Moving from Palliation to Cure: Progress in the Treatment of Non-Small Cell Lung Cancer

October 10, 2023

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Yale Cancer Center Grand Rounds | October 6, 2023

Presented by: Dr. Roy Herbst

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00:00Real pleasure to introduce Roy Herbst.
00:03Roy of course needs no
00:05introduction to all of you.
00:08You can see his title on the screen Moving
00:10from Palliation to Cure Progress in the
00:13treatment of non small cell lung cancer.
00:15But let me just make a couple of comments.
00:18So Roy has really witnessed over the
00:23course of his 25 year career or so since
00:29completing training of has has witnessed
00:31a real revolution in lung cancer.
00:34And I remember when I was a fellow
00:38and nobody was interested in lung
00:40cancer and there seemed to be little
00:42hope for progress in lung cancer.
00:44And that has really changed so very
00:48dramatically And as Roy has witnessed
00:51that he's also participated in it
00:54and he has been involved in the vast
00:58majority of clinical trials that have
01:01led to major changes in lung cancer,
01:03whether that's related to EGFR,
01:07associated lung cancer or for
01:09that matter trials focused on
01:11immunotherapy and other treatments.
01:13So great pleasure to introduce Roy.
01:16He will take us through this talk
01:18and is a great inaugural speaker.
01:22Thank you, Eric.
01:23And it's great to be back here in person in
01:26the auditorium and happy Friday everyone.
01:29And what I'm going to do in the
01:32next 45 to 50 minutes is give you a
01:34little bit of a tour of lung cancer.
01:37So actually my journey began here
01:39at Yale 44 years ago and my Pecam
01:42professor's in the front row,
01:43Don Engleman and and it's amazing
01:45to see you and you know,
01:47and I I actually wasn't his
01:48course like he would probably
01:52but it's you know,
01:53Yale's just a phenomenal place.
01:54So it's just so amazing for
01:55me to be to be here and I gave
01:57a grand rounds about 12 years
01:59ago when I first arrived.
02:00So a little bit of progress
02:02since then and I'll show you
02:04that now my disclosures.
02:08So we're back. This was last week at
02:14East Haven. We had our ASCO review and
02:16and a dinner for some of the faculty.
02:19It was just great to see so many
02:21people there and the spirits there.
02:23We had a great day discussing
02:24all of our different divisions,
02:26both solid and liquid advances in the
02:30field and it's good to see so many
02:32of those being done here at Yale.
02:34And then of course we we had many of
02:37our fellows and actually we're we're
02:39really multidisciplinary of course
02:40we have our hospitals team was there,
02:43many of our fellows were there,
02:44we had surgeons there,
02:45we'd love to have our surgeons there,
02:48radiation oncology.
02:48One thing that I want to get across
02:50today is the way we're making progress
02:52in lung cancer and many diseases.
02:54This is in a in a multi modality
02:57fashion and you know the the
02:58burden of lung cancer is is great.
03:00I think most of this group is aware of that,
03:02but it's the leading cause
03:04of cancer death worldwide.
03:05You know, more, more cases,
03:07probably a skin cancer diagnosed of course,
03:09but for you know, more,
03:11more, you know,
03:11it's more breast cancer in women
03:13and prostate cancer in men.
03:15But lung cancer is the number one
03:17killer with over 2 million deaths
03:19a year in the world with over
03:21200,000 deaths in the United case,
03:23200,000 new cases in the US
03:25with over 130,000 deaths.
03:26So this is the reason there's so
03:28much research and pharmaceutical
03:30development in this area.
03:3184% of lung cancer is non
03:33small cell lung cancer.
03:34A a great effort now still with small
03:36cell lung cancer used to be that
03:38was only associated with smokers.
03:39It's still mostly with smokers.
03:41But now we know that EGFR mutated lung
03:43cancer can develop into small cell
03:44lung cancer and Sheng lives in the
03:462nd row sort of leads to that effort
03:47here and she'll probably give a grand round.
03:50Oh yeah,
03:51please.
03:51It is a little distracting
04:00thank you
04:05and and we'll hear from Ann hopefully
04:07in in this series later this year Well
04:09when I started out you know as after
04:11I I left Yale and I spent some time in
04:13New York at Cornell and Rockefeller.
04:15I went up to Boston and I I was working
04:19at Dana Farber and I I I said this last
04:22week at the to some of the fellows.
04:24I got the job in lung cancer
04:26because that's all it was.
04:27You know the breast cancer
04:28jobs were all filled.
04:29The leukemia and lymphoma jobs actually liked
04:31lung cancer and was very interested in it.
04:33I had a wonderful mentor,
04:35Emil Fry, also a Yale graduate,
04:38But it was pretty dismal and it's very hard,
04:41you know, you know,
04:42as oncologists to work in the clinic
04:43when you don't have tools to offer.
04:45We had tools of chemotherapy,
04:47but this is what survival curves look
04:49like about 25 years ago for lung cancer.
04:51And you can see there's really none at at,
04:53you know, at at two years.
04:55There's very little survival at three years,
04:57almost nothing.
04:58And progression was quite steep and
05:00there was all this excitement about Dosi,
05:02Taxol, Packley, Taxol, Amcitabine,
05:06Carboplatinum.
05:07These drugs made a difference
05:08and they did improve survival,
05:10but to a very small extent.
05:12A median survival is of 7 to 8 months.
05:14So the question was a paradigm
05:16shift was needed.
05:17And you know, you're you're
05:18really a product of your mentors.
05:20And I was very fortunate at at Dana Farber,
05:22Tom Fry.
05:23In the later years of his career,
05:25I became his mentee and we we met,
05:27you know,
05:27at least two or three times a week.
05:28And he always said take your best
05:31drugs and use them early use them you
05:33know in the multi modality setting
05:35with surgery with radiation and we
05:37already had seen that in lung cancer
05:39back in those days because chemo
05:40radiation it was a study done by
05:42Doctor Dillman back in the the late 80s,
05:45early 90s had shown that there was a
05:47benefit for chemo radiation in this
05:49disease and it did improve survival.
05:52So what causes lung cancer?
05:54I could give a whole talk on this
05:55and and tobacco cessation efforts
05:57that we're we're doing here and
05:59with the ACR and you know we have a
06:01a large tobacco grant here at Yale
06:02and that that's very important for
06:04our community cause New Haven is a
06:05community where smoking is higher than
06:07than in the rest of the United States.
06:09But as I said many of the lung
06:11cancers are non-smoking related now
06:12and you can see actual mutations
06:14and that's the excitement.
06:15This is why so many people want to work
06:17in this field because 20 years ago
06:19each GFR mutations were identified.
06:21So we actually know driver mutations
06:22so we can target those.
06:24But there are now at least ten other
06:28targetable alterations and we're
06:30seeing evidence of of benefit,
06:33you know,
06:34with a broad perspective.
06:34I can see it.
06:35Of course, to any given patient,
06:37it's still not nearly enough.
06:38And I'm sure almost everyone here has
06:40some experience either as a physician,
06:42as a, as a family member, as a friend,
06:44with someone who's had lung cancer.
06:45And while we can see that in men
06:48survival death rates are coming down
06:49and in women with a little bit of
06:51a of a lag smoking in women began
06:54later but still if you look in men
06:56the incidence is coming down a lot of
06:58that's screening and smoking cessation
07:00but the mortality is coming down even more.
07:02And in in women the same 1.2 and 3.1.
07:05So we are making a difference in these data.
07:07You know the data you get from the American
07:08Cancer Society is always two or three,
07:10four years old.
07:11So I think this,
07:12this shows some of the targeted therapies
07:14which I'll talk about in the first
07:15half of the talk and the immunotherapy
07:17benefits are are still on the horizon.
07:19Well, we've built an outstanding program.
07:23We've had retreats over the years.
07:24This is a retreat about 5-6 years ago.
07:26And I guess want to point out
07:27two things about this picture.
07:29One actually three things.
07:30One, this is a great group
07:33multidisciplinary working as a team.
07:35There's myself that's Dan Baffa,
07:37this is David Swenson.
07:38We we held this at the Business
07:39School and and David came in and
07:41inspired us with some of his you know
07:43you know go after the problem hard.
07:45He gave a very amazing speech.
07:48Of course David passed away or
07:49in the last few years,
07:50but then I also want to point
07:51out that's Roy Decker.
07:52We had one of the best
07:55radiation oncologists ever,
07:56both as a clinician,
07:58as a person in with patients and
08:01he passed away recently as well.
08:02So we lost a great member of our team.
08:04But I just wanted to just say
08:07we miss you dearly Roy.
08:09And then you know we've continued to to meet,
08:11this is a few years later
08:13and you can see it's a team.
08:15The only way we're going to
08:16make progress is as a team,
08:17as a multi modality team and this
08:19is more of a clinical meeting.
08:20I'll show you a translational
08:22meeting at the end.
08:23But you can see you know it's a it's a
08:25team approach to lung cancer and you can
08:27see there's Dan Lynn Tenui from pulmonary,
08:29Frank Getterbach,
08:30Sarah Goldberg who unfortunately
08:31can't be here today,
08:32but she sent me a nice note and this,
08:35this was over at the West campus.
08:38Now the centers,
08:39you know these disease centers,
08:40I just say thought I'd say
08:41a few words about that.
08:42We talk about it a great deal.
08:43That's the goal.
08:44Centers of excellence,
08:45multi modality centers of excellence,
08:47taking care of lung cancer throughout
08:50Connecticut throughout the network.
08:51You know we have I I lose count.
08:53What is it Eric,
08:5415 sites
08:55around We we are going to have experts
08:57at all those sites seeing lung cancer.
08:59We might not have every
09:00discipline at each center,
09:01but we will work as a team to
09:03coordinate and really build a big tent,
09:05bring the science to the patients.
09:07The only way to continue to make progress
09:08and I hope you'll see that at the end of
09:10my hour is by bringing science to the clinic.
09:12That's the theme of today's talk.
09:15And we also have a spore.
09:16So we began the spore now a God,
09:18it's hard to believe almost 10 years ago.
09:21We have three projects
09:23in the spore cyclic 15,
09:24which is and I'll tell you a lot about that,
09:27that's actually featured in the CCSG grant
09:29both in the DT and the immunology programs.
09:31And what you'll it's a new agent developed
09:33here at at at Yale and liping Shen's lab.
09:36The mechanism based approach is to
09:37targeting EGFR are very relevant to
09:39the first part of my talk and brain
09:41metastases which I'll talk about as well.
09:43And you can see we have Coors and and
09:44David and David's in the front row.
09:46We have wonderful bio statistical core,
09:48we have developmental programs and
09:50we we were first funded in 2015.
09:53So this effort began on March 1st, 2011.
09:56When I arrived here we had a number
09:58of submissions just for anyone
10:00who is getting depressed.
10:01It took three submissions to get
10:03this score and so it's not easy
10:05but it's it's been great and you're
10:07gonna see and why in a moment.
10:09And it was renewed in 2020 a lot more
10:12easily and now we're gonna renew it
10:14again because I've taken on a new
10:15MPI and Doctor Paletti who's in the
10:17front row and 2nd row and working
10:19with Lee Ping who remains the Co Pi.
10:21We're we're going back in in January.
10:22So we we wanted to wait till the
10:24core grant went in so we weren't
10:26competing for the same resources.
10:27Although there there is I guess a
10:29site visit coming up too and the
10:31beautiful thing about the Spore is we
10:33have developmental projects over 50 of
10:35them over the years and you can see
10:37these are career enhancement program,
10:39you know young investigators
10:40who aren't working lung cancer,
10:42we're getting them involved in lung cancer
10:43and this is a developmental research program.
10:46We could have 10 projects on the SPORE.
10:48The problem is you can really only have
10:49three projects on these grants because
10:51the NCI continues to cut the funds.
10:52We have developmental funds and and
10:54and donor funds we used to enhance it.
10:56But look at this,
10:57all the different departments
10:59that are involved,
11:00it's building a community of
11:01lung cancer here at Yale.
11:02And I think they're about 17 or ones.
11:06And this is the team.
11:07And again,
11:07I just want to point out Anna Esteppe here,
11:10who now Ed Cafton,
11:11actually Julie Boyer many years
11:13ago was our initial
11:15administrative leader and then
11:16Ed Cafton for many years.
11:17Now of course he's working closely
11:19on the CCSG but there's Anna
11:21Esteppe are now staff who who who
11:22just is doing a phenomenal job and
11:24actually made this slide for me.
11:25We probably need a second slide.
11:26These are all the people that are working
11:28in the community of lung Cancer Research.
11:29And then I just want to give
11:31a little shout out to Katie.
11:32So we had a little we went to New
11:34York last week and maybe two weeks
11:36ago now and Katie was honored by
11:38the Lung Cancer Research Foundation
11:39and see the multi modality in this
11:41Shen Liu of the Sheriff Pathology
11:44Valentina from genetics.
11:45Some of us really, we're a community
11:47that's tackling this disease.
11:49So now let's do a little science.
11:50I've already used 10 minutes up,
11:51but you know, I'm always taking pictures.
11:54You see why.
11:56So So what about targeted therapy?
11:57I'm going to tell you about targeted therapy,
11:59immunotherapy in the future.
12:00And I, I might skip through
12:02some slides if it's going along.
12:03So we have time for questions
12:04because you're here in person.
12:05We should be interactive.
12:07Well,
12:07I began when I when I I finished
12:11my my work at Dana Farber.
12:13I,
12:14I,
12:14I went to MD Anderson and I was
12:15telling one of the fellows yesterday
12:17when I was meeting with her,
12:18it's all about the mentors
12:20you have and I had worked,
12:21I had been at Yale,
12:22I had worked in Kim Darnell's
12:24lab at at Rockefeller.
12:24I was very interested in signal
12:26transduction and I was very
12:27interested in EGFR and EGFR receptor.
12:29And just around that time the first
12:31small molecules and antibodies
12:32had been developed against EGFR
12:34and we knew that in epithelial
12:36tumors such as lung cancer,
12:37EGFR was up regulated.
12:39So I was very fortunate.
12:41Juan Kihan,
12:42who is my mentor and who had
12:44recruited me to MD Anderson brought me
12:46upstairs to the president's office.
12:47John Mendelson,
12:48who had worked in the e.g.
12:49Fr field and these new molecules were
12:51coming through and they they offered
12:53me the project and I just said sure.
12:55And I I,
12:55I don't think I realized how
12:57good it was at that time.
12:58I knew that it was a good science
12:59and the science was evolving and and
13:01then we started to do clinical trials.
13:02But also we worked in the lab to try
13:04to identify biomarkers and I went
13:06to start my first clinical trial
13:08and a drug called ZD 1839 and the
13:10investigator meeting was in Palm Beach,
13:13FL which is nice.
13:14My parents live there and then I
13:15go to the hotel and who's sitting
13:17across from me but Pat Larusso
13:18that's when I met Pat in 1997 and we
13:21started and we were the Co leaders
13:24of this first trial of ZD 1839,
13:26which became known as confitinib
13:27and some might know it as Aressa.
13:29And we started using this drug,
13:30an oral agent against patients with
13:33lung cancer, with what we would
13:35call broncholoviral lung cancer.
13:36And in one of 10 patients we saw this,
13:38this clearing unheard of.
13:39You saw the survival curves I showed you.
13:41And these would be patients who could
13:42hardly walk into the clinic and then a
13:44week or two later they'd be feeling great.
13:46We didn't know at that time
13:48what the biomarkers were.
13:49We thought it was easy of our expression.
13:50It it wasn't.
13:51Of course, mutations were found after
13:53about 1002 thousand patients were
13:55treated and and people looked back.
13:57I'll show you that in a moment.
13:58We we knew that it was women were
14:00more likely to respond than men,
14:01but it was really people who
14:03had smoked less and smoking.
14:04You know, if you smoke,
14:05you're more likely to have
14:06other mutations like K Ras.
14:07And the never smokers did well,
14:09we did a lot of skin biopsies.
14:10That's that's when I first met Pat
14:11because we were talking at the meeting
14:12about doing skin biopsies and I was
14:14at MD Anderson at the time and I said,
14:15oh,
14:15I need to bring in my dermatologist
14:17and we need to do a contract and
14:18Pat just gets up and says I do
14:20them myself and then sew them up.
14:21And I was a little scared of her at the time.
14:22It was like pretty.
14:23She was pretty intimidating and and and
14:25now you know why she's been so successful.
14:27She does it herself.
14:29Well, then of course skipping a
14:31little ahead because it's only an
14:33hour talk about four years later,
14:34five years later.
14:35And John Mendelson and I used
14:36to always talk about that.
14:37How can we keep it?
14:38Actually it was eight years later,
14:40the mutations were discovered.
14:41How can we do this more quickly?
14:43That's why with all the work we're
14:44doing with pathology and biomarkers,
14:45we've got to be even quicker now.
14:47But back then it took a while.
14:48Sequencing techniques were still developing.
14:50You know, it wasn't long before this.
14:51We're just doing the Max and Gilbert
14:53sequencing and reading the gels, right.
14:54So but,
14:54but a couple of centers,
14:56Boston and New York took the samples from
14:58patients who were getting these drugs.
15:00These drugs went to what we call
15:02an extended access trial.
15:03People could get it off label while
15:06that while we were waiting for the
15:07drugs to be approved and many patients
15:09were treated and of course it was
15:10found that in the EGFR receptor,
15:11which of course would be a dimer.
15:12This is a simplification in
15:14the tyrosine kinase domain.
15:15There were specific mutations mostly at
15:17that time discovered in exxons 19 and 21.
15:19Now we see them in Exxon 20 as well.
15:21And these mutations of course activated
15:23and caused this to be a driver.
15:25And then these small molecules bound
15:27into the ATP binding site and we're very,
15:29very potent.
15:29They had some rash,
15:30they had some diarrhea,
15:31but they were very potent.
15:32And that led to this is actually being
15:34in a place like MD Anderson patients just
15:36flowed in and we had a big phase one clinic.
15:38I think we must have treated a couple 100
15:40patients in the first two or three years and
15:42I LED the trial and that's Cicely Harris.
15:44She was one of the first patients.
15:46And, you know, she was written up
15:47in the Wall Street Journal because
15:48the idea was we probably didn't.
15:50We didn't cure her lung cancer.
15:51She only lived for nine years,
15:52but we prolonged her survival
15:54with good quality of life.
15:55And that's why Tara Parker Pope,
15:57you know, wrote this article about her.
15:59It's like insulin for diabetes
16:01or or hypertensive medicine.
16:02But that's the problem.
16:04And it continues to be the problem
16:05with EGFR mutated lung cancer.
16:06I've been doing this for 25 plus years.
16:08No one's unfortunately in the
16:10advanced stage ever cured.
16:11That's why the work that Katie
16:12and her lab are doing.
16:13Mark Lemon, I'll show you the project.
16:14We have to find new agents because
16:16we to always stay one step ahead
16:18of the cancer and this just shows
16:20that these are the first generation
16:22drugs gafitinib and orlatinib.
16:23This was known as OSI 774.
16:25For those those interested,
16:26this was actually a Pfizer drug
16:28and Pfizer when they merged,
16:30when they took over the Pharmacia drug,
16:32they they went with the Pharmacia
16:33product and made a bit of a mistake
16:35because this drugs actually became
16:36the the number one ETFR inhibitor.
16:38These are, these are reversible inhibitors.
16:39They're non specific for mutated cells
16:41that get both wild type and mutated cells.
16:44Then there was a second generation drug,
16:46a fat nib,
16:47which also blocked her two and her four.
16:50You add more TKI activity,
16:51you get more toxicity.
16:53We actually did a big trial of
16:55this with cetuximab showed some
16:57increased activity but not enough.
16:59And then of course the the third
17:01generation drug asimertinib which
17:02is an irreversible inhibitor which
17:04has good brain penetration and it's
17:05easier for our mutation specific.
17:07So they'll there's less rash and diarrhea.
17:09It can be given to patients for longer
17:11periods of time without toxicity
17:12and that's how it we were able to
17:14move this drug to the earlier stage.
17:16And this is just an example and
17:18again I'm just giving you a bit
17:19of an overview today,
17:20but the most common mutation for
17:22resistance is known as T790M And the
17:24patients that have that this drug
17:26lasimertinib you know was first studied
17:28to target that resistance mutation
17:30which is about 50% of the resistance
17:32and you can see the activity that
17:33was seen there over 6070% response.
17:35And this quickly became the
17:37front line agent again bring your
17:38best drugs to the front line.
17:40But again few if any are cured.
17:42That's the problem.
17:43That's what I'm gonna talk to you
17:45about now I was at MD Anderson
17:47and you know when you you know
17:49here we put about 100
17:51and 10120 patients on lung trials
17:53in a Goodyear there we're putting
17:55with three or 400 patients on trial.
17:56But what I noticed I was leading
17:58the group lung group there is we're
18:00doing it on 20 different trials.
18:01So we we said can we do one trial
18:04and and and use biomarkers to
18:06decide who should get which drug
18:09and wasn't easy 'cause you know if
18:11you have a group that's 20 people
18:12everyone has their own favorite drug.
18:14It it really is a a sociology project
18:16and we didn't have a sociology department
18:19there like we have here or or psychology.
18:21But what we did is we actually
18:23convinced the team that it would be
18:25better for all of us to work together
18:26on one trial and we used a little
18:28bit of push and and and and and
18:30there was a pull though because the
18:32science was exciting and at that time
18:34and and David Meta who's here now,
18:36I work with him at that time we
18:38we we we could get biopsies.
18:40Core biopsies, prior to 2004,
18:442005, most lung cancer biopsies
18:46were fine needle aspirations.
18:47You had a little bit of few cells,
18:48maybe you made a cell block,
18:49but you didn't have really
18:51enough tissue for sequencing.
18:52But now that sequencing
18:53was coming to to bear.
18:54We said can we do a trial called Battle
18:56and we worked with a pathologist,
18:58Ignacio Astuba Jack Lee,
19:01a biostatistician,
19:02Ed Kim now at City of Hope and
19:04with our mentor Wang Ki Han.
19:06We developed a trial we called Battle
19:08and what we called it is biomarker
19:10integrated approach of targeted
19:11therapy for lung cancer elimination.
19:13So what we did is we had four
19:15or five different drugs.
19:16We did a biopsy.
19:17We got the result within 14 days
19:19and then we used that result to say
19:20this patient has an EGFR mutation,
19:22they should go on herlatinib.
19:23This patient has a VEGF up regulation,
19:25they should go on VET detonib and
19:27I actually think it's and we used
19:29an adaptive statistical design and
19:30I've talked about that here before.
19:32The results did pan out.
19:34We,
19:35we found new biomarkers for VEGF inhibitors.
19:37The EGFR mutation came out of the story.
19:40Now of course you say we knew that already,
19:41but we didn't.
19:42This was before the mutation was fully
19:44validated and we showed that core
19:45biopsies were feasible and and safe.
19:47And this is about when I came to Yale.
19:49So when I came to Yale,
19:50I said let's let's do a battle trial here.
19:51And David RIM, my friend in the
19:53front row and that's Jeff Sklar.
19:54I miss good old Jeff.
19:56You know,
19:56he used to always be in the front row
19:58at the grand rounds he'd be here and
19:59I I said can we do a core biopsies?
20:01And they told me we had one
20:02table where we could do it.
20:03You know, there's no, no capacity.
20:05I was saying I should go back home and then
20:07that that was Rocco who was
20:09working with us from the CTO.
20:11And that's Julie Boyer,
20:12that's Emily who now works as an APRN.
20:15She was a researcher nurse at the time.
20:16We put a little team together and
20:18we ended up putting about 40 or 50
20:19patients on the on the battle trial.
20:21Now it wasn't as many as a 300
20:23MD Anderson but we started doing
20:24a tissue based approach and and
20:26the team started to work together
20:28and and that that's how that was
20:30we were doing that and that was
20:31actually funded by an RO one that I
20:34brought with me from from Anderson.
20:36But moving to the what I want to tell
20:37you about it in my first story is
20:39how can we do better in lung cancer.
20:41We're not going to do better by
20:42using these targeted therapies
20:43just in advanced disease.
20:44We have to find the disease earlier
20:46and we're finding disease early
20:47because of screening and because of
20:49smoking prevention and at the time
20:51that someone comes in for smoking
20:52prevention that's a teachable moment.
20:54But we know that even in lung
20:55cancer when you find it early you
20:57know and so often they find it
20:58in the emergency room these days,
21:00right they're doing a cardiac
21:01scan or some other scan.
21:02Someone has a small nodule,
21:03the five year old survival even
21:05even there is only 60 to 74% that's
21:07how metastatic lung cancer is.
21:09And if it's stage 2 with a few other nodes,
21:1147 to 55% and it happens to be
21:14stage 3 with N2 lymph nodes or
21:16stage 3 B 38% five year survival.
21:18So even early disease even with chemotherapy
21:21is not as curable as we would like.
21:24So if someone has an EGFR mutation which
21:26are about 1015% of the patients in the
21:28Western world and as many as 40% in the East,
21:31Asia,
21:32China,
21:32wouldn't it be nice if we could
21:33and we know that the percentage
21:35of mutations are about the same
21:36across the spectrum of stages.
21:37Wouldn't it be nice if we could
21:39give the EGFR inhibitor earlier.
21:40So that's that we we sat down about
21:4310 years ago now a group of us
21:45and I had a colleague Masa Hara
21:47Suboi from Japan and Ylan Wu from
21:50China working with AstraZeneca.
21:52We said let's let's design this
21:54trial now and they were very
21:56proactive and and and they said,
21:57yeah,
21:57let's do it because they we knew an
21:59active and trial would take a long time.
22:01So that's the Adura trial and the idea
22:03was to take patients who had been
22:05completely resected for lung cancer
22:07and you can see the eligibility here.
22:10And then we stratified them by
22:12their their stage 1B2 or 3A,
22:13they all had R0 resections,
22:15meaning all the tumor was removed
22:17with clean margins.
22:18We only took the two most
22:20canonical EGFR mutations,
22:2119 and 21 and we we did stratify by race.
22:24About 2/3 of these patients were Asia.
22:25You can imagine it.
22:26There were more of these mutations in Asia,
22:28so more patients went on there and
22:30then the patients were randomized to
22:32firstly they could get chemotherapy
22:33if if it was deemed appropriate.
22:34Most of this takes two and three
22:36lung cancers, get chemotherapy,
22:37platinum based chemotherapy and it's
22:38about a 5 to 6% improvement in survival.
22:40Not a lot but it does improve survival.
22:43I I would use it because it's something but
22:45then we randomized to either acimertinib
22:47at 80 milligrams once a day or placebo.
22:49I'm often criticized how could you do
22:51a placebo, but there were no data.
22:53There were plenty of trials before this
22:54that had tried other EKFR inhibitors and
22:56looked in this setting and nothing worked.
22:58They're all too toxic.
22:59But we figured this drug was brain penetrant,
23:01it was EKFR mutation specific,
23:03it could be used and it
23:04would be safely administered.
23:05So we used OSTEO Mertini versus placebo
23:07and we treated for three years.
23:08But the primary endpoint of this
23:09trial was disease free survival,
23:11no disease recurring.
23:11Remember they started with no disease.
23:13So we're seeing if anything recurs and the
23:15trial was powered for a hazard ratio of .7,
23:18meaning a 30% improvement.
23:20So about I guess it's almost four
23:22years ago now in April there was a
23:24safety review of the trial going on.
23:26We no efficacy but the cure
23:27of that safety committee.
23:28I don't know if anyone here has
23:29ever been on a safety committee.
23:31He said something's wrong here.
23:32It looks like one of the groups is
23:34doing better than the other and
23:35normally it's the control group
23:36is doing better and they stop the
23:38trial but they actually looked at
23:39it and said the the treatment group
23:40is doing so much better,
23:41it's unethical to keep the trial going.
23:44So,
23:44so we actually got a call it was in April.
23:48We we looked at the data and and
23:50actually the hazard ratio I'll show you
23:52in a moment was so good that you'll
23:54you'll see where things went after that.
23:56So this is what we saw.
23:57So this was depending on your religion,
24:00it was Good Friday and Passover,
24:01I I'll go with Passover,
24:03but you can see here,
24:04here it was in in in that year the
24:05stakes 1B and 3A patients here are
24:07patients who got the acid mertinib
24:09in the adjuvant setting and here
24:10is the control and the hazard ratio
24:12was .2 or an 80% improvement.
24:14So that that was phenomenal,
24:17better than expected.
24:18Of course,
24:18you would expect that this would work,
24:20but with this sort of separation and
24:21this sort of result and it actually
24:23made a plenary talk at ASCO that
24:25year and then we've updated it
24:27just earlier this year.
24:28This is the,
24:29this is actually the review at the
24:31time when it would have normally
24:33been been analyzed and it's still
24:35.27 or 73% improvement.
24:37So using a drug early keeps the disease
24:39from recurring. Now where do you think
24:42the disease is kept from recurring from?
24:44Well, the first, I guess we'll show you
24:46that all all parameters benefited sex,
24:50age, whether or not the patient was
24:51a prior smoker, Asian or non Asian,
24:54all three stages, both mutations.
24:56So you always do better with XN 19 deletion,
24:58it's a loss of it's a deletion versus the
25:00point mutation which can revert a bit
25:01easier and you can see whether or not
25:03the patient got adjuvant chemotherapy.
25:05When you look at a forest pot like that,
25:06for those who aren't used to it,
25:07anything to the left of 1 is good.
25:10And then if you look what happened is in
25:13the patients who got out to Mercenib,
25:16you can see actually let's start here,
25:18here the patients got placebo 46%
25:20who recurred.
25:20You can see that many of those
25:22are distant recurrences.
25:24Whereas in the small number of
25:25patients in the early data who who
25:27who recurred on the ASA emergent
25:28of on the treatment job drug only
25:30about half as many were distant.
25:32The drug is keeping patients
25:33from getting distant metastases.
25:35That's what causes patients to
25:37die metastases to other organs,
25:38brain, liver and bone.
25:39And actually we looked at that
25:41and this is pretty phenomenal.
25:42This is looking at the brain as
25:43the first site of recurrence,
25:45which is a major issue.
25:46If if you ask a patient with lung cancer,
25:48he or she will tell you I'm
25:49worried about my brain.
25:50We just had AEAB for our spore last Monday.
25:52That's exactly what our
25:53patient advocate told us.
25:54But you can see here's patients adjuvant
25:57disease who got last Emergenib.
25:59Here's the control group hazard
26:00ratio for recurrence in the brain
26:02.24 meaning a 76% decrease in in the
26:05first recurrence being in the brain.
26:07So it's keeping the tumor from the brain.
26:09We'll we'll do this forever probably not
26:11but but it did it for a long period of time.
26:13We treated for three years and
26:16here you can see now now everyone
26:18was sceptical you know I don't I
26:19I never used to do the Twitter.
26:21Then I started doing the Twitter
26:22because people said you have to
26:24read the Twitter because people
26:25are being critical of your data.
26:26And now now and I don't know how to
26:28do Twitter because it's called X and
26:29I haven't figured that out yet but
26:31there were all these people that said
26:33well there's no survival benefit.
26:34Now the drug got approved based
26:36on disease free survival,
26:37but there hadn't been a survival
26:38benefit and we had to wait for a
26:40number of years to have 20% of the
26:42patients unfortunately die because
26:43that was the end point that had been
26:45pre specified to look at survival
26:46and it's API you hate for that to
26:48happen you know because I'd rather
26:49there never be an end point because
26:51you don't want anyone to succumb
26:52to their disease.
26:53But I got a call
26:54last November that the trial was nearing
26:56the end and it was very you'll see
26:58a very interesting because Eric was
27:00you know here and the ASCO President.
27:02I'm thinking well this could
27:03be an ASCO presentation.
27:04So we're waiting for the data
27:05to make sure over the, over the,
27:07over the winter and and then about
27:10March saw this curve and this
27:12is the survival curve and again
27:14it was a very big DFS benefit.
27:15But in survival the hazard ratio is .49.
27:18So here's the patients who got
27:20osteomertinib and here's the control
27:21and you can see at at five years,
27:2488% versus 78%,
27:25so 10% improvement in survival,
27:27the hazard ratio .49,
27:28so a 51% improvement in survival.
27:31And remember the drug stopped
27:32here at three years.
27:33We only treated for three years.
27:34So now we have to continue
27:35to watch these patients.
27:36We have liquid biopsy samples.
27:37Hopefully next year I'll give
27:38another grand rounds.
27:39I have those samples.
27:40I'm analyzing them now,
27:41but we're not ready to talk
27:43about them unfortunately yet.
27:44And then it was pretty cool.
27:45So who knew that Eric was
27:46going to be the director here?
27:48It's just like,
27:48it's almost like an amazing coincidence.
27:50He's the ASCO president and
27:51there I am presenting it to the
27:53plenary beside him and Kimi Ying.
27:54It was really pretty cool.
27:55And you little can't make this stuff up.
27:57It just sort of happened, right Eric,
27:58it's who would have known?
27:59So it was really, that was phenomenal.
28:02I was pretty nervous.
28:03The only the best thing about,
28:05best thing about the plenary
28:06is the green room,
28:07the drinks and the food in there.
28:08Phenomenal.
28:09See, that's that's the secret of the ASCO.
28:11OK.
28:12Now you you see the overall
28:15survival both if patients got
28:16actually in chemotherapy or
28:17without actually in chemotherapy.
28:19So you give it if you know sometimes
28:22patients don't want it and there's
28:23a big push now to avoid the
28:25chemotherapy we're looking at that.
28:26But right now we we we we we we
28:28we we suggest that patients get
28:30chemotherapy if they can And then
28:32you know the the big critique
28:33of this trial and for those that
28:34read the New England Journal,
28:35there's there's a letter I I
28:37responded to a letter today from
28:39an investigator in Italy who
28:40said well you didn't not all
28:41your patients got ostomertinib.
28:42So it's not really a fair trial
28:44and they're right.
28:45Not everyone could get ostomertinib.
28:47But look in the ostomertinib
28:48group and in the placebo group
28:50about 8080 to 90% got an EGFR
28:52inhibitor in a second line setting
28:55did only 43% got ostomertinib.
28:56But the drug wasn't even improved
28:57in the front line setting
28:58when we started the trial.
28:59So well it's not perfect,
29:01it's not a perfect would would
29:02patients have done better if they
29:04got an osteomordinib early probably.
29:05But I I would what we said in this
29:08reply is the difference is so great.
29:11I think use your best drugs earlier and
29:14I think this these data hold hold water and
29:17then you know it's not without toxicity.
29:20Be careful as physicians,
29:21as nurses, as caregivers, you know,
29:22it's easy for you to say there's no problem
29:24when you're giving a drug versus a placebo,
29:26there's always going to be added
29:28toxicity and this drug does cause some
29:29rack and it does cause some diarrhea
29:31and it is debilitating for patients in,
29:33in about 4 to 5% of the cases.
29:35We have to be sensitive to that.
29:36Some patients need breaks,
29:37some need dose reductions.
29:39But for the most part, if you look
29:41at discontinuations and serious AE,
29:43there were 14% on placebo versus 20%
29:45on the drug which is pretty low.
29:47But again there is toxicity and this
29:49is where quality of life and you know
29:51the survivorship clinic and others,
29:52you know we need to look at this
29:54and help patients.
29:55So what's in the future,
29:57we're continuing to file the overall
29:59survival because what's going to
30:01happen in five years and 10 years,
30:02we're doing a bunch of
30:04translational analysis.
30:04We're going to have Pasayani here for the
30:07Calabrese lecture this year and he's going
30:09to tell us about procester Tri cells,
30:10which he studies and Katie
30:12studies these as well.
30:13There are still cells that remain that
30:15remain resistant to to EGFR inhibitors.
30:17We actually have blood from
30:18about 1/3 of the patients.
30:19It's very hard to get samples out of China,
30:23but from the Western world and from Japan,
30:25we do have blood samples and tissue samples.
30:27So we're looking at at at at that.
30:29We're also looking at, you know,
30:31there are trials looking at
30:32neoactuvent osteomerotradium.
30:33Now that's all the rage right now.
30:34We're looking at earlier disease.
30:37Adura 2 is looking at this
30:39was stage 1B disease,
30:40so more than 3 centimeters.
30:41Everyone always calls me
30:42what about the small tumors,
30:43I think it'll probably work there too.
30:45But we need to do the trial and
30:46we're actually doing a trial where
30:47we're giving the drug for five more
30:48years because there is some sense
30:49when you stop the drug that the the
30:51brain metastasis started to increase.
30:52So there might be some patients
30:54who are cured in my opinion,
30:55but some who are just having cytostatic
30:57stability of disease and that's
30:59something we have to figure out.
31:01So I'll just end this portion
31:02of the talk with this slide.
31:03So another mentor of mine,
31:04I don't know if anyone knew Josh Fiddler,
31:06but I I,
31:06I actually when I was at MD Anderson,
31:08I had a small lab with him and and Josh
31:11used to always say metastases are are
31:13are what would kill patients and he
31:15talked about the metastasis cascade.
31:17So I think what we've really shown
31:18here is we've taken our best surgery
31:20and chemotherapy and we've added
31:22targeted therapy to keep patients
31:23from progressing in the brain,
31:25liver and bone.
31:25And I think this is a paradigm
31:27now we're going to see more of
31:28the drug was approved as I said in 2020.
31:31There are a whole host of other mutations.
31:32As I mentioned,
31:33there's a trial called Alina that will
31:35be in the news in two weeks from today,
31:36you'll hear about Alina, this is electinib,
31:38it's the Roche drug for ALC.
31:40And we, we have a press release that
31:43that trial is positive for disease,
31:45for disease free survival.
31:46And I bet they're not going to
31:48say wait for overall survival.
31:49I think based on the Adura results
31:51and actually Anne and I are going to
31:53the American Medical Association next
31:54week for clinical trials meeting and I
31:56think at that meeting we're going to
31:57discuss this trial because as a paradigm
31:59what should the right end point be,
32:00you know in in patients
32:02in the accident setting.
32:04But I think we've shown that
32:05disease free survival works. OK.
32:07And here's a little plug for Katie.
32:09I don't have time to talk about this,
32:11but Katie and and Sarah and Mark,
32:13what an amazing team,
32:14Mark's a little younger there.
32:16So here, here, here's the group,
32:18I'm,
32:18I'm a little older so here here's
32:20here's the group that that that's
32:22been meeting and you know Mark's
32:24now the Chief of Pharmacology and
32:26super duper team obtaining samples.
32:27You can see we have Anna and
32:29Heather and the entire team are
32:31getting samples from the clinic.
32:32We're banking the samples,
32:34we're looking at these samples
32:35that's how science is going to be
32:37made and understanding resistance.
32:38And then we also have a project three of
32:41the spore looking at brain metastases.
32:43I'm just putting a little plug
32:44in for that that project.
32:45No time to talk about it today.
32:47And then we oh, this is important.
32:48We have an alliance with AstraZeneca.
32:50This has been critical for the
32:51sport because by developing industry
32:53alliances and this is one of the
32:54things I've been working on with the
32:56Dean's office in the last year and
32:57a half and I'm really enjoying it,
32:58working very closely with MENA Wang,
33:00who's pictured down here.
33:01And here's Kathy Lynch from Yale Ventures.
33:04There's Pat.
33:04We, we, we,
33:05we started this together about 5-7 years ago.
33:08Here we are in Cambridge 2017 and
33:122022 we all look the same and and
33:14you can see that this this is just
33:17an amazing collaboration because
33:18that's how we're we're really making
33:20difference and I I got to move on but
33:22this this is the timeline of that
33:23alliance and here's the most recent
33:25visit actually Dean Brown was with us.
33:27We we're really we're getting
33:29funds but we're getting drugs
33:31and compounds test compounds.
33:33Marcus I see in the front row.
33:34I know he's very excited about this.
33:35It really is the way we're bringing
33:37this in and we're expanding this
33:38now to head and neck cancers.
33:40We're heading to breast cancer and
33:41other other cancers in the future.
33:43So this is going to be something
33:45that's with AstraZeneca and
33:46other companies that will,
33:47I think be very important.
33:49So just in the last 20 minutes,
33:50a little bit about immunotherapy.
33:54That's also an amazing new paradigm in
33:56lung cancer targeting immunotherapy and
33:58of course the checkpoint inhibitors.
34:00You know, the first trials
34:01were done here at Yale.
34:02I don't know if everyone realizes that.
34:04And of course, we have Lee Ping Chen here.
34:06There's a very nice article about
34:08him in fierce Biotech yesterday
34:09talking about his contribution to the
34:12development and discovery of PDL 1.
34:14So this is the probably the
34:15first responder in lung cancer.
34:17I don't know if Scott.
34:18Scott's probably in clinic now
34:19because that's why he sees so many
34:21patients and helps so many people.
34:22So this is a patient Maureen
34:25who came to Yale Squamous lung
34:26cancer wasn't a candidate for any
34:28of those targeted therapies,
34:293 times refractory lung cancer.
34:31And June 2010 she went
34:32on the trial of MDX one,
34:34one O 6 that Mario was running with
34:37Scott and Harriet and you can see these
34:39large tumors in her lung and her liver.
34:41Within months they responded.
34:42The trial was for two years of
34:44what we now know as novolumab.
34:46Here she is a year 8,
34:47but her X-rays look this way.
34:49Now she comes back.
34:50We've seen her.
34:51I'm sure Tara's seen her at some
34:52of the survivor events.
34:53This is the promise of a phase one
34:55trial of new drug development.
34:57The problem is this is only 15%
35:00but for This is why everyone
35:01wants to work in this field.
35:02We see a light at the end of the tunnel.
35:03It's just a very long tunnel,
35:05but we know that 15% of patients
35:06are going to benefit.
35:08And then Scott and he he ran
35:11this trial OO 3:00 and basically
35:13this is an actuarial survival
35:14curve because it's now with more
35:16than five years of follow up.
35:18He published this in JCO in 2018 at
35:20five years in the refractory setting on
35:23the volnab 16% of patients are alive.
35:26And when I use this slide to teach
35:27in my clinical trials course,
35:29I talk about the tail of the curve
35:31because this is a non proportional hazards.
35:33You have two slopes, 1 here,
35:34one here.
35:35We know that there's a tail problem is
35:37how do we get more people off the tail.
35:39These patients have primary resistance.
35:40There are other things going on.
35:42Maybe it's another checkpoint,
35:43maybe it's a regulatory T cell.
35:45This is why we shouldn't just
35:46study the next PD1 inhibitor
35:47or the next PDL 1 inhibitor.
35:48We need to think about what's going
35:50on in the micro environment and
35:51I'll show you how we're doing that.
35:53So just quickly keynote one, Paul.
35:55ADA ran this trial here at Yale a decade ago.
36:00It was Melanoma lung cancer,
36:01small cell lung cancer.
36:03This was with Keytruda with
36:04tembrelizumab that led to a trial
36:06that I LED called KEYNOTE 10,
36:08which established PDL 1 as a biomarker.
36:11If you have high levels of PDL one,
36:12you do better than if you have lower levels.
36:15That led to using the,
36:17the pembrolizumab in the frontline setting
36:19and then that led to accurate therapy.
36:22Sarah Goldberg and and and Harriet
36:24working with Veronica Shang,
36:25they did the first study,
36:26the very first study and this is when
36:28we're saying we we can get this study.
36:30We got this still plan on in three
36:32months and we're getting back to that.
36:33They did a study where investigator
36:35initiated study where they took
36:36pembrolizumab because we're already
36:38working with Merck and they did it in
36:40and we're still getting data from this.
36:42And we took patients with small brain meds,
36:44they had to be less than two centimeters
36:46and we treated those patients with, with,
36:48with the drug without any radiation.
36:50If someone's going to live for 2-3 years,
36:52the the one year survival with pembrolizumab
36:54and a high PDL one patient is 35%.
36:56So if you're going to be alive,
36:58actually the five year survival is 35%,
37:00excuse me.
37:00So if you're going to be alive in five years,
37:01you'd rather be alive without any
37:03cognitive impairment from radiation.
37:04So this was really established in this
37:06trial that was both a collaboration
37:07between Melanoma and the lung cancer
37:09group and you can see here's extra
37:11cerebral response and brain response
37:12and you can see they're about equal.
37:14And Harriet, it won't tell you this,
37:16but I'll tell you this and it
37:17wasn't the New York Times.
37:17So I'm not reaching any, any confidentiality.
37:20But when a 99 year old ex president had
37:22Melanoma in the brain about eight years ago,
37:25they called us at Yale.
37:26And while Curran asked what are you
37:28doing with pembrolizumab in that setting?
37:30And you can,
37:31you can put the pieces together yourself.
37:33So what about precision medicine?
37:34How can that help?
37:36Well,
37:37David RIM,
37:37I was asked to be the discussion
37:40at ASCO about six years ago for
37:42the early studies on the Volumab.
37:43So I went to my my good friend David,
37:45who by the way used to work on breast
37:46cancer and he moved over to lung
37:48cancer and now Eric's getting him back
37:49and I'm a little worried about that.
37:51But but but it's OK.
37:52He works on the head and export too.
37:54The very the pathologists are
37:56your pathologists,
37:57your your your statisticians,
37:59critical core members.
38:00For any of these grants,
38:01you've got to have a good course
38:02and that we always get exceptional
38:04thanks to David and Kurt and
38:05now Sonia's working with them.
38:06So you can see, I said, David,
38:08why is this PDL one marker so,
38:10so bad And Li Ping was with us and
38:12Li Ping said of course it's not bad.
38:14I discovered it.
38:15It's actually very good,
38:16but you just don't measure it properly.
38:18And then David made this slide for me
38:20that everyone's now used and and I
38:21make sure the credit was there David.
38:23So everyone uses this and and
38:25David has done very
38:27well at meetings and and and
38:28being involved in the panels.
38:30Here's one piece of lung cancer,
38:31one tissue piece and two different areas.
38:34One area is stone cold negative for PDL,
38:36one for two different antibodies and one
38:38area is positive with two different results,
38:40you know slightly different and it
38:41it matters where you measure it.
38:42The the green is cytokeratin,
38:44so that's tumor. The the blue,
38:46the Dappy is the nuclei and that and
38:47you can see the the red is PDL one.
38:49It could be either in the tumor
38:51or the stroma.
38:51So it's the variability of
38:53measurement and the sensitivity asset.
38:55But you gotta have PDL ONE for
38:57PD1 and PDL 1 blockers to work.
38:59And we have, we're so fortunate.
39:01So Katie deserved 2 awards last
39:04week because she and Scott set up
39:07this amazing repeat biopsy program.
39:09That's why we got to make sure the
39:11freezers are backed up in our office.
39:12And we also have to make sure we
39:14have more liquid nitrogen because
39:15these samples are so valuable
39:17because for the last decade,
39:18the lung group has been collecting
39:20samples when someone comes in and they
39:22have recurrent disease and they've
39:23putting a little plug in for the.
39:25When someone comes in and
39:26they have recurrent disease,
39:28we actually get consent to
39:29get their old biopsy.
39:31And then when we get the new biopsy,
39:32the biopsy's done with the help of the team.
39:34And there's Anna and Heather
39:35works with her sometimes goopang,
39:37I don't know if he's here
39:38or maybe he's online.
39:38The team gets a fresh biopsy and and we
39:41get fresh tissue and we get paraffin,
39:43we make transgenic, we make,
39:44we make PDX mice, This is, this is.
39:47And zenta or pathologist is usually
39:49there to make sure we get good tissue.
39:51This is the key,
39:53having samples from refractory patients.
39:54We started this with TKIS,
39:56but then we did this with IO agents.
39:58We went and have the spore 10 years
39:59ago if we didn't have this data set.
40:01And we've used this both with our
40:03own samples and with industry.
40:05This is a very nice trial that
40:07Scott and I and others did with
40:09the drug known as MDX 1107.
40:11Now it's known as pembro as a tezalizumab.
40:14So this was a phase one trial which we
40:16led here at Yale and it actually was
40:18published in Nature almost a decade ago.
40:20But in this trial,
40:21we had patients with lung cancer
40:22who responded to a PDL 1 inhibitor.
40:24But because we could get those fresh
40:26biopsies, we had pre and post biopsies.
40:28So here's a prebiopsy on this
40:30responding patient and you can see
40:31you know CD 8 positive T cells and
40:33then post you can see a lot more.
40:34This is what you call the adaptive
40:36immune response.
40:36This is,
40:37this is the blocking the PD1 PDL
40:39one up regulation of interferon
40:40T cells coming to the tumor and
40:43then using an RNA chip.
40:44And why did this?
40:45Why did we get this trial?
40:47Ira Melman, good old Ira Melman
40:49had moved to Genentech and I
40:50went out and had dinner with him.
40:52I I had remembered IRA from cell
40:54biology that was when I was at
40:56Rockefeller done but but still
40:57I knew Ira and Ira helped us to
40:58get this trial and and with IRA's
40:59group did this work for us the
41:01RNA shift and you can see pre and
41:03post green is pre yellow is post.
41:05You can see this is an example
41:06of what's happening when the
41:07immune response is active.
41:08So we we understand what the active
41:10immune response is how is how do we
41:12get this to go on in every patient
41:1420% of patients responded in that
41:16trial but the other 80% did not
41:17and those patients that did not we
41:20described in this paper the immune
41:21desert you know CD 8 before and
41:23after the tumor just laughs at,
41:25at the PDL 1 inhibitor nothing happens
41:27or you can have a non functional
41:29immune response where you have some
41:30CD8 cells and maybe a few more posts.
41:32But if you look at that immune
41:34shift completely flat and then this
41:35is actually something we're seeing
41:36more and more of and I don't have
41:38time to talk about it today but our
41:39next trial on the sport is going
41:41to target this that that the cells
41:43that get inhibited that can't get
41:44to the tumor because you get this
41:46line of interference and we call
41:48this the the immune excluded cells.
41:51So more to come on this,
41:52I'm going to skip this for the sake of time.
41:56We just have to do a little editing.
42:02So I I will just say that now all
42:05these agents are moving up up front.
42:08We're we're now in the process of
42:10taking immune therapies that are being
42:11used in the neo accurate setting.
42:13And it's actually a very fertile time
42:15because when we sit at the tumor board,
42:17we have to decide are we going to do
42:19surgery and accurate therapy like
42:20I showed you for TKI inhibitor.
42:22So we're going to use the neoactivant
42:24therapy 1st and we're seeing about 15%
42:26half CR rate and a 30 to 40% minor CR
42:31rate PR minor major PR rate, excuse me,
42:34when we use these agents upfront.
42:36So that's going to be the next stage
42:39neoactivant trials and I just want
42:40to make a plug for tumor boards.
42:42This is sort of what our tumor
42:43boards look like lately.
42:44So I I would just like to as long
42:46as I have the podium today encourage
42:47people to go to tumor board and start
42:49having our tumor boards hybrid.
42:51We can't have them all in person
42:52because we're 15 sites.
42:54But the tumor board discussions
42:55are going to be really critical.
42:57These are drugs that were approved from
42:59Yale LED studies very proud of that.
43:01All these drugs had some of their
43:03first studies here at Yale in the
43:04lung program and we have many more
43:06to come and we're seeing that in
43:08all of our programs and that's our
43:10experimental Therapeutics or DT.
43:11We can do the science on these studies.
43:13But the reason I skipped is I'm much
43:15more interested to tell you about the future.
43:17So we're we now have to target
43:19immunotherapy but I showed you at
43:21the beginning of my talk was how
43:23we used targeted therapy.
43:24We understood the target brought it
43:26earlier to have the greatest advantage and
43:29I told you about the the biobank we have.
43:33Well let me show you how it has paid off.
43:35So here we had patients who had
43:37immune therapy and they responded
43:38and then they had more immune therapy
43:40and they became resistant.
43:42So thanks to that poor protocol that we've
43:44had running for I guess what what Katie,
43:4612 years or or more,
43:47right.
43:47And we now have tumor tissue,
43:50germline DNA pretreatment and that
43:52resistance and working with Rick
43:54Lifton a number of years back before
43:56he left and and his lab,
43:58we we we sequenced all those tumors.
44:01And very interestingly you can see
44:03here the 14 tumors and you can see
44:05the first response shown here in
44:06the green and the resistance shown
44:08in the yellow triangle.
44:10So we had pre and post samples on
44:11patients who responded and then
44:13became resistant to immune therapy.
44:14And you can see it was from a
44:16hodgepodge of different trials,
44:17some with anti PDL 1, some with anti PD.
44:19One the drugs are different but quite
44:21frankly for this type of analysis I
44:23don't think it makes much of a difference.
44:25Well, two stories emerge from this.
44:27They've both been published
44:28several years back,
44:29one that that Katie and Scott LED
44:31where we actually had one patient.
44:32This patient was on Tremolomab and
44:34Debiolomab had a tumor that responded
44:37and then it became resistant.
44:38And actually by looking at
44:40the the biopsies pre and post,
44:41we didn't see much different in PDL one.
44:44But what we did see is this is
44:47loss of beta 2 microglobulin.
44:49So if you look at copy number,
44:51there was already lost a pre immunotherapy.
44:54The patient had already lost one
44:55copy of Beta 2 microglobulin.
44:57And then when the patient became resistant,
44:59they lost both copies of Beta 2
45:01blackroglobulin and Beta 2 microglobulin of
45:03course is an essential component of MHC one.
45:05So these tumors lost the ability
45:07to present neo anakin to T cells.
45:10So we are actually seeing that about
45:11five to 10% of the time in lung cancer.
45:13So these patients are going
45:15to need more of this.
45:16This immune approach won't work.
45:18We need to use other other ways.
45:20Maybe the innate immune system's going
45:21to be the way we target these tumors
45:23and K cells or something like that.
45:25And then what what Kurt and and David did
45:27is this is quantitative amino fluorescence.
45:29We took a whole bunch of
45:30samples of responders,
45:31non responders.
45:31These are samples that Scott had
45:33collected over the years and we
45:34looked at those samples and we
45:36stained for CD3 and and when double
45:38labeling and we looked at CD3.
45:40So we looked for tumors that were low CD3,
45:42so low T cells.
45:43We looked at tumors that were low CD3,
45:46high CD3 and low grand Simon Ki 67 and
45:48the idea there were these are tumors
45:50that were not activated in their T cells.
45:53And then we looked at some tumors
45:55that were high CD3 and high Granzyme
45:57and KS 67 and that Granzyme and KS 67
45:59are the are the white and the green.
46:02And I would have predicted that
46:04this is the group Group C here
46:06that would have done the best.
46:07But interestingly the group that did
46:10best was you can see here's here's
46:12the the type 2 group shown here,
46:15high CD3 and low granzyme and low KS 67.
46:18So why is the group that has many
46:19T cells but has the non activated
46:21T cells doing better?
46:22And that was something we really
46:24couldn't explain until recently when
46:26Li Ping Chen and and Kurt and others.
46:28Miguel Sanam Ahmed who was in Li
46:31Ping's lab did a study and actually
46:33using citep analysis showed that
46:34many of those T cells that are
46:36in the tumor are burned out,
46:37they're they're not active.
46:38And it probably explains why
46:40chemotherapy works with immunotherapy
46:41because chemotherapy kills the T
46:42cells that are in the tumor micro
46:44environment making room for more
46:45active and newer T cells to come in.
46:47This is a work in progress and we need
46:49fresh tumor samples to study this more.
46:51But the idea is that it's
46:52the quality of the
46:53T cells of the tumor that matters,
46:54not just whether the T
46:56cells are there or not.
46:58In the last few minutes,
46:59I just want to tell you about one
47:00more story and that's how how,
47:02how we, how we, how we look at resistance.
47:04So what we're thinking here in
47:06our group is when we looked at
47:09250 cases of of lung cancer,
47:11you can see that about 70% of these
47:14tumors were high PDL one and high kill.
47:17So they have a lot of PDL one and
47:18a lot of T cells in the tumor.
47:20These are probably the tumors that
47:22responded quite well to immunotherapy.
47:24But here's another 26% of tumors
47:26that have high tail.
47:27There's a lot of blue but no PDL 1,
47:29so probably suggest there's
47:31another checkpoint in play.
47:32And then very interestingly 45 or twenty
47:377057% of lung cancers are cold.
47:38So it's really these type 1 tumors
47:40I've already talked to you about.
47:41These are the type 2.
47:42I'm sorry, these,
47:43these are the tumors that probably respond,
47:45have a durable responder, Maureen.
47:47They either require resistance
47:48like I just showed you or they're
47:49probably resistant for mechanisms
47:51we don't yet understand.
47:52But it's the other other tumor types
47:53that we've been targeting in the
47:55spore and type three of the tumors
47:57that must have some other checkpoint.
47:58So Li Ping and you know,
48:01I became involved with this 'cause I
48:03did a sabbatical in this lab in 2015
48:05and they were working on this project.
48:07I said can we bring this
48:08project into the spore?
48:09And and he,
48:09he said sure he was developing it
48:11with a company called Nexcure and
48:13this is a drug known as cyclic
48:1515 and I'm running low on time,
48:16but basically this is a homolog to PDL one
48:19and in in tumors that are interferon high,
48:22you know that activates PDL one,
48:23but it actually down regulates cyclic 15.
48:25So it makes sense that this,
48:27this marker,
48:28this,
48:28this protein might be more important
48:30in tumors that are PDL one negative
48:33and actually that's been shown.
48:34So here's cyclic 15 and here's
48:36PDL one and you can see in
48:38tumors that that have cyclic 15,
48:40it's a suppressor of T cells.
48:43So the idea was could this be
48:44an alternate target we can use
48:46in these tumors that are low
48:47PDL one and the answer is yes,
48:49we were involved in the phase one trial,
48:51Pat Larusso was API on that.
48:52We did that with a company,
48:54There's a company sponsored trial.
48:55Often times you have to do the first
48:57trial with a company and then your
48:58next trial can be your own Ind.
48:59So the first trial was a company
49:01sponsored trial and you can see
49:02here's patients two patients with
49:03lung cancer who had response,
49:05one with a complete response,
49:06one with a partial response.
49:09That response and lung cancer wasn't
49:10here at Yale but this was a patient
49:12who had already had immunotherapy
49:13and failed and you can see they're
49:14responding to the CIGLIC 15.
49:16But the phase one team we Katie Kirk
49:20was here we got a nice picture at
49:21least she she did the picture not me
49:23she had her own photographer with and
49:25and then this is what I want to show you.
49:27Scott Gettinger has these data I
49:29presented on his behalf because
49:30he couldn't make the meeting.
49:31But this is Scott's work.
49:33Scott has LED a trial of NC 318,
49:35which is the antibody against
49:37ciglic 15 and this is totally
49:38investigator initiated.
49:39Yale holds the I and D We've put
49:41almost 40 patients on this trial.
49:43We have two arms of the drug alone,
49:44different schedules.
49:45Then we combine the drug with pembrolizumab,
49:48the PD1 inhibitor.
49:49We also have an arm of IO naive patients.
49:52We're just starting,
49:53so we've been studying this here at Yale.
49:55We've been getting biopsies pre and post
49:56and again I don't have a lot of time left,
49:58but I'll just get cut to the chase.
50:00The biomarker that David's been
50:02developing has been helpful to to date.
50:04We as always happens,
50:05we don't get biomarker on the
50:06patients that have the best response.
50:08We actually just had another
50:09response yesterday.
50:10So stay tuned.
50:11But what we have done is we've looked
50:12at patients and we've looked at a
50:14number of patients have benefited
50:16some of them that are getting
50:18pembrolizumab plus cyclip 15 and
50:19some of them cyclip 15 alone.
50:21And you can see we're seeing PRS,
50:23I'll tell you as someone who works
50:25in this field of lung cancer to see
50:27an immuno refractory patient respond,
50:28you can count on one hand how often
50:30that happens with some of these new agents.
50:32So we're very excited about this.
50:34We're trying to understand the
50:35molecular mechanisms,
50:36but we've had four responders now to
50:38the combo and one to a single agent
50:41and actually pictures are worth 1000 words.
50:43So here's that patient who had got
50:45the single agent liver lesion that's
50:47responded and here are three examples
50:49of patients who are responding to the combo.
50:51So we are we are seeing activity here
50:53and we're in the process of working
50:54with next Cure and with other other
50:56groups to decide what our next trial will be.
50:59So I'm going to skip this.
51:00I'm, I'm running, I was very ambitious.
51:02I haven't given our live talk in many years,
51:04OK.
51:05But what I do want to tell you
51:07about is just get to the end.
51:08So what I've tried to show you today is
51:11we're making progress in this disease.
51:13It's really phenomenal progress.
51:15It doesn't always seem like that
51:16if you're on the inside,
51:17but you know if you look back at
51:19it from a 2030 year perspective,
51:20we we we now have patients with lung cancer.
51:22Ironically the patients who are
51:24smokers who have many more mutations
51:26probably have the chance of cure with
51:29immunotherapy and as we move that
51:31immunotherapy earlier maybe even more so.
51:33But the targeted therapy produces
51:34amazing benefit and quality of
51:36life and if we use it earlier I
51:38believe we could probably cure some
51:40patients there as well.
51:41The theme I think of of Yale as a
51:43whole and certainly of the lung group
51:45is that we used to call these Darts.
51:46I haven't made the change the slide,
51:49but our clinical trials team uses
51:51the institutional science and our
51:54industry collaborations to develop
51:55trials that lead to advances grants
51:57and we're feeding on that cycle
51:59and we're building a team that's
52:01focusing on lung cancer advances.
52:03We have many other you know targets.
52:07We're working with Aaron Rings,
52:09Teen BP and the Melanoma group
52:11and the lung group as well.
52:12CD 93 is a target for vascular permeability.
52:15We're starting to work with
52:17here at Yale with Lee
52:18Ping and other other targets.
52:20And I didn't know Don was going to be here,
52:21but you know we're certainly
52:23interested in the flip as well.
52:25We're doing trials.
52:26This is an example of a biomarker adaptive
52:28trial we did with with with Merck.
52:29But I'd rather tell you about
52:31the trial that we're developing
52:32in the last minute called the I
52:33Bulldog trial and Maina's here.
52:35So Maina's been coordinating
52:36with us doing a great job.
52:37How are we going to do another
52:39battle trial here at Yale?
52:41What I would suggest is we have to
52:43pull together and and do a trial
52:44where we now take advantage of the
52:46pathology that I've shown you today
52:48of the science here at Yale and of
52:50our ability to do clinical trials and
52:52lead that next generation of studies.
52:54And we are now looking for new ideas.
52:57Here's,
52:58here's our current idea that we've
53:00been shopping around and we've
53:01had meetings with three different
53:03pharma groups in the last month
53:04and they're all interested.
53:05So we'll have to see who works with us.
53:07We, we're really excited about this
53:09and we're going to do real time tumor blood,
53:11real time immune profiling.
53:12We can do that here.
53:14We can do it in a clear appropriate way.
53:16And then we're going to initially
53:18equally randomized patients to treatments.
53:19But then once we learn about how
53:21these biomarkers pretend response,
53:22we're going to do a biomarker enrichment,
53:24adaptive randomization and Steve
53:26Miles very excited to do that with us.
53:29Here's the team that's working on that,
53:31just the core team,
53:33but we'll be getting everyone
53:34involved very soon.
53:35So as I conclude,
53:37can we cure metastatic lung cancer?
53:39Yes, I couldn't have said that 10 years ago,
53:42but only in some cases.
53:44We have 12 plus year survivors
53:46from our very first trials.
53:48Treatment was well tolerated
53:49and retreatment was possible.
53:50I didn't show you that,
53:51but sometimes you can retreat,
53:52but we don't even know what
53:53the markers are for that.
53:54But the problem is we don't have
53:56any way of knowing this in advance.
53:57We've got to do more biomarker work.
53:59So do we need to personalize immunotherapy?
54:01Absolutely.
54:02We spent 20 years personalizing
54:05targeted therapy.
54:05You'll you'll hear about that next June 10th,
54:08but we're still not there yet.
54:10We need biomarkers and better combos.
54:12We need innovative trial designs.
54:14But the future for this is now,
54:16so last slides,
54:17we need to personalize immunotherapy,
54:19identify biomarkers and
54:21improve combination therapy,
54:22identify new targets and
54:24rational combinations,
54:24establish novel endpoints,
54:26innovative trial designs.
54:27We can do that here,
54:29address mechanisms of resistance
54:30and bring disease early.
54:32It's sort of reads like the CCSG.
54:35We can do it,
54:35but I'm just my charge on this
54:37first ground round to the Friday.
54:39To the fellows, the scientists here,
54:41the translational scientists,
54:42everyone.
54:42We're we're a continuum from
54:44the clinic and the lab working
54:46together to help the patient.
54:47We need to develop drugs in real time,
54:49and it's only going to be with science.
54:50Ben Lewis here, He gave an amazing
54:51talk the other day on a trial
54:53that we're doing with ipilumab,
54:54nivolumab biomarkers.
54:55That's going to be the future.
54:56But then to translate those into new studies,
54:59So I'll just end with a picture.
55:01So this is Ben's talk.
55:02The other day we had 50 people
55:03at a translational lung meeting.
55:05Katie and Sarah have been organizing this.
55:07This is how we're going to make progress.
55:09We have to meet on a regular basis,
55:10go over our science,
55:11do as many Iits as we can.
55:13This trial actually was a trial of ipilumab,
55:15nivolumab that we went to meet
55:17with Bristol-Myers at the Yale
55:18Club about six years ago.
55:19Several of us,
55:20and we're not running it under our own ID,
55:23but we're getting the samples.
55:24We just got to get the samples
55:25here and get the science here.
55:26So we can make the next step.
55:28So with that I'll just end
55:29by saying save the date.
55:31Katie and I and and the whole
55:33committee are are gonna hold the
55:34interest for meeting here next
55:36June and we're gonna be celebrating
55:3820 years of EGFR mutations.
55:39The guest list is is everyone's
55:41saying yes and we're gonna we're
55:42the hotels will be full.
55:43So with that off,
55:44thank you very much.
55:52It's it's the hour. But I'm happy
55:53to take one or two questions
55:54I I'm supposed to look online
56:00a lot of people online.
56:01Oh, here's a question.
56:10Can you comment on giving the
56:11therapy of the new, Yeah, so,
56:12so new immunotherapy and the accurate
56:14setting does seem to have some benefit.
56:15The, the results are a bit mixed with
56:18the tezalizumab in a trial known as
56:20Keno 10 in the accurate setting in
56:22patients that were PDL one more than 1%,
56:24the hazard ratio is about point 6.7.
56:26So there is, there is a benefit but when
56:29if you look at those patients who were
56:30PDL one negative in their initial sample,
56:32there was no benefit at all.
56:33Hembalizumab interestingly in a
56:35very similar trial didn't didn't
56:38see any biomarker prevalence but
56:39they did see a benefit as well.
56:41My sense is that neoadjuvant is
56:43probably better because when you and
56:45and it comes from Melanoma I see
56:47Marcus shaking his head yes in in
56:49Melanoma and in lung cancer you you
56:50have a tumor and you have the lymph
56:52nodes that are involved as well.
56:54So if you use your your immunotherapy
56:55in the Neoactivate setting you've got
56:57the tumor in situ in in its micro
56:58environment with its lymph nodes.
57:00So you really get the entire T cell
57:02micro environment I think you know affected.
57:04So it's it's better.
57:05The problem is we're only going
57:06to be able to do neo activate on
57:08a selected group of patients.
57:09What we're seeing now is I'm sorry I
57:11didn't have time to show those data,
57:13but you know it works but you have
57:14to pick carefully because you're
57:16not going to really take someone
57:18who's not a candidate for surgery
57:19and bring them towards surgery.
57:21So we have to be somewhat selective.
57:22But at tumor board we'll look at a case,
57:24we'll say this patient looks like
57:26they're surgically resectable they
57:27they can take the three months to get
57:29the neoadjuvant therapy and and we're
57:31treating those patients in that way.
57:33Some of them might not be in that situation
57:36And and chemo radiation David you know is,
57:38is very is with immunotherapy
57:40is also very beneficial.
57:41So we have multiple options.
57:43I'll leave you with this word.
57:45Everyone should get immunotherapy
57:46in some way if they can.
57:48They,
57:48the patients that don't get immunotherapy
57:50would be ones who have autoimmunity or
57:52some reason that they're intolerant
57:54or certainly those with molecular
57:56drivers because in those cases we know
57:58immunotherapy doesn't seem to work as well.
57:59But I'd say if there's any
58:01hint of metastatic disease,
58:02I try to find ways that I can
58:04give immunotherapy to a patient.
58:05Yes,
58:05because
58:08you
58:10give her her expression so much more comment.
58:13Any thoughts on have we target that or why
58:17doesn't EGFR inhibition work for those?
58:19Yeah, we we've tried that.
58:20In fact that was the mark as we worked
58:21at an MD Anderson and actually we worked
58:23with Jose Bazaga on that many years ago.
58:24We thought it would be EGFR
58:26expression and and that is helpful.
58:28You know, if you're using an
58:29antibody that could be, you know,
58:30if you're using satuximab in,
58:31in certain tumors.
58:32But but it really isn't, it's it's not,
58:34it's not the absolute level
58:36of EGFR but it's the quality,
58:37it's it's whether it's being driven
58:39by those mutations and you know the
58:41TKI is you know where the you know if
58:43you've got that addicted tumor that then
58:45the TKI is will have that amazing effect.
58:47But you know the expression can be
58:49helpful maybe for AD CS right now,
58:50now now there's a whole new now
58:52that now that we're sort of at a
58:54standstill with a new immunotherapy
58:55resistant drugs and with new
58:57targeted drugs for EGFR resistance.
58:58We're using the address now with with,
59:00with with with with with payloads.
59:03So that might be an an area done since early
59:08detection, this subject key
59:10piece puzzle, what are your
59:12thoughts on possible innovation?
59:16Well certainly you know there's the the
59:18easy one which is screening which now
59:21with helical CTS and low dose CTS it
59:23does pick lung cancers up earlier and
59:24it's been shown to improve survival.
59:26You know in the US only about 7% of patients
59:29eligible for screening get screened.
59:31You know the criteria were a bit
59:33strict they've they've been reused a
59:34bit but you know it has to have been
59:36someone who's had a smoking history.
59:37So of course it it it,
59:38it doesn't take into account any of
59:40these patients who are the never smokers
59:42or the light smokers which are the ones
59:44that have these different mutations.
59:46Certainly you know looking in in
59:48the DNA and and and and CTDNAI think
59:51that's going to be the way to go.
59:52We're already using that for minimal
59:55residual disease both to determine
59:57whether or not patients need more therapy
59:59and and now of course we can look at
01:00:01the quality of of what we're finding,
01:00:02you know what are the new mutations,
01:00:04those techniques are getting
01:00:05more and more sensitive.
01:00:06I'll tell you in the enduro trial
01:00:08we only picked up you know post
01:00:11resection a sample 1020% of the time.
01:00:13So. So even though many of them,
01:00:16many more of them probably
01:00:17did have residual disease,
01:00:18but it's getting more and more sensitive.
01:00:19Now you asked about you know,
01:00:20screening someone with a history
01:00:22or family history or will we
01:00:24start looking for for tumor DNA,
01:00:26think we need a lot more work to do that.
01:00:28But you know the techniques are
01:00:29getting so much more sensitive.
01:00:30Certainly if you know that someone
01:00:31has a tumor or if they have Melanoma,
01:00:33you know what the antigens are.
01:00:34So you know what what panel to look
01:00:36for and lung cancer which has so
01:00:38many different you know types of
01:00:40mutations there is what Charlie
01:00:41Swanton is doing now and I would I
01:00:43would put my money on his approach.
01:00:44You know there would be spoke models
01:00:46where you actually can sequence a tumor
01:00:47get a panel of mutations and that
01:00:49makes your your sensitivity much more,
01:00:51much better
01:00:54absolutely. And you know that's something
01:00:56we've talked about and maybe I know
01:00:58David and I have talked about it in
01:00:59both David's you know we don't we don't
01:01:01really have a liquid approach here.
01:01:02So we need to think about how we're going to
01:01:04maybe that's the way to jump jump forward.
01:01:06You need AI, you need pre
01:01:08competitive collaboration,
01:01:09you need big data sets.
01:01:11There's a meeting in two weeks at
01:01:13the National Academy of Medicine
01:01:14on public private partnerships
01:01:15and you know data sharing.
01:01:17We're going to have the editors of
01:01:18some of the big journals there.
01:01:19We're going to have people from
01:01:21UK Welcome Trust from the NCI.
01:01:23That's, that's what we need
01:01:24to take these big approaches,
01:01:25large sample sets that's love to talk
01:01:28to you more about that get your ideas.
01:01:30I think we better stop because it's late.
01:01:32I'm starting to go a little over.
01:01:33But thank you all for coming.
01:01:34It's it's it's exhilarating to see
01:01:35people in the talk to a live audience.
01:01:37So. So thank you.