14where did appear that the benefit was
01:14:16greater with higher PL and scores,
01:14:19especially TPS.
01:14:20We did not appear to see that same
01:14:23phenomenon in Jupiter 06 or in Orient 15,
01:14:27but there was an association with Epoxy
01:14:30and PDL one and escort the escort study.
01:14:33So again not completely consistent.
01:14:35But overall,
01:14:36I think these are really impressive results,
01:14:38and again,
01:14:38if you look at the forest plots
01:14:40and again the the big picture here
01:14:42is the the hazard ratio is less
01:14:44than one in almost all of these
01:14:46studies in all PDL 1 subsets.
01:14:48So my take away message is that PD
01:14:51one inhibitors added to chemotherapy
01:14:52and this disease improves survival
01:14:54and the magnitude of benefit has
01:14:56been similar across different studies
01:14:58with different PD1 inhibitors and
01:15:00different chemo backbones and the 648
01:15:03study did lead to the FDA approval.
01:15:05For me, vote and that is a a PDL 1 agnostic.
01:15:10So your respective of PDL one expression.
01:15:13And we also have an approval
01:15:16from Keynote 590 for Pembroke.
01:15:19Also,
01:15:19irrespective of PD L1 expression in
01:15:23esophageal squamous as well as adeno.
01:15:26So I'm going to pivot now to adenocarcinoma,
01:15:28and here the story is a little less clear.
01:15:32The data is more conflicted and I
01:15:35would say that conclusions certainly
01:15:38can be made with caveats,
01:15:41but it's it's this is a little bit
01:15:43more of a challenging story, I think.
01:15:45So here we have 5 randomized
01:15:48phase three studies,
01:15:50all similar designs of chemotherapy
01:15:53doublets against chemotherapy.
01:15:55Plus PD1 inhibitor.
01:15:59Two of these studies,
01:16:00keynote 62,
01:16:01which was using Pembroke with
01:16:03chemo and also had a chemo through
01:16:06free arm of Pembroke alone.
01:16:08Traction four was a negative
01:16:10study and then checkmate 649,
01:16:12keynote 590,
01:16:13and adenocarcinoma subset and Orient
01:16:1516 were all viewed as positive studies
01:16:18and the two the two Checkmate 649 and
01:16:22590 like to FDA approval in adenocarcinoma.
01:16:26I think in the aggregate,
01:16:27even though there is conflicting
01:16:29results here,
01:16:30there's a trend towards improved
01:16:31outcomes with the addition of PD1
01:16:34inhibitors to chemotherapy in the
01:16:36adenocarcinoma Histology as well as squamous,
01:16:38and again I'm going to
01:16:40highlight Checkmate 649.
01:16:41And because,
01:16:42again,
01:16:42this led to an FDA approval and you
01:16:46you have seen the design of 648,
01:16:48this is very similar chemo as
01:16:52the control arm chemo plus anevo
01:16:54and then a chemo free arm of.
01:16:56Nivo and IPI and here the ippy
01:16:59doses 3 megs per keg and neevo 1.
01:17:02The chemotherapy free arm was closed
01:17:04early due to futility and they carried
01:17:06on with the other two arms and
01:17:08then the key points in terms
01:17:10of results are shown here.
01:17:11They primary end point was in
01:17:13the CPS 5 or greater subset and
01:17:16that was positive with a three
01:17:18month improvement in survival and
01:17:21again this is in in this disease.
01:17:23Pretty impressive.
01:17:24We haven't seen this kind of result.
01:17:26In in decades,
01:17:28except in the her two positive
01:17:30group with a hazard ratio,
01:17:32.71 was also positive study in
01:17:35all randomized patients about a
01:17:37two month improvement in survival
01:17:38with a hazard ratio of .8.
01:17:40So this was a positive study.
01:17:43Now everybody is interested in the PDL
01:17:461 subsets and is there a benefit in PDL?
01:17:49One negative and low and that data
01:17:52is shown here and so you can see that
01:17:55in the PDL one CPS less than one,
01:17:57the hazard ratio just is just under
01:18:00one but not impressive and the
01:18:02same thing with less than five.
01:18:04But if you look at responses the
01:18:07response rates are higher in all
01:18:10PDL 1 subsets including less
01:18:12than one and less than five.
01:18:14So again,
01:18:15this study strongly suggests that
01:18:16there is a relationship between PD
01:18:19L1 expression and efficacy from
01:18:22the addition of a PD1 inhibitor.
01:18:25So again, here are the the five studies.
01:18:29And in terms of how they look
01:18:32in terms of geography,
01:18:33there they were all large studies except
01:18:36the keynote 590 adenocarcinoma subset.
01:18:39Most of them were focused on GE,
01:18:40J gastric,
01:18:42but Checkmate 649 fortunately
01:18:44included Asopus and keynote.
01:18:46590 excluded gastric.
01:18:50And they used again different chemo
01:18:53backbones and different PD1 inhibitors,
01:18:56and for the positive studies the
01:18:58hazard ratios in the overall patient
01:19:00population were quite similar and
01:19:03hazard ratios are not significant
01:19:06in keynote 62 and Attraction 4.
01:19:10And these are the Kaplan Meier
01:19:12curves for the two negative studies.
01:19:13They really, really were negative studies.
01:19:17When you look at the hazard ratio
01:19:18you you ask the question.
01:19:20Well,
01:19:20the negative studies did the
01:19:21PDL 1 high subset benefited?
01:19:23That did not seem to be the case and in the.
01:19:29Other studies we don't really have good
01:19:33data in the PDL negative or low subset,
01:19:35so it's hard to draw a lot of conclusions
01:19:38other than from Checkmate 649 about
01:19:41PDL quantification and benefit.
01:19:45Now it's a different story in patients who
01:19:48are mismatched pair definition or MSI high,
01:19:50and I think this is a really interesting and
01:19:52important story that deserves highlighting.
01:19:54So in in both Keynote 62 which
01:19:57looked at Pembroke chemo versus
01:19:59chemo and Checkmate 649 Nevo chemo.
01:20:01They looked at retrospectively at the
01:20:04small numbers of patients that were MSI high.
01:20:08These numbers are small but
01:20:09look at these results.
01:20:10They're really dramatically.
01:20:12Favorable and dramatically similar
01:20:15with almost identical hazard ratios,
01:20:18and so I think there's no question
01:20:21that chemoimmunotherapy should be
01:20:22given to all patients without other
01:20:24contraindications who have mismatch repair,
01:20:26deficient MSI high tumors.
01:20:28This is a huge story,
01:20:29I think.
01:20:30In my opinion,
01:20:31New England Journal of Medicine Worthy,
01:20:33but I think definitely worth highlighting.
01:20:36So can we explain the
01:20:38discrepancies in these studies?
01:20:39I would say I'm challenged
01:20:42to really rationally.
01:20:43Explain the discrepancies.
01:20:46We can talk about biology because
01:20:48gastroesophageal adenocarcinoma from a
01:20:50biological perspective is very heterogeneous.
01:20:53We've identified the four
01:20:54major molecular phenotypes,
01:20:56but that's just I think the tip of
01:20:58the iceberg, and we know, of course,
01:21:00that MSI high and B positives will
01:21:02be the ones likely to respond.
01:21:04A lot of challenges in the trial design.
01:21:07You know, excluding esophageal
01:21:10adenocarcinoma or excluding,
01:21:11gastric, different chemo backbones.
01:21:13And then of course,
01:21:15the impact of post study treatment.
01:21:17I think the explanation for the very
01:21:20negative attraction for study was
01:21:22that that many of those patients
01:21:24did get PD1 inhibitors in the
01:21:26second and third line and beyond.
01:21:30Now, how about her two positive
01:21:33gastroesophageal cancer?
01:21:34All those studies that we just reviewed
01:21:36excluded her two positive patients,
01:21:38so we now have pretty exciting
01:21:39data in this patient population,
01:21:41with the inclusion of a PD1 inhibitor
01:21:44with chemotherapy and trastuzumab.
01:21:45This is the keynote 811 study.
01:21:48Also got a lot of publicity appropriately,
01:21:50so simple design, trastuzumab,
01:21:53chemo versus trastuzumab,
01:21:56chemo and Pembroke, and on what we.
01:21:59See here are the response data and
01:22:02you can see very high response rate.
01:22:04Very deep responses with Pembroke
01:22:07added to chemo and Herceptin.
01:22:10Higher response rate and
01:22:12a complete response rate.
01:22:13That's very impressive at 11% versus 3%.
01:22:18This study led to the provisional
01:22:21approval of Pembroke,
01:22:22added to trastuzumab and
01:22:24chemo and her two positive
01:22:26gastroesophageal adenocarcinomas.
01:22:28So obviously this is provisional.
01:22:29We are waiting for.
01:22:31PFS data and overall survival data.
01:22:33To see what the final impact is going to be.
01:22:37So we have three FDA approvals now
01:22:42and gastroesophageal adenocarcinomas.
01:22:43So Pembroke from Keynote 590,
01:22:46which did not include gastric cancers.
01:22:48Neevo based on Checkmate 649 and
01:22:52Pembroke added to trastuzumab.
01:22:54Chemo based on keynote 811.
01:22:57All of these studies.
01:22:59All of these approvals by
01:23:01the FDA are PDL 1 agnostic.
01:23:04Which is, I think,
01:23:05interesting and and can be debated.
01:23:07So my take away message in the last few
01:23:12minutes is that adding a PD1 inhibitor.
01:23:15To chemotherapy and adenocarcinomas
01:23:17improves overall survival in most studies,
01:23:21but not all.
01:23:23That benefit has been seen
01:23:24with different PD1 inhibitors.
01:23:25Chemo doublets and different PD,
01:23:26one cut offs.
01:23:28I think we can conclude safely that efficacy.
01:23:32Diminishes with decreasing PD L1 expression.
01:23:36And so, how do we use this information?
01:23:39So I think that most patients with
01:23:42adenocarcinoma should be offered
01:23:44first line chemoimmunotherapy.
01:23:46But I I recognize that we are
01:23:49conflicted about what to do
01:23:51with patients who have no PD L1
01:23:54expression or low PD L1 expression.
01:23:57So just for a few minutes for the
01:23:59last few minutes I'm going to pivot
01:24:01to the data in guest Russophile
01:24:03deal cancers for first line
01:24:06immunotherapy without chemotherapy.
01:24:08So chemotherapy free immunotherapy
01:24:10and there are three randomized phase
01:24:13three trials that have addressed this
01:24:15question with the control arm of
01:24:18chemotherapy against an experimental arm
01:24:20of immunotherapy without chemotherapy.
01:24:23So we've heard about Checkmate 648.
01:24:27Squamous cell carcinoma that had
01:24:29the ippy Nevo chemo free arm.
01:24:31We'll discuss in a minute led to
01:24:34FDA approval just this past month
01:24:36for it being EVO in squamous cell
01:24:39carcinomas for adenocarcinomas.
01:24:41We have Checkmate 62 which looked at
01:24:44chemo versus Pembroke and Checkmate 649
01:24:48again which looked at a chemotherapy
01:24:51free dual immunotherapy Nevo.
01:24:53These studies in adenocarcinoma
01:24:55were considered.
01:24:57Negative studies and we do not
01:24:59have FDA approval.
01:25:00And then again I'm going to highlight
01:25:02the data in MSI high adenocarcinomas.
01:25:06So we've seen the Checkmate 648 and
01:25:09649 designs very similar except
01:25:11for the dosing of Yippee Nevo,
01:25:143 megs per kig in adenocarcinoma,
01:25:16one Mig per kig ippy in squamous
01:25:20cell carcinomas, and side by side.
01:25:22Here are the Captain Meyer plots for
01:25:25overall survival and in their primary
01:25:28endpoint of PD L1 positive tumors and
01:25:32then down below all randomized patients.
01:25:36And so, in adenocarcinomas,
01:25:38this was viewed as a negative study,
01:25:41median survival,
01:25:42the same.
01:25:43Although you can see the curves
01:25:45do separate at later time points,
01:25:48I think which is interesting.
01:25:50The response rate was notably
01:25:52substantially lower.
01:25:53Would it be neevo different story
01:25:55and squamous cell carcinoma?
01:25:57This is a positive study with a
01:26:00significant improvement in overall
01:26:02survival in PDL and positive
01:26:04patients and also in all randomized.
01:26:07Patients so no approval for apnea
01:26:11and adenocarcinoma,
01:26:12but it is approved in squamous
01:26:14cell carcinomas.
01:26:14Now what are the red flags here
01:26:17for squamous cell carcinoma?
01:26:18So a big red flag is this crossing
01:26:21of the curve survival curves in the
01:26:24first six months so a higher rate of
01:26:27death and patients getting immunotherapy
01:26:30alone versus chemotherapy.
01:26:31And we don't know the full
01:26:33explanation for that.
01:26:34We can come up with some
01:26:35plausible explanations,
01:26:36but we're not certain.
01:26:37I think we'll get more information
01:26:40from this study about that.
01:26:41If you compare immunotherapy alone
01:26:44versus chemotherapy immunotherapy in 648,
01:26:46which is not fair by our statistically,
01:26:48it does look like the
01:26:51survival curves are similar,
01:26:53but the duration of response and the
01:26:55responders does appear to be longer.
01:26:58With dual immunotherapy
01:27:00versus chemoimmunotherapy.
01:27:01When you look at immunotherapy versus chemo,
01:27:03you have the very predictable expected
01:27:05differences in treatment related AE.
01:27:07But there were fewer treatment
01:27:09related AE's leading to treatment
01:27:12discontinuation with dual immunotherapy.
01:27:14So this is really exciting.
01:27:17This has led to the first FDA approval
01:27:20of chemotherapy free treatment for
01:27:21squamous cell of the esophagus,
01:27:23and for those that like the
01:27:25forest plots here we go.
01:27:26Most subsets benefited, but again in the TPS.
01:27:31Less than one, the hazard ratio was .96.
01:27:36Now in adenocarcinomas we have
01:27:38another study and this was did
01:27:40not lead to FDA approval.
01:27:42That was Pembroke versus chemo.
01:27:45Pembroke was non inferior to
01:27:47chemo but again you see those
01:27:51troubling survival curves crossing.
01:27:52So with the higher rate of death
01:27:55early on and so right now there's
01:27:57no approval for immunotherapy
01:27:59alone and adenocarcinomas.
01:28:01We have to talk about the MSI high patients
01:28:04though with adenocarcinomas and again.
01:28:06We have keynote 62 where they
01:28:08went back and looked at this and
01:28:10Checkmate 649 again small numbers.
01:28:14But really impressive survival curves
01:28:18and very similar outcomes with really
01:28:21virtually identical hazard ratios.
01:28:23Again,
01:28:23I think this is a a huge story,
01:28:26and so it it begs the question
01:28:29could could we?
01:28:30Should we consider immunotherapy loan
01:28:33as first line treatment in patients with
01:28:35MSI high guest Raphael adenocarcinoma?
01:28:38So a story to be continued.
01:28:40And also I think of course
01:28:41begs the question you know,
01:28:43are we going to be curing these patients?
01:28:45With MSI high guest reseal endocarp sinoma,
01:28:47either with immunotherapy
01:28:49alone or chemoimmunotherapy,
01:28:51so to to conclude to the
01:28:53base to the question.
01:28:55Chemoimmunotherapy for all or not so fast.
01:28:57So I think here are the considerations
01:29:00squamous versus adeno it matters
01:29:02PDL one matters I think,
01:29:03especially in adenocarcinoma,
01:29:05but as we heard so brilliantly from
01:29:07Marie it is such an imperfect biomarker.
01:29:10Is it good enough to guide us to
01:29:13select patients in whom we will
01:29:16not give immunotherapy?
01:29:17This is a really troubling question
01:29:19for us as clinicians in terms of
01:29:22anatomic site for adenocarcinomas.
01:29:23I don't think we have any data yet
01:29:25that esophagus versus GE junction
01:29:27versus Gastro is gastric is the issue.
01:29:29I think MSI mismatch repair
01:29:31deficiency Trump's PDL one.
01:29:33All those patients should get
01:29:36chemoimmunotherapy and similarly
01:29:37for her too regardless of PD L1.
01:29:40Those patients now inclusion of
01:29:42Pembroke I think is reasonable.
01:29:44We're waiting for survival data.
01:29:47So here are my conclusions.
01:29:50So for a sophal squamous I am
01:29:53offering chemoimmunotherapy to
01:29:55most of my patients irrespective of
01:29:58PD L1 and for the adenocarcinomas I I
01:30:01am taking a similar approach but I am
01:30:05very circumspect about what we may be,
01:30:08how, how much we're helping patients.
01:30:10If the PDL 1 score is 0 or very low.
01:30:16So again, the question should should
01:30:18we use PDL one course to exclude
01:30:21patients from frontline PD1 inhibitors?
01:30:23If if we do I think it has to be
01:30:26with circumspection and caution.
01:30:28I think particularly you know after the
01:30:31information that we heard from Marie about
01:30:34some of the challenges with this biomarker.
01:30:38Chemotherapy free immunotherapy, for whom?
01:30:40And in what settings?
01:30:41So this is very exciting.
01:30:43It is approved it be neevo and squamous
01:30:45cell carcinoma irrespective of PD one.
01:30:48But again that cautionary note we
01:30:49are seeing increased deaths compared
01:30:51to chemo in the first six months.
01:30:53So that gives one pause.
01:30:55And so I think careful patient
01:30:57selection is the key.
01:30:58But I don't think we know yet
01:31:00how to select patients.
01:31:01Is it PD one or PDL?
01:31:03One score?
01:31:03Is it the tumor burden so you know again,
01:31:07I think. To be continued.
01:31:08This is an interesting story.
01:31:10And then for gastric adenocarcinomas,
01:31:12we're not there yet for immunotherapy alone,
01:31:15as the initial treatment.
01:31:16I think even in MSI high patients, I think
01:31:20it's still would be chemoimmunotherapy.
01:31:24So where we go from here?
01:31:26I think the questions are are obvious.
01:31:29I think adenocarcinoma we just
01:31:31we do need more better data.
01:31:33We have the keynote 859 and other
01:31:35large randomized phase three trial
01:31:37of chemo versus chemo, plus pember.
01:31:39We're going to learn a lot from that study.
01:31:40It's a huge study.
01:31:43Clearly,
01:31:43as Marie articulated we we do
01:31:46need a better biomarker period.
01:31:48Full stop writ large.
01:31:50And now the next phase.
01:31:53This is a big advance.
01:31:55Forward for us.
01:31:55I mean really huge when you look at the
01:31:58history of the treatment of metastatic
01:32:00and advanced gastroesophageal cancers.
01:32:02So now we need we want more.
01:32:05So we need more effective immunotherapy
01:32:09agents or immunotherapy combinations.
01:32:11And now we're going to be moving into
01:32:13the realm of adding immunotherapy
01:32:15to other targeted therapies.
01:32:17So some studies that were planned or
01:32:19underway have now had to be redesigned.
01:32:22In light of this data.
01:32:25Adding immunotherapy to a targeted
01:32:27therapy and chemotherapy,
01:32:28and I've highlighted 2 studies such
01:32:31studies that will be open here
01:32:34at Smilow Cancer Center shortly.
01:32:36And of course,
01:32:37now the widespread use of PD1
01:32:39inhibitors in the first line setting
01:32:41really changes the landscape in the
01:32:43second line setting and beyond in
01:32:44terms of how we design those studies
01:32:46and how we're going to be treating
01:32:48those patients so much work to be done.
01:32:51But this is an incredibly exciting era.
01:32:54For those of us.
01:32:55Who treat this these diseases
01:32:57and thank you for your attention,
01:33:00and I'm happy to take any questions
01:33:03in the chat box,
01:33:05but I know we are overtime so I'm
01:33:09happy to take questions by e-mail.
01:33:12I know Dan shared his mind as the
01:33:16typical Yale e-mail jill.lacey@yale.edu
01:33:22Still, I will ask
01:33:23a question to close. Thank
01:33:26you so much for that.
01:33:29Really. Sort of exhaustive and and
01:33:33deep dive into the differences
01:33:34between squamous and the salvageable.
01:33:36And it's so interesting to see about
01:33:39the PDL 1 scores and where they are
01:33:42making sense and where they may not.
01:33:44Might not be making sense.
01:33:46Are you ever in a situation
01:33:48where, Despite that, it's sort of the
01:33:51deregulated to order this the PDL?
01:33:53One stain that you might say you
01:33:55know I'm going to proceed without it?
01:33:57I'm going to do for XYZ.
01:33:59Reason is that is that ever a part
01:34:01of the conversation at this point.
01:34:06Yeah, so you're getting at the heart of
01:34:08what we struggle with in the clinic. I.
01:34:14My my bias is to to include immunotherapy
01:34:17as I I concluded in in the slides for
01:34:21most patients with gastroesophageal
01:34:23cancers with metastatic disease.
01:34:26Not that I know that it's benefiting
01:34:28everybody, because I certainly
01:34:29know that it is absolutely not,
01:34:31but I just don't have confidence that we are.
01:34:36Able to sort out those patients
01:34:37that are getting no benefit,
01:34:39so this is not like a K rest mutation
01:34:42in colorectal cancer that's very
01:34:44black and white and very clear.
01:34:46There's not benefit to adding
01:34:49cetuximab or panitumumab.
01:34:51This is much more ambiguous and nuanced,
01:34:54so I I think we're just not there yet.
01:34:58I do know that.
01:35:01Key opinion leaders you know will
01:35:03agree to disagree about this point,
01:35:06and I know that people have different
01:35:09approaches to how to use immunotherapy
01:35:15in this patient population.
01:35:17We're we're all I would say we're
01:35:19all struggling and so I think at
01:35:22this point it's just keep at it.
01:35:24More studies, more data.
01:35:26Looking for better biomarkers?
01:35:29Useful for us to know.
01:35:31This pathologist, because of
01:35:32the the because of our struggles
01:35:35with interpreting that stain.
01:35:37Eventually I it's not needed.
01:35:40That'll be great.
01:35:41I can't speak for all oncologists.
01:35:43Obviously. I do know that some
01:35:45oncologists if the PDL ones,
01:35:47if there is no PDL one anywhere,
01:35:50it's just flat out,
01:35:51no PDL one are are not including
01:35:55immunotherapy because there's
01:35:57there there there are toxicities
01:36:00the treatment discontinuation rate
01:36:02was higher in all these studies
01:36:04in the immunotherapy arm and
01:36:05that makes sense because you're.
01:36:07Adding in a whole another class of
01:36:09toxicities that may lead to treatment
01:36:12discontinuation and of course
01:36:14we're all now experiencing that.
01:36:17We start chemo immuno and have a
01:36:20treatment related immune adverse event
01:36:22and and are are withdrawing the drug.
01:36:25It's also a cost issue but I think
01:36:28I I think that's a health economics
01:36:32issue for individual decision
01:36:34making for patients you know unless
01:36:36it's personal financial toxicity.
01:36:38I think it's a little hard for
01:36:39me to argue well,
01:36:40it's costly to our healthcare system,
01:36:43so I'm going to withhold immunotherapy
01:36:45if it's personal financial toxicity.
01:36:48That's of course a different story,
01:36:49so that's kind of how I think about it.
01:36:51But everybody I think looks at this
01:36:53differently and right now I don't think
01:36:56anyone has has the right right answer,
01:36:58or there's a truly a wrong answer.
01:37:01Well, you touched on something
01:37:02that we can do, and that is
01:37:05the completely negative stain.
01:37:07We can agree on that
01:37:08and and definitely I know they're
01:37:10oncologists and some of our key opinion
01:37:12leaders in the field who feel we should.
01:37:15That's a setting where very
01:37:17comfortable withholding anything
01:37:18you can rely on. Our result is
01:37:20what I meant that we can reliably.
01:37:23We can agree this is negative.
01:37:25That's that is important to know.
01:37:27Actually all right,
01:37:28we are beyond the hour.
01:37:30Thanks everyone who stayed to
01:37:32the end for your attention.
01:37:33And again, I think we're all
01:37:35happy to take questions by e-mail
01:37:36and have a good evening. Thank
01:37:38you very much everyone. Thank you Jill.