Translational Lung Cancer Research at Yale: 10 Years-in-Review

September 16, 2020

Roy S. Herbst, MD, PhD

Yale Cancer Center Grand Rounds | September 15, 2020

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00:00Logon wanna thank everyone for for
00:03joining us for Cancer Center grand
00:05rounds and we really are very fortunate
00:08to have a special guest speaker today.
00:11Doctor Roy Herps.
00:13Before I introduce Troy as some
00:15of you may have over heard,
00:18I alluded to just want to remind
00:21everybody that tomorrow at 5:00
00:23o'clock we have a special smile.
00:26Oh, town Hall with a guest Speaker,
00:29Doctor Ned Sharpless, the director of
00:32the National Cancer Institute, too.
00:34Provide some comments and answer questions.
00:36As many of you may have seen on Friday,
00:40Doctor Sharp lez offered up his
00:42priorities for the NCI for the coming
00:45year and I think it would be great
00:48to get clarity on what his plans are,
00:51how that aligns with our initiatives
00:53and interests and to assist in general
00:56have him answer our questions.
00:59So without further ado,
01:01let me introduce our speaker,
01:03who really requires no introduction.
01:05Doctor Roy purposes,
01:07the Ensign Professor of Medicine
01:09Professor of pharmacology,
01:11the chief of medical oncology,
01:13and The Associated Cancer Center
01:16director for translation and
01:18research at the Yale Cancer Center.
01:21Roy, as you know,
01:22is an internationally recognized
01:24leader in innovation in the treatment
01:27and research of lung cancer.
01:30His efforts really over the many
01:32years of his career have have really
01:35led have changed the landscape of
01:38our understanding of the biology and
01:41frankly launching new therapies both
01:44with respect to targeted therapy and
01:46more recently, with immunotherapy.
01:48And that work continues with
01:50such impact in productivity.
01:52In along,
01:53Roy's accomplishments span far
01:55beyond just his ability to innovate
01:58as a researcher and clinician.
02:00But also as a leader,
02:03having brought the spore to the long program,
02:07his leadership along program,
02:09which now makes it one of the most effective,
02:14most impactful thoracic oncology
02:16programs on the planet,
02:18Roy has beyond that,
02:20trained countless leaders globally.
02:22And frankly, the influence of
02:25his commitment to clinical care,
02:27education, and research really can be.
02:30Is beyond measurement so really
02:32pleased to have Roy share with us
02:35his perspectives on the work and
02:37you know the accomplishments he's
02:39had recently and over the years,
02:42so Roy, thank you.
02:44Thanks Charlie for that wonderful
02:46introduction and thank you Paula and the
02:49team here at North Haven where I was
02:51seeing patients this morning who sent me
02:54up in this wonderful conference room.
02:56We're getting back to some normalcy.
02:58'cause staff are all having lunch.
03:01We put a lunch out today and watching
03:03from distant locations so I'm really
03:05happy to be here today to give
03:08this grand rounds translational
03:09lung Cancer Research at Yale.
03:1210 years in review.
03:15And here in my disclosures.
03:19So long answer of course is
03:21a major problem in cancer.
03:23In medicine you can see on
03:25the left with the pie chart.
03:27Lung cancer is the biggest single
03:29piece of that pie you know you can
03:31see breast and prostate right there.
03:33Of course GI cancers,
03:35but the leading cause of cancer
03:37death in most countries,
03:3884% of lung cancer is non small cell
03:41lung cancer and more than half present
03:44in the advancement of static setting.
03:47That tobacco is the single largest
03:49preventable cause of lung cancer and
03:51cancer in general and in lung cancer.
03:53We have actionable genetic mutations,
03:54so those are mostly in non smokers.
03:56But there's been a great deal of progress
03:59and I'm going to talk about that today.
04:02Well, I went into lung cancer when
04:04I was a fellow at the Dana Farber
04:07in the mid 90s and this was the
04:10status of lung cancer at that time.
04:12And you might ask,
04:13why did I go into the field?
04:15You can see here's survival curves
04:17in progression free survival curves
04:19for patients with lung cancer.
04:21This was the top trial at the time
04:23that took platinum plus gemcitabine
04:24or paclitaxel docetaxel and the
04:26bottom line is all of the regiments
04:29were about the same.
04:30The one year survival 33%
04:31median survival only 7.9 months.
04:33So if you have a diagnosis
04:35of metastatic lung cancer,
04:36it wasn't really that much hope.
04:37There were no predictive markers.
04:39So why did I go into the field?
04:41Well, two reasons I happened
04:42to meet a fellow Tom Fry,
04:44a meal fried actually yell medical graduate.
04:46He took me under his wing and said,
04:48well, translational research in this
04:49field can only be a positive thing.
04:51Give it a try and two,
04:53it was really the only job
04:55available back then,
04:55so I took it.
04:57Now of course you know the field is very
04:59competitive to work in and I'll show you why.
05:02So paradigm shift was clearly needed.
05:06So here you can see the
05:07lung cancer mortality,
05:08this being from the American Cancer Society.
05:11And there really is progress
05:12being made men up top and women
05:15up on the bottom and you can see
05:1751% decline since 1990 mortality.
05:18Now some of that is incident so
05:21you can see the incidence rates
05:22are going down but mortality is
05:24going down in excess of incidents.
05:26So clearly we're making progress
05:28and I'm going to tell you a little
05:31bit about that during this talk.
05:33So really,
05:33we've seen a new era in lung cancer.
05:36We had some better chemotherapies.
05:37No doubt they were better.
05:39Then we had bevacizumab Avastin,
05:40Antiangiogenic therapy.
05:41That certainly helped,
05:42and then the Genomic Revolution and
05:45then hit lung cancer like no other disease,
05:47a common disease,
05:49and especially in the never relied smokers,
05:51actionable mutations were seen.
05:52And then you can see all these
05:55different mutations that could
05:56be targeted with drugs.
05:58The era of personalized therapy,
06:00though the work that had been
06:01done CL and breast
06:02cancer transferring very quickly to
06:04the large population of lung cancer.
06:06And then of course in the last decade alot
06:09of it LED from here at yell be immunotherapy.
06:12So I'm going to tell you a little bit
06:14about our young spore and the areas where
06:17we've made progress in lung cancer really
06:20mirror what we study in our long sport.
06:22Whether it be smoking cessation,
06:24targeted therapy. Immunotherapy and
06:25then I have some future thoughts that
06:27I want to share with all of you.
06:29But we're very fortunate to
06:31have such an amazing team here.
06:33And remember, it's all about the team and
06:35the people that are working together.
06:37Everyone from the doctors,
06:38the nurses to the research scientists,
06:40the whole Cancer Center.
06:41So we put Asporin started working on
06:44this when I arrived here in 2011.
06:45We were awarded a lung cancer spore in 2015.
06:48That's the New Haven Country Club
06:50where we had a little celebration.
06:52We renewed this more in 2020.
06:54We couldn't,
06:54of course go to the Country Club,
06:56but we had a very nice zoom cocktail party.
06:59C. Charlie Is there with us.
07:01It was really an amazing thing.
07:03We've now refunded the sport and
07:05you can see the four major areas
07:07we started with targeting PD one.
07:09Obviously with leaping,
07:10targeting, EGFR resistance,
07:11smoking cessation,
07:12and we had a project with micro RNA with
07:15Frank Slack who has since left for Boston.
07:18And we have a team and just an amazing team.
07:21And these are just the leaders of the team.
07:23There are so many others that
07:25have developmental projects and
07:26career developmental projects.
07:27But working together to combat
07:28this deadly disease,
07:29and I'm really fortunate to have been
07:31able to work with such an amazing group.
07:33So here is the spore,
07:36as it's a volved and I'm going to tell
07:39you about each of the projects in
07:42brief immunotherapy of advanced lung cancer.
07:45Leaping Scott myself and David Rim targeting
07:48the EGFR pathway in lung adenocarcinoma.
07:51Katie Poletti,
07:52Sarah Goldberg, Mark Lemon.
07:54Molecular determinants of lung
07:55cancer metastasis and drug regiments
07:56in the central nervous system.
07:58Don when Veronica Chang and Abby
08:00Patel and then we haven't carried
08:02this on to the new sport,
08:04but we're continuing the work personalized
08:06intervention project for tobacco treatment.
08:07Probably the most important thing
08:09I trained with Weinke Hung and if
08:11we prevent cancer,
08:12will actually save many more lives
08:15in any other therapies ever talk
08:17to you about today?
08:18And one important thing is we
08:20develop that new project on the left
08:23from 2 developments or research
08:24projects over the last six years.
08:26So here again are the projects
08:28in the leaders.
08:29I just want to point out the cores.
08:31The amazing thing about aspor other cores.
08:34I'm very fortunate to have a partner,
08:36an Ed captain who I've been working
08:38with now for six years and has
08:40helped to bring the team together,
08:42helps to manage your team.
08:43Very successful.
08:44They had an export,
08:45was just funded in large part to it.
08:47His efforts working with Barbara
08:49statistics and Bioinformatics.
08:50I won't say much about it because their work
08:52is in every project I talked about today.
08:55But Steve Mahan Usau he can't
08:57do anything without statistics.
08:58And I will highlight a little
09:00bit of by open specimen.
09:01Core pathology is key tissue banks,
09:03but found he studies and then the
09:06developmental research program
09:07in career enhancement program.
09:08I thank Karen Anderson,
09:09Pat Larusso and Harriet Kluger for this.
09:1250 projects.
09:12Young investigators.
09:13People who weren't working in lung
09:15cancer in the developmental field.
09:17Now we're working on lung cancer with
09:19many nuara ones and other team grants.
09:21So it really has created a whole culture
09:24of lung Cancer Research at Yale.
09:27I don't want to forget the clinic I'm
09:29in the clinic I'm in North Haven today.
09:31He can't do this without the clinic.
09:33It's gotta be a seamless transition
09:35and I won't have too much time to
09:37talk about the top program today.
09:39Maybe another grand rounds,
09:40but we had to retreat back in
09:422012 and then you can see.
09:43And this is just as we both care centers
09:45in the care centers are critical to this.
09:48I'm out of care center patients are
09:50being seen here with lung cancer.
09:51Tissue specimens are going back to Cedar St.
09:53This is what we need. The top team?
09:56Linton Uian Frank form top.
09:571520 years ago,
09:58it's tremendous user clinical
09:59trials director Roy Decker.
10:00This is our most recent retreat
10:02at the Business School,
10:03and here I am at the very first.
10:05We talking about a truckload battle
10:07that I brought over from MD Anderson.
10:09We put 40 patients on this drive with
10:12biopsies and help get this war going.
10:14So what about smoking cessation?
10:16Well,
10:16the health consequences of
10:18smoking are just enormous.
10:1980 to 90 different toxins in tobacco
10:21smoke and you know the decrease
10:23in risk and lung cancer is seen.
10:26Usually takes about five years,
10:27but you never reached the baseline
10:29and a sensation after diagnosis
10:31clearly improves treatment tolerance,
10:32an outcome.
10:33So we have a very concerted
10:35effort on smoking cessation here.
10:37And it was one of the projects of the score.
10:41Certainly we want to do a lot
10:43of work with policy.
10:44I've been involved with the ACR
10:46we've now gotten into work with the
10:49cigarettes you can see on the bottom
10:51right this to chytra with me at
10:53in Washington, along with Durbin,
10:55an E cigarette briefing.
10:56We've done one with Senator
10:57Blumenthal as well.
10:58We need to stop the initiation
11:00of tobacco use.
11:01We worry about the E cigarettes and
11:03whether patients and people will
11:05start to smoke tobacco cigarettes,
11:07smoking rates still remain about 18%,
11:09but why is it so important?
11:11Because it's higher in our community.
11:12Because we have community,
11:14that's that's a more diverse
11:15that has more long-term smokers.
11:17So look at the right for a section a second,
11:21you can see that we did a study
11:23personalized intervention
11:24project. I could see 42% of
11:26our people on that study where
11:28unemployed or on disability.
11:29You can see the large number of minority
11:32patients that were on this trial.
11:34So this is so vital for our community.
11:37So Ben told. Along with the team
11:39and Susan main work with us before
11:41she came and Brenda Cartmel created
11:44a trial where we had patients.
11:46Our target was 276.
11:47We enrolled about 200 and we're
11:48analyzing the data now and they
11:50either had standard cessation
11:51treatment or they had cessation
11:53treatment with personalized messaging.
11:55Gained frame messaging.
11:56What is that for?
11:57Anyone who's traveled?
11:58We haven't done that too much recently
12:00and you've seen those cigarette
12:01cartoons in the airports that have
12:03those really horrible looking pictures.
12:05That's negative non gained frame messaging,
12:07but more positive messages
12:08which we actually translated.
12:09Into several languages were used to see
12:11if that would help patients to stop
12:13smoking and then to keep them from smoking.
12:15We had a biomarker biofeedback method
12:17that Susan main developed looking at
12:19skin carotenoids which actually got
12:20higher in patients who stop smoking and
12:22patients could see their their number.
12:23So this trials under analysis right now.
12:25But you can see the team that
12:27came together to do this and now
12:29of course Lisa for Cheeto who
12:31leads that effort here at Yale.
12:32Now with the team doing a great job,
12:35we brought that group to Medical
12:36University of South Carolina.
12:37Here's the team there.
12:39We would go out to different.
12:40Forums and we talk about our work.
12:42You can see it was only possible because
12:45of the work of linen afoul rose at the VA,
12:48and Alyssa Roy Tobacco treatment groups
12:49at yeah and all the different groups.
12:51And there I am doing the Roman spectroscopy
12:54wasn't too difficult procedure,
12:55but you know the real thing is
12:57it got us into the community.
12:59We're continuing this work.
13:00We spoke with a caring ambassador program.
13:02There's teacher Johnson and that
13:04program and we were able to work
13:06with them to get this out there.
13:08We were able to get grand Beth Jones.
13:10Tina and myself,
13:11a grant from BMS to go out and do
13:14more of this work in the community
13:16and here we are just last week.
13:18Giving masks at Fair Haven clinic
13:20as an and the message of sensation
13:22so smoking cessation very important.
13:25What about targeted therapy?
13:28Well,
13:28I got into this about 1990 seven
13:301998 when I was first at MD Anderson
13:32and I was called into the office
13:35with John Mendelsohn and kihon.
13:37I talked to them about you know,
13:39some targeted therapy and I've been
13:41reading about this and I said,
13:43how would you like to lead this effort
13:46and the address, and it says sure,
13:48and Fortunately there were trials,
13:50both in-house trials and industry
13:51trials at the time.
13:53And there's a drug called ZD 1839 and we
13:56did the first phase one trial of that.
13:58And it works.
13:59Now you can see I ended up
14:01working with my future
14:02collaborator and friend Pat Aruiso.
14:04We met in 1998 working on this trial and
14:07patients with lung cancer like this,
14:09he would have had less than six months
14:11to live had these wonderful results.
14:13So this was the dawn of
14:15EGFR therapy in lung cancer,
14:17and they have a friendship and partnership
14:19with Pat that's lasted to this day.
14:22So of course I'm not going to go
14:25through everything in this short talk,
14:27but through those works,
14:28the EGFR Mutation was was discovered.
14:30Of course, Tom are former director
14:32was very involved in that and Bruce
14:35Johnson and Pasion in the group Boston.
14:37We actually got to a point in the
14:39mid 2000s where patients could live.
14:42Here's a patient with metastatic lung
14:44cancer who is living with cancer,
14:46taking oral EGFR inhibitor each day,
14:48some some skin issues, some mild diarrhea.
14:50But Tara Parker,
14:51Pope wrote this article in 2003.
14:54Why curing your cancer may not
14:55be the best idea.
14:57The idea was lung cancers become a
14:59disease like hypertension or diabetes.
15:01The problem with the targeted therapy
15:02for EGFR is no ones really ever cured.
15:05Resistance will ultimately develop well here.
15:07It's a little bit about that.
15:09So we started in 1997.
15:10The second line therapies with
15:12the different nib or laugh and
15:14have some of those agents.
15:15The mutations were discovered
15:17right around in here.
15:18The decision was made to give these
15:20drugs only to patients with mutations.
15:22So then we started to use these
15:24drugs in the frontline setting.
15:26And then we had new generation drugs and
15:28a new generation drive was Aston Martin.
15:30If this drug being less toxic because it
15:33was targeted just to EGFR Mutant Receptor,
15:35the other drugs targeted all EGFR receptor,
15:37so it had fewer side effects.
15:39And it also was developed to
15:40go to the brain to the CNS.
15:42So with this drug we had better
15:44therapy in the metastatic setting.
15:46When I'm going to tell you about now
15:48is something that I got involved with
15:51right around this time with the team
15:53to take the drug to Azure and therapy,
15:55take it to earlier disease.
15:56And I mentioned Tom Fry and the one
15:59thing he always would tell me is
16:00bring your drugs to the earliest most
16:03curable setting. Well, we did that.
16:05So in early lung cancer.
16:06Let's say someone where to find
16:08themselves to have an early lesion
16:10in the lung,
16:11perhaps a few local lymph nodes or
16:13even some mediastinal lymph nodes.
16:14The chance of them being cured with
16:16surgery is reasonable, but it's not.
16:18It's not good enough, so we would.
16:20We would cut these damn boffa Frank
16:22better back in the team would cut these out.
16:25But then we might even give
16:27acumen chemotherapy.
16:27Which maybe has a 5% or so improvement in
16:30outcome but still in stage one disease.
16:32The earliest disease you know only
16:3460 to 70% of patients are cured.
16:36Stage two patients only 47 to 55%
16:38and it stage three only 38%.
16:40So if you have these patients and they
16:43have each year for mutations and it's
16:45only 10 to 15% of patients in the US,
16:48about 20 to 30 in Asia but still
16:50enough lung cancer patients that
16:51if you could find these patients
16:53and give him something else,
16:55it could make a big difference.
16:58Well here comes the Adora trial.
17:00I was very fortunate to be one
17:02of the people who designed this
17:04along with Masahiro Suboi from
17:06Japan and Ylang Wu in China.
17:08Of course, EGFR mutations being
17:09much more prevalent there.
17:11We've been working on
17:12this for almost a decade,
17:14so here we took patients who quit
17:16completely respected stage 1B,
17:17two or three.
17:18A disease with or without
17:20active chemotherapy.
17:21So patients could receive their standard
17:23of care and you can see they all had
17:26recently good performance status.
17:27They all had rain.
17:28Imaging they had the two most
17:30common types of each year for
17:32mutations in Exon 19 or 21,
17:34and they could have actually been therapy.
17:36They started within 10 weeks if
17:38they did not have action in chemo
17:40and within 26 weeks if they did.
17:42There were stratified by their stage.
17:44The trial is about an equal
17:46number of stage one B2 and three
17:48a weather each year from mutation
17:50status 19 or L858R21 or their
17:52race Asian versus non radiation.
17:54About 1/3 of the patients
17:56came were non Asian,
17:572/3 Asian and a very simple trial
17:59and you know simple trouser.
18:01Sometimes the best answer merchant 80
18:03milligrams orally once a day versus placebo.
18:05I'm often asked how could you
18:07do a pussybow because there
18:09was no other standard of care.
18:11We just waited for these tumors to come back.
18:14Coding insights like the brain delivering
18:16the bone 682 patients on trial.
18:18The planned duration of treatment is 3 years,
18:21so they got three years of
18:23treatment and they stopped.
18:24If they record and the follow up you
18:26can see every 12 weeks for the first
18:29few years and then every 24 weeks.
18:31The primary endpoint of this
18:33trial was disease free survival,
18:35so surviving without recurrence
18:36in the patients with stage two
18:38and three disease it was power
18:40for a hazard ratio of 0.7.
18:42So for 30% improvement.
18:44The secondary endpoint was disease free.
18:46Survival in the overall population
18:49with source continuing and then
18:51234 and five year landmarks.
18:53Overall survival, safety and quality of life.
18:56I was not expecting to be
18:58presenting these data this year.
19:00It was a plenary talk at Asco.
19:02I gotta call during Passover.
19:04I guess it was on Good Friday.
19:06So around April 10th or so the
19:07trial had been underlined.
19:09It why?
19:10Because the independent data monitoring
19:11committee unblinded study early.
19:12Do the Efficacy they were
19:14doing a safety review,
19:15but they saw that the Efficacy was so good,
19:18which is almost unheard of and they
19:20did an unplanned interim analysis and
19:22the study had completed enrollment.
19:23All patients ran for at least one year,
19:26so they decided to unblind the trial.
19:28So I got that call and by the next week we
19:31were already preparing an Astro presentation.
19:33Why? Because these were the data.
19:35Remember, I told you that was
19:37powered for a 30% improvement,
19:39but look here on the left.
19:41These are patients with stage
19:42two and three a disease.
19:44The primary population.
19:45This is a disease free survival for
19:47patients on the astroneer can have
19:49the pill versus those on the placebo.
19:51The hazard ratio here is 0.1 seven.
19:53That means there's an 83% improvement.
19:55Again, we expected that this drug would work,
19:58but with this much magnitude.
19:59It was just incredible.
20:00And then when you add in the 1B patients,
20:03patients who would have a
20:05good prognosis to begin with,
20:06I told you half of those were cured.
20:08The hazard ratio still 0.2
20:10zero 80% improvement.
20:11So these these data were quite
20:13impressive to all of us and that's
20:15why it was presented so quickly.
20:17This is a forest part,
20:19which is often done in these types of trials.
20:22Here you can see the unity line,
20:24anything to the left favors the App Store
20:26merchant and they think of the right favors.
20:29The placebo.
20:29You can see everything is to the left,
20:32whether it be sex, age,
20:33former smokers still did well
20:35whether they were Asian or non Asian.
20:37The race,
20:38the stage I told you,
20:39equal numbers and all three.
20:41Even the early stage ones still make
20:43it across the line and then each
20:45information status didn't matter.
20:47And of course.
20:48Whether they got acumen chemotherapy
20:49enough or not didn't seem to
20:51make a difference as well,
20:52so all this was positive, really,
20:54really very positive trial.
20:55So where are we at with this?
20:57Just to give it in perspective,
20:59I'm sure many of you want to know
21:01what about overall survival.
21:03We won't have that for a couple of years.
21:06The trials continuing on,
21:07and that will be filed.
21:08But right now we want to know the
21:10local versus disease recurrence,
21:12including the sites of recurrence
21:13I mentioned the brain,
21:15the liver and the bone.
21:16And actually I this is a nice.
21:18Picture from an Chang and an article she
21:21wrote with Johann Mascia number years ago,
21:23but that's the thing.
21:25Even without the survival result,
21:26our patients are occurring in
21:28these very sensitive sites.
21:29What were the subsequent therapies
21:31in one of the quality of life?
21:33All this is still percolating
21:35and will present it shortly.
21:36In fact,
21:37I'd like to just say a word about this.
21:40The idea that we've taken targeted therapy,
21:42and we've added it to our best surgery,
21:45an Azure in therapy.
21:46And now we're seeing better
21:48outcomes for patients.
21:49And I can't help but think about
21:51my late mentor, Isaiah Fiddler,
21:52Josh Fiddler.
21:53He digester earlier this year.
21:54He would always talk about that that
21:57biology is the foundation of therapy and
21:59that's what we've done with your trial.
22:01Now I wish I could tell you more,
22:03so I hinted to you about the brain Mets.
22:06I'll tell you that it's good
22:08enough that there's going to be an
22:10embargoed presentation at Esmo this
22:11Saturday at 12:30 our time and a
22:13paper coming out in the Journal.
22:14I'm not supposed to talk about it,
22:16but in a Journal that the Mass
22:18Medical Society publishes.
22:19So this. So this will be out.
22:21You'll be able to see it by Saturday.
22:24So where are we at with this now?
22:26Now we have to even add in more science.
22:29So now we have an alliance with
22:31Astra Zeneca that Patton Russo
22:33and I were able to develop.
22:35And you can see we're working with
22:37their tool compounds with them on
22:39all the different questions I just
22:40talked about brain metastases,
22:42resistance mechanisms and you
22:43can see that here is our summit
22:45meeting exactly a year ago,
22:47but now we just had a call
22:49with them yesterday morning.
22:50And now with Katie plenty and on when
22:52an hobby re biopsy study and analysis.
22:55Cell free DNA from Adora to understand
22:57mechanisms of resistance we need
22:59to use this trial and the samples
23:01for the patients who are still on
23:03a trial to understand when do they
23:05develop resistance in their blood.
23:07When can we measure the resistant clones?
23:09How can we determine how long to
23:11treat when to start new therapies?
23:13So all of this is very very
23:15exciting and really speaks to have.
23:17Science has gone into the clinic
23:19and how we've evolved over 20 years
23:21to really make a difference in lung
23:24cancer with these targeted agents.
23:26And you can see here's project two
23:28of the spore so Katie Poletti leads
23:30us along with the rest of the team.
23:33You'll see in a moment,
23:34so we actually have programs here to
23:36optimize approaches to counter on target.
23:38EGFR dependent mechanisms of
23:39resistance so you can see up here we
23:41have mice when when patients recur,
23:43we get tumor and they go into the
23:45mouse and we have mice that are
23:47resistant to these drugs and we can
23:49try to look at new therapies and
23:52correlate that with patient data.
23:53Some of these are genetically
23:55engineered mice and then we can look at
23:57vulnerabilities of Teeki Resistance.
23:58In two minutes without on target.
24:00Here for resistance,
24:00there are other mechanisms and we
24:02have clinical trials and studies
24:03to look to understand why the
24:05patients would become resistant,
24:06because as good as we are,
24:08we're going to see this resistant merge.
24:10So we have to stay one step ahead of this.
24:13And that's what Katie and the team are doing.
24:16So here's that wonderful project team I
24:18mentioned Katie working with Sarah Goldberg
24:21and Mark Lemon Collaborative Group.
24:23You know each other projects has its
24:25own team that meets on a regular basis.
24:28Here's the list,
24:29you know,
24:30just just amazing that teamwork getting
24:32samples from the clinic PDX models,
24:34genetic models,
24:35drugs in collaboration with industry
24:37investigator initiated trials.
24:38That's the way we're going
24:40to continue to make progress
24:43in lung cancer.
24:44And you can see productivity.
24:46No problem with this group.
24:47You can see a number of key publications,
24:50allele specific patterns of resistant
24:52resistance approaches to overcome and
24:54prevent the emergence of resistance
24:56mutations to ascertain if which of course
24:58has only been used for a couple of years.
25:00So it's taking time to develop
25:02all this and molecular modeling
25:04to understand these mechanisms.
25:06So really really talented
25:08group working together.
25:09And then, of course brain metastases.
25:11We have a separate team doing that.
25:14We have done along with Veronica Chang
25:16neurosurgeon done being a basic scientist
25:18and Abby patellar radiation oncologist.
25:20That translation researcher,
25:21so there trying to look at mediators
25:24of CNS metastasis to lung cancer
25:25were getting CSF samples from
25:27patients who have lung metastases.
25:29To understand what's going on going on
25:31in the CSF in the cerebral spinal fluid.
25:35And then we're going to understand
25:37adaptive mechanisms of tumor dissemination
25:39and drug resistance in the brain.
25:41A number of key papers already published,
25:44and then we're going to use this
25:46CSF to identify biomarkers and
25:48genetic drivers of metastases.
25:50So all of this already on going again,
25:53the lab,
25:55the clinic interspersed together.
25:57So with that on now focused on immunotherapy.
26:01So if all we have already talked
26:04about was not enough,
26:05amino therapy is perhaps even more powerful
26:09tool if we can learn how to harness it.
26:14Well, I've been at yell since 2011.
26:16This is the patient from 2010,
26:18so one of the reasons I was attracted
26:21to come here as I met with Scott and
26:24Mario and they told me about this thing.
26:27MD X 1106 I was at MD Anderson.
26:30We didn't know anything about it.
26:32We weren't doing any immunotherapy
26:35work back then and Scott showed me
26:37some X Rays and I said wow and really
26:40is Scott Mario, Harriet Cougar.
26:42They really, you know,
26:43initiated this clinical field.
26:45Patients with refractory lung cancer.
26:46This is Maureen.
26:47This is a center point so I'm
26:49able to show her picture.
26:51But here we have a patient with
26:53refractory disease three times
26:54refractory squamous lung cancer.
26:56Very few of them Lego markers would be there.
26:58There would be very little targeted
27:00therapy for this type of patient,
27:02but look at this response but
27:04more important than this amazing
27:05response is now 10 years later,
27:07she's still alive and well.
27:11So we actually because of the
27:12work we've done subsequently,
27:13Bob Sherwin and teacher Johnson
27:14put us in for Team Science Award at
27:17the Association for clinical and
27:18Translational Science and loan.
27:19Behold, we got it.
27:20You know,
27:21a little bit of money that we split,
27:23but you can see you know these are just
27:25a few of the many people at captain.
27:28Of course, Harriet Mario snow.
27:29And then of course sleeping my
27:31good friend and collaborator
27:32a team working on this,
27:33and I'm going to show you more
27:36recent work from this team.
27:38So I'm going to ask the question
27:40and I don't
27:40know if it's the beta is watching if
27:43this weather regular grand rounds.
27:44I looked on the right and I'd seen there,
27:47but he's inspired me for many years.
27:49Can we cure metastatic lung cancer?
27:51A question you wouldn't
27:52even asked 20 years ago.
27:53Of course, not even ten years ago,
27:55but I'd like to ask that question today.
27:57And then we'll we'll talk about
27:59it at the very end of my talk.
28:01I tried to read up a little bit.
28:03What's the definition of cure to restore
28:05health to bring about recovery from?
28:07I look up at Hippocrates.
28:08Cure sometimes.
28:09Treat often comfort always,
28:10but this is the most inspiring book we,
28:13of course, had a grand rounds with
28:15Vince and Elizabeth a few years ago.
28:17The way that they cured,
28:18shouted Lymphoma and adult lymphomas.
28:20Can we do that in lung cancer?
28:22Remember,
28:22lung cancer is a little bit different.
28:25Disease also affects people who
28:26are older and more comorbidities,
28:28but keep that question in mind.
28:30'cause I'm going to ask you
28:32again in about 20 minutes.
28:34Well,
28:34lung cancer therapies just evolve so quickly,
28:36so this first round up here keynote,
28:38one call later, was the of this.
28:40He's an author on the New England
28:42Journal of Medicine Paper.
28:43We had this in our phase one clinic
28:45you'll still bump into patients in
28:47the Hall who were on this trial 678
28:49years ago who are alive and well.
28:51This was Pember Lizum app.
28:52It was given to all comers in a
28:54number of different lung cancer types,
28:56but subsequently the biomarker was
28:58shown to predict who did a bit better PDL 1.
29:02I got involved.
29:03This is a trial Iran keynote 10.
29:05This resulted in Pember Lizum app
29:07getting licensed in the second line setting.
29:10We actually showed that a two doses when
29:12you use pembrolizumab versus docetaxel,
29:14either selecting for all
29:16patients with 1% or more PDL.
29:18One or patients with high PD L1 at 50%.
29:21We saw a significant benefit.
29:24Then of course,
29:25from this trout the biomarker
29:26was used in Frontline.
29:27Keynote 24.
29:28Parallelism addresses chemotherapy
29:29the five year data for this will also
29:32be presented this this week in Ezmo.
29:34Trust me,
29:34it looks pretty good and then
29:36you can see the Pacific Travel.
29:38This is even this is again sort
29:40of like with the Dora.
29:42This is stage three lung cancer
29:44using their vile map and you
29:46can see improvement in survival
29:48after chemo radiation.
29:49But I wanted to show some of our own data,
29:52so here's Scott's trial. Scott and Mario.
29:54This is where Maureen was.
29:55She was on this trial and look at
29:57the actuarial five year survival
29:59from that first trial.
30:00And if all mad here at Yeah 16%
30:02and you know what Scott knows,
30:03everyone of those patients who is
30:05alive and he's got their samples
30:07and he's analyzing them right now.
30:08But you know, it's really all about the tail.
30:11So if you look at this survival curve now,
30:13we gotta do better here.
30:14We lose a lot of patients early
30:16on when they get to this tale.
30:18Is it as good?
30:19I look at this with Mario.
30:21Today is it as good as Melanoma?
30:23Maybe not quite it, still earlier too.
30:25And this is a disease you know of.
30:27People who smoke and have other mutations,
30:29but you know what?
30:30It's looking pretty darn good to me.
30:32And then of course,
30:33you know you've got a credit Harriet,
30:35for her constant mentor ship.
30:37We know working with Sarah early on in
30:39her tenure here and Veronica again,
30:41our neurosurgeon.
30:42And they actually said,
30:43why do we have to exclude patients
30:45with brain Mets from these trials?
30:47That's not the real world
30:48questions have brain Mets.
30:50So here's a patient with lung
30:51cancer with brain Mets was
30:53treated with Pembrolizumab,
30:54and those brain Mets went away.
30:56This was an investigator
30:57initiated trial because we're
30:58doing some of the keynote trials,
31:00we were able to get a
31:02relationship with Merck.
31:03It helped us to get this
31:04drug in lung and Melanoma.
31:06They collaborated together and what this
31:08is showing as this is a wonderful plot.
31:10Each of these points below the
31:12line is a patient who responded,
31:14but what you can see is the
31:16response in the brain and the
31:17lung looked to be about the same.
31:19So now real world trials and
31:21neutrals are allowing patients
31:22with brain Mets to get parallelism
31:24at 'cause it apparently works
31:26across the blood brain barrier.
31:27That's very important.
31:28So where are we at right now?
31:31Again,
31:31I only have an hour,
31:33but here's a nice slide made by hand Chen.
31:36She wrote a beautiful review in nature
31:38reviews clinical oncology earlier this year,
31:40and basically we look at squamous
31:42or nonsquamous lung cancer.
31:43And we look at PDL one expression
31:45and we have we have therapies for
31:48patients who have less than 1% PDL,
31:501 one to 49% pdo one or greater
31:53than 50% PDL 1,
31:54and that's sort of the way things
31:56are assorted right now and approved
31:58as a single agent are two drugs.
32:01Humble is a map and a Texel is
32:02a map where you can give these
32:04to patients with high PD L1.
32:06They don't even need chemotherapy just
32:08for the sake of today's discussion,
32:10I'm going to talk about a Tesla is
32:12a mad 'cause Yale has had a very
32:14big part in its development and
32:15I'm going to show you how we took
32:18this drug all the way from the very
32:20first in human dose now to face.
32:22So about 2012 you know Paul and I
32:25were approached by by IRA Mellman.
32:27Some of you might know, IRA and IRA,
32:29of course, had an affinity for Yale.
32:31He had,
32:32I believe he was the scientific director
32:34of the Cancer Center for many years,
32:36and I actually knew him
32:37'cause I took his course as a
32:40Rockefeller graduate students.
32:41So I've ever called and they said,
32:43would you like to be involved in this trial?
32:46And he said, yes, we said,
32:47can we do a trial with your
32:49new drug test Alyssa Map,
32:51which is a PD L1 inhibitor.
32:53That PD, one PD, L1 or can we include
32:56biopsies because we like to do biopsies.
32:58We had that working and we want to
33:00understand the mechanism and they actually
33:02said sure so working closely with Scott
33:05and then Petrol Act was very involved.
33:07They had amazing data and bladder
33:09cancer and with Paul and then Pat.
33:12When she arrived we did this trial and
33:14we treated almost 30 patients, maybe 35 here.
33:17And yeah and we got biopsy.
33:19So here's a patient with multiple lung
33:21metastases who had a complete response.
33:23And in this patient we gotta buy a
33:25seat recruitment and biopsy where
33:27they they went off treatment.
33:28And that's very helpful because you
33:30could look at CD 8 cells and these are T
33:33cells and you can see before treatment
33:35there's not very much CD sales here.
33:37But after treatment the T cells
33:39all swarm into the tumor.
33:40That's an example of the adaptive
33:42immune response,
33:43so we actually in our publication
33:44and from this work described what
33:46was happening at the level of the
33:48tumor in patients who are getting
33:50these drugs even more incredible
33:51is this RNA chip that we did.
33:53Again, working with Iran.
33:55Danshen Steve Odeon Farberware involved.
33:56We had a collaborative team as many
33:59of these clinical trials are but
34:01you can see pre and post on this.
34:03The Green is pretty yellow is post
34:05so you can see Granzyme granzyme is
34:07an enzyme that's made by cells having
34:09an active immune response so you can
34:12see the grandson goes up in the post.
34:14This is a patient having good immune
34:16response on here is perforant
34:18preference thing about Perforant as
34:20being an enzyme that makes a hole in
34:22the tumor cell and cause it to burst.
34:24Looking at the hyperforin that you
34:26see after treatment versus before,
34:28so we defined in this the adaptive
34:31active immune response.
34:32This was 20% of the patients keep
34:34that number in mind,
34:35but most of the patients did not respond,
34:38so we also had profiles of Nonresponders.
34:40So here are three different profiles
34:42of non respondents,
34:43again with CDA we had one group
34:46called immune ignorance.
34:47These are patients with no T cells to
34:50begin with and no T cells to be at the end.
34:53The tumor just laughs at what we're doing.
34:56We call this the immune desert.
34:59Then you have the non functional
35:01immune response.
35:01We can see a good number of
35:03cytotoxic T cells,
35:04maybe get a little bit of an increase.
35:06It's in the paper.
35:07I don't have time to show it to you with
35:10that immune ship would be negative.
35:11No activation of the T cells.
35:13You don't send it.
35:14See anything going up and then
35:16we have the immune excluded.
35:17This is very interesting where the
35:19T cells don't get to the tumor and
35:21this is something we're very actively
35:23studying in the lab.
35:24How can we get these T cells
35:25to the tumor because of their
35:27interact with the tumor and within?
35:29They're not going to activate,
35:30so we understood the patterns of resistance.
35:33Now let's do something about it.
35:36Well, we get a great deal of work
35:38with the Tassel is a might Academy
35:40licensed in the second line setting.
35:43You'll see patients around our
35:44center who are benefiting from this.
35:46It's just amazing.
35:47So then we're off for the opportunity
35:50to lead the phase three trial using
35:52the drug in the frontline setting
35:54and we said sure so here you can see
35:57this is the trout in Power 110 and
35:59this trial chemotherapy naive PDL,
36:01one selected patients with stage
36:03four non small cell lung cancer,
36:05either squamous or nonsquamous.
36:06So untreated patients 572.
36:07We used a little bit of a
36:09different asset here.
36:10Based on the work we had
36:12done in the biopsies,
36:13we thought it would be important to
36:16look at PDL one both in the tumor
36:18cells more than 50% and also PDL one
36:21in the immune cells more than 10%.
36:23So we call that TC three IC 3.
36:25So we use that in this.
36:27In this study we also use a
36:29slightly different antibody.
36:30I'll get to that in a moment,
36:32but it pretty simple design at
36:34TES Alisme am versus chemotherapy.
36:36Maintenance of Texel is a map
36:39versus maintenance chemotherapy
36:41endpoint being survival.
36:42Well, here is that result in.
36:44These data are now impressed,
36:46though not too long from now.
36:48You can see the curves.
36:50Cross definitely tells us we
36:51we still could do a little bit
36:54better with our biomarker,
36:55but here's the patients who had the high
36:58PD L1 and got the test losing Matt here.
37:01The patients who got the control
37:03chemotherapy has a ratio is 0.59 and
37:06these data will be followed out more.
37:08But again an incredible result.
37:10Single agent immunotherapy
37:11versus chemotherapy.
37:12We also then looked at this in
37:14this paper with other markers,
37:16so these are two.
37:17Here's the SP 142 which is the
37:19market we used for this study.
37:21It's the one that's used in breast cancer.
37:23Is the antibody against PDL one.
37:25And then here you can see there
37:27are more commonly used to see
37:29three 'cause I believe what we
37:31run at least used to run it.
37:33Yeah the results with the same
37:34slightly different populations.
37:35I won't get into this today but this
37:38trial allowed us to sort of develop
37:40some of the biomarker comparisons
37:42which beforehand had not been done.
37:44But even more interesting,
37:45I wanted to show this just one slide and
37:48again the full report will be out soon.
37:51This was already presented at Esmo,
37:52but what you can see is we looked
37:54at tumor mutational burden,
37:56the number of vacations for megabase
37:58of DNA and we did it in the blood
38:01using the foundation medicine platform
38:03and what you can see is here's
38:04another one of those forest plots.
38:06Here's all patients with any PDL one
38:08expression, but you can see that
38:10when you took patients with a blood
38:12based tumor mutational burden,
38:13you see a progressive.
38:15Increase in referee survival as you go up
38:18in the number of mutations per megabase.
38:20Why is this important?
38:22Predict that someday will use this as a
38:24biomarker, perhaps in Association with
38:27other biomarkers in in this setting.
38:30Well, what about biomarkers developed
38:31at Yale and mechanisms of resistance?
38:33Again, I'm giving an overview today,
38:35but you know,
38:36so fortunate to have such an amazing team.
38:39These are two papers with
38:41Scott's first author,
38:41but when was led through Katie's
38:43lab and was led through Kurt slab
38:45just really seminal results.
38:47So and I have to credit Rick Lifton.
38:50We used to meet with Rick and work with
38:52let Rick we used to go meet weekly
38:55over at his lab so we had a great
38:58team working together so we actually
39:00sequenced patients at resistance.
39:01I've actually learned a whole
39:03found that those tumors that
39:04were resistant had lost beta,
39:06two microglobulin and a
39:07sexual component of M HC One.
39:09So if you know that these are these
39:11patients can't get anymore PD one PD L1,
39:14they need other ways of
39:15activating the immune system.
39:17And then Kurt.
39:18This is a work in progress,
39:20using quantitative immune fluorescence.
39:21Had a wonderful study with Scott and
39:24cancer discovery and the rest of the team,
39:26but they look at different
39:27combinations of Biomarkers.
39:28Group AB&C. So what this group is?
39:30These are patients that have
39:32low tell cells and very little.
39:34These are patients that have low
39:36til cells and these are patients.
39:38These two groups that have a lot of T cells.
39:41But then he looked at the
39:42characteristics of the T cells.
39:44These T cells had low ground
39:46Simon and located at 67.
39:48So we're sort of exhausted and these
39:50details you can see by the white.
39:52They had high K 67 and high
39:55granzyme and lo and behold,
39:56he showed that that group that had
39:59the low chaos 67 and a low granzyme.
40:01They did the best small numbers,
40:03but we're now using our stand up for
40:06cancer alliance to validate this more,
40:08but it shows that you can identify
40:10a group of patients who probably
40:12had more ability to respond
40:14to immunotherapy biomarkers.
40:15Predictive biomarkers.
40:16Very exciting, this work continues.
40:19I just point that out now,
40:21what about resistance?
40:22So we have to understand resistance better.
40:24This is work from David Rim
40:26leaping bans eval Chevy.
40:28One of our fellows.
40:29He now leads among group at NYU and what
40:32you can see is we actually took 450
40:35samples from our archive here at Yale.
40:37When I told you pathology is key and
40:40we actually found that only 17% of
40:43the tumors at high PD L1 and hide
40:45til tumor infiltrating lymphocytes,
40:47the same 1720%. I've been telling you.
40:49Do real well,
40:50but here's 26% of the tumors that
40:52have a lot of PDL one have sorry
40:54they have a lot of chill but no
40:57PDL one so it doesn't matter
40:59how much you block PDL 1 here,
41:01it's not going to matter,
41:02but perhaps there are other
41:04checkpoints in play and then
41:06you can see type one and four.
41:07These are tumors where there
41:09are no tells their cold tumors,
41:11so it doesn't matter how much
41:12you play around with these
41:14immune checkpoint inhibitors,
41:15we have to inflamed them first so we call 1,
41:18three and four off target.
41:19Target missing resistance and type
41:21one is the on target resistance.
41:22Let me talk about that first.
41:24Even when you give immunotherapy
41:26to these patients,
41:26they still only respond 3040% of the time,
41:29so something else is going
41:30on in the macro environment.
41:32Well known, behold,
41:33we have David Rahman team
41:35quantitative mean for essence
41:36lovely paper recently looking at
41:38Co localization in macrophages.
41:39The macrophages are going to be
41:42important to micro environment
41:43and outcome looking at markers
41:45of PDL one and macrophage this
41:47is what we need to do more of
41:49like not just these two markers
41:51that markers in other cell types
41:53in the tumor microenvironment.
41:55And we had some extra money on the store.
41:58We still need more money Charlie,
42:00but we just had a little bit
42:02of extra surplus last year.
42:03So what we did is we we put it into
42:05tissue microarray with some of the
42:08responders nonresponders very valuable
42:09so we can test different biomarkers now.
42:12And I think they've been in his
42:14group for their complete innovation.
42:16And you can see the rim lab,
42:18just just a wonderful lab.
42:19The only problem is David is
42:20so good he is now part of it.
42:23Had an export of course he's leading
42:24breast cancer for many years.
42:26We need many more groups like this
42:27at the Cancer Center and an ocean.
42:29Lou is very supportive of that.
42:31This pathology group is just good key.
42:33But what about the Type 1,
42:34three and four tumors?
42:35Well,
42:35about three years ago we were
42:37thinking about the new spore
42:38and what we're going to do,
42:40and I was meeting with limping and he said,
42:42well,
42:42you have a sabbatical coming up
42:44when you come work in the lab.
42:46And I said, sure,
42:47the only problem is I still had
42:49all my other administrative work,
42:51but I got an office over there and and
42:53we work very closely together and I
42:55learned to laugh, even put me to work.
42:57They they got me working
42:58in the lab and I I'm a PhD.
43:00I did this 20 years ago,
43:02so it's actually really good
43:03to get in the lab,
43:05but it's about the people
43:06talking to people at coffee and
43:07understanding the different projects.
43:09I also went back to school.
43:10It went back up to Science Hill
43:12and I took immunology course.
43:13There's Peter Cresswell, you know,
43:15when I I, I learned and through that.
43:17I learned what was going on in
43:18the lab even better, and I said,
43:20Hey,
43:20here's a project we should take
43:22to the clinic. So that's project 1,
43:25the new project one cyclic 15.
43:28So this is a sciatica acid bound,
43:32electing its a receptor.
43:33It's known to be on macrophages Annand.
43:37Micelles this came through a large
43:39screen that leaping had developed
43:41in the lab to find new targets.
43:43Looking at other membrane jeans
43:45home Alexa PDL one so we were going
43:48to not work on the next PDL one.
43:51So here sleeping myself Scotsman
43:53critical to this and David.
43:55So this is an antibody against
43:57us now accompany.
43:58Next you're being involved and this trial
44:01is led by Pat Larusso and here you can
44:04see these are patients with lung cancer.
44:06On that phase one trial and there
44:09have been a couple of responses.
44:11There's a CR here.
44:12There was a PR and there were a number
44:15of patients is the CR is appear at a
44:18number of patients with stable disease.
44:21So signs of early activity.
44:22That's good.
44:23Here is the responder I mentioned,
44:26so this drive already in
44:27phase one and we said OK,
44:29maybe we can learn more about the
44:31mechanism in the lab and more about
44:34the mechanism in the clinic and
44:35make this a trial in our long spore.
44:38So it is project one and we have
44:40other candidates of course that
44:41we're developing as well.
44:43But this is this is a project now
44:45and again path being very closely
44:47involved the phase one results.
44:48They're OK,
44:49but I think they benefit from some
44:51more science and from a biomarker.
44:54So one of the things I was able to do
44:56having been working in the lab is I
44:58put David rim together with sleeping
44:59in the company and it's taking a few years.
45:02This is not simple stuff.
45:03You don't just developing
45:04Immuno Chemistry Assay.
45:05You've gotta validate it.
45:06You've got to know the
45:07prevalence of that marker.
45:08Might not be so high you
45:10have to enhance for it.
45:11So David now I believe has an assay
45:13to measure S 15615 and actually it's
45:15very interesting as he's looked at it.
45:17He found that when you look at
45:18patients that are high in PD, L1,
45:20the tumors tend to be low in S15.
45:22So it looks like there might be some
45:24sort of mutual exclusivity there.
45:25Which could be very important
45:27as we decide who to treat,
45:28so this works on going and the
45:30new trial we're going to do that.
45:32Yeah,
45:33the plan is very soon to
45:35include biomarker selection.
45:36And then here's the Travis Scott
45:38Gettinger is running as an IIT.
45:40We reached out to next cure but
45:42also through our great deal of
45:44work with mercantilism app.
45:45They've provided us Pember
45:46Lizum app for this trial.
45:48So now we're going to take patients
45:50who have failed immunotherapy.
45:51And I'm hearing clinic today.
45:53I almost every patient.
45:54I see there having issues.
45:56You know,
45:56they they need what's next
45:58after being in therapy.
45:59So for that we now need to get new biopsies
46:02and we're going to have either NC
46:05318 that signal 15 or NC 318 plus.
46:07Embolism app, so we're now going to
46:09take refractory patients and either
46:11give them the single agent alone,
46:13hopefully someday with biomarker
46:14selection or a combination with
46:16the standard immunotherapy.
46:17We're also going to few patients
46:19in the frontline setting,
46:20so we're very excited about this.
46:22This should hopefully be open very soon.
46:25So again, science from Yale moving to the
46:28clinic with science going back to the lab.
46:32And of course, again,
46:33I can't emphasize enough.
46:35Today. It's all about the team.
46:37So Katie Kirk came to visit,
46:39so that was easy to form an idea.
46:41So people who wanted to be in the picture,
46:44you know there sleeping.
46:46There's pad.
46:46Pleinair Charlie, I got myself a good spot.
46:49You can see we have a team.
46:51It's all these people.
46:52The other ones were doing the work
46:55that we're seeing the patience
46:56Jochim This is just amazing.
46:58The team we have probably have.
46:59I know we have the best phase
47:02when you did in the world.
47:04So I've talked.
47:05I've gone through a couple of
47:06little vignettes you can see.
47:08I'm excited, I'm enthusiastic.
47:09I think we've made a difference.
47:11I've seen it myself.
47:13There's nothing like seeing a patient
47:15who's alive 10 years later that you've
47:17treated it with your own clinic.
47:19What is the future?
47:21But it's very hard to predict the future.
47:24But can we cure metastatic lung
47:25cancer with immunotherapy?
47:26And I've been asking this question to a
47:29lot of people and I'm going to say yes.
47:32But in some cases,
47:33or at least patients can remain alive
47:35with controlled disease, we've seen it.
47:37I started to Scott earlier today
47:38in the clinic we have 10 years
47:40survivors from the very first trial.
47:42Maybe 1020 of them.
47:43Know we have people who are alive.
47:45Maybe that 10 years,
47:46but ten years up to 10 years at
47:497 six years we used to celebrate
47:51survival at MD Anderson in stage
47:53three disease at five years.
47:54So it might be time to start
47:56getting these patients together.
47:58We have to learn though a little bit more.
48:00My point now to all of you.
48:02Is we can treat these patients.
48:04It was well tolerated,
48:05but we need to know in advance who
48:07are these patients so that those who
48:09can get immunotherapy alone can get it.
48:12And those that the combinations
48:13of drugs or chemotherapy.
48:14They can get it.
48:15So that's where I think we need to
48:18put all of our efforts in the next few years.
48:21So do we need to personalize immunotherapy?
48:24Absolutely. We spent 20 years
48:27personalizing targeted therapy.
48:29I showed you that we're still not there yet.
48:32We're still waiting for more data.
48:34It's still a small population that
48:36we're treating. We need biomarkers.
48:38We need better combos.
48:39We need more science.
48:40We need innovative trial designs,
48:42collaboration,
48:43and public private partnerships.
48:45I would say to all of you watching right now.
48:47The future is now I'm going
48:48to give you an opportunity to
48:50work with us in the last slide.
48:52So what are we waiting for?
48:53It's time to target immunotherapy,
48:55and you know, we can't just give
48:57these drugs to all patients.
48:59We've we've we've,
49:00it's amazing the number of
49:01diseases that it benefited.
49:03All diseases benefit to some extent,
49:04but there are cold tumors there too,
49:06is it don't have much PDL?
49:08One we have to better understand
49:10this and that's going to mean
49:12better science in the clinic.
49:14Now Scott shared this with me this morning
49:16and this is our exceptional responder cohort,
49:19so you can see these are
49:21patients for whom we have tissue,
49:23and you can see months from
49:24starting immunotherapy.
49:25So we've got quite a few there
49:27that are out three four years.
49:29So now what we need to do is we
49:31need complete analysis of these
49:33patients apples to inform future
49:34studies to personalize immunotherapy.
49:36That's on going.
49:37My prediction is it's not going to
49:39just sequencing if we do sequence,
49:41we're going to sequence.
49:43So tumor and the host.
49:44So maybe this generations project will
49:46help us that's being done at Young Haven,
49:48but this is something we can do.
49:50We will do, we must do.
49:53Adaptive trial designs and
49:55new protocols are needed.
49:56I didn't have much time to
49:58talk about this today,
49:59but a lot of this tissue sampling
50:01has come from the battle trial.
50:03It's 15 years since we started
50:05that trial at MD Anderson.
50:07I think the same principles would
50:09apply adaptive trial design.
50:10Europe,
50:10England has a national lung matrix project.
50:13I think this is something that
50:15we certainly want to think about.
50:17Targeted therapy for patients based on
50:19biomarkers we already happened in the US.
50:21This is the lung map trial
50:23in which I'm the Pi.
50:24A large public private partnership.
50:26About 100 of us in the
50:27leadership working together,
50:28we have this open at yellow or
50:30one of the number one cruisers.
50:32Her child does a great job with this,
50:34and if so, how?
50:35At the VA,
50:35but targeting patients with mutations but
50:38also patients who are immune resistant.
50:40There are many new drugs we
50:42need to work with these drugs.
50:44We need to combine these drugs.
50:47Again,
50:47this I just meant to show that
50:49if we combine them,
50:50You have to do it rationally and
50:52we have to do it based on the
50:55science and what we've learned
50:56about the immune microenvironment.
50:58This is an amazing trial that
51:00Scott leads with Richard for Val,
51:02David, Hafler, Kurt, Katie.
51:03We have ample amount of all map now
51:06and approved regimen and we have
51:07about 3040 patients in this trial.
51:09It's Open at 9 or 10 other sites.
51:12Everyone gets tissue,
51:13blood and stool for microbiome and
51:14we're putting the markers together.
51:16It's just at the point now.
51:18It's been 3 four years,
51:19then we're going to try to get some
51:22information on who benefits and who doesn't.
51:24So finally I told you I'd
51:26give you a challenge.
51:27I would propose that we need
51:29to do the eye bulldog trial,
51:31and I've been talking to Pat and
51:33best phase one and drug developer
51:35I know and she'll get the drugs.
51:37She understands a science Ed Captain.
51:39We need him. It's just the amazing,
51:41most amazing person at bringing teams
51:43together and where we work so well together.
51:45So we're going to actually take a trial.
51:48Now we're going to try to use biomarker
51:51development biomarker prediction to
51:52treat patients based on that with trials
51:54and the reason I want to show this now.
51:57Is we're now accepting applications,
51:58so I'm announcing a new PO1
52:00group that's forming today.
52:01We're going to start having some meetings.
52:03I'd like to take the best science of yell,
52:05the best clinical science.
52:06I'd like to merge them together.
52:08I can tell you it's not really easy.
52:10In fact,
52:10most people tell you it can't be done.
52:13Used to work a lot of the Folkman
52:14he used to tell me that's exactly
52:17the time when you should do it,
52:18so we're going to make this
52:20happen and I'm very excited,
52:21and I think I've shown you
52:23that progress can be made.
52:25So I just want to thank all of you today.
52:28It's just been an amazing team effort.
52:30I want to especially thank the Yale School
52:33of Medicine by Albert for his support.
52:35The teacher grants that have led to
52:37these spores and now Nancy Brown and her
52:39team have continued to support this.
52:41Brian Smith and of course Charlie in
52:43the Yellow Cancer Center for all the
52:45money we get from the NCI we get all
52:48the resources of the Cancer Center.
52:49We get additional money for the DRP&C
52:51programs that career development
52:52and that's really important.
52:54So with that out. Thank you.
52:56And hopefully we have time for
52:57a couple of questions.
52:58Thank you very much.
53:00Or
53:00thank you. That was just fabulous.
53:02And congratulations to you and
53:04really everyone on the team or just
53:07amazingly impactful work in this field.
53:10I got some of the team
53:12here so I had a little
53:14bit of a live audience so.
53:17Excellent so folks should submit their
53:19questions on the chat function,
53:21but I I'll start while people are typing
53:24so you have a couple of questions.
53:27One that I'm just curious 'cause I've I've
53:30seen the data from the Bureau study before,
53:34but I didn't fully appreciate
53:36when you look at mutation type
53:39on the Florida forest plot.
53:41There seemed to be potentially a
53:43difference depending on the mutation
53:45type where it almost look like.
53:47They're confidence limits were
53:49not overlapping.
53:50did I misinterpret that
53:51no well, the good news is that both
53:54mutation types benefited in this
53:56trout in the metastatic setting.
53:58There is much more of a benefit
54:00for the exon 19 deletion versus
54:03the exon 21 point Mutation.
54:05As you can imagine,
54:06you would think that deletion might
54:09be less likely to become resistant.
54:11But yeah, I think you know
54:13the numbers there are.
54:15About equivalent there,
54:16one of them does a little bit better,
54:19but I think the good news there
54:22was that both, or at least quite
54:24well significant compared to.
54:26The one the travel, of course,
54:27was empowered to compare the two.
54:29And then sort of on a related note.
54:33Curious to see what your you know
54:36what your expectations are for IO
54:38in the future value in the Agement
54:41set setting and then you know to
54:44what extent targeted agents in iok
54:46and can be combined either in the
54:49Azure and or the metastatic setting.
54:51That's a great question,
54:53so I of course trials are ongoing so.
54:56They are being done in many cases
54:59without biomarker, so I worry a little
55:01bit about that because you know,
55:03these agents do have to access city.
55:05I didn't mention it, I know I assume
55:08most of us are familiar with this,
55:10but the idea is that you can get with these
55:13immune therapies while mostly low level.
55:16Certainly pneumonitis is
55:17something to worry about,
55:18and Carditis and other things.
55:20In the aggregate setting,
55:21I think that I would give it a 5050.
55:25Whether these trials will be positive.
55:28It's hard to file.
55:29We don't know the PD L1
55:30status often of these.
55:32These tumors were not following
55:33micrometastatic disease.
55:34I think in the future shortly we're
55:36going to use MRD techniques and these
55:38bespoke models to know who has minimal
55:40residual disease and much rather see it.
55:43Try where we know that someone has
55:45minimal residual disease and then
55:47use that route immune therapy to
55:49enhance that so it's being done
55:51sort of just as the next step and
55:53it might be that these are tumors
55:55that are not driven by PDL 1 maybe.
55:58They are the type 1 three or five or four.
56:00So I do worry about that a little bit,
56:03but you know, like anything else,
56:05depending on the population, they get.
56:06If it's a highly smoking related
56:08population that might have higher
56:09tumor mutational burden,
56:10perhaps it will be positive, but no,
56:12it gets all the same questions.
56:14How long to treat know what are you treating?
56:17But I'm glad that the experiments are
56:19ongoing and hopefully there are blood
56:20samples that are being obtained from
56:22those trials so that we can look and
56:24see what's happening in real time now.
56:26The other question you answer is.
56:28But I'd love to do, you know,
56:30we know that targeted therapy you
56:32have in each year for mutation,
56:3580% chance of tumor,
56:36will respond to patient.
56:38Feels better within days,
56:39so why not use immunotherapy
56:41targeted therapy early on,
56:42knowing that resistance will ultimately
56:44develop and then bring on the immune therapy,
56:47which takes awhile to work,
56:48but will have a mug shot but will have
56:51a much more durable response that's
56:53been tried an at least in lung cancer.
56:57The toxicity has just been.
56:58Unbearable both in Asia and in the US.
57:01Not sure why,
57:02but I guess the reactivation of the
57:05immunity in patients that are getting
57:07these EGFR agents that do tend to
57:10have issues with the skin and the
57:12long term institutional lung disease.
57:13Those toxicities have precluded that so far.
57:16That said,
57:17there are other ways to other agents that
57:20can be looked at that are now being tried.
57:23Lag 3 Tim.
57:243 maybe the cyclic that
57:25all should be looked at.
57:27So I think that.
57:28That has to be the next step,
57:31because each year for mutated disease,
57:33as good as it is,
57:35at least in the metastatic setting,
57:37we still have many patients.
57:38In fact, most will recur,
57:40and so I think trials are
57:42warranted there and then.
57:43You know, I'm hoping that in the Dora the
57:46longer duration of therapy with better
57:48agent in an earlier setting will result in.
57:51Curious, but we don't know that yet either.
57:53Going to follow those patients
57:55for awhile for survival.
57:56Thank you. Actually a few questions
57:58coming in one comment that will offer
58:01quickly is Stephanie Lien Rights.
58:03Congrats, beautiful multiple
58:04exclamation points Stephanie.
58:05Thank Stephanie Pat Larusso asks,
58:08do you think the scenario will be
58:11the same with G12C rash mutations
58:14in combination with IO? OK so
58:17so I didn't mention that but that's
58:20K wrasses, been the Holy Grail.
58:23So G12C mutations in lung cancer
58:26account for about 12 to 13%.
58:29That's more than each year for mutations.
58:33Now there will be a big talk actually.
58:3512 C&K Ras the engine drag asmo.
58:38I believe this Sunday or Monday.
58:40We know that their responses.
58:42You know that's been presented already.
58:44In fact, Yosi and I wrote an
58:46editorial on this last year.
58:48We also know that the activity
58:50was best in preclinical models in
58:52immune competent animal models.
58:54So I do think that those agents are just
58:57begging to be combined with a new therapy.
58:59The one thing we don't know yet and
59:02hopefully will see this weekend.
59:04Is what is the durability of
59:06response for K Ras agents alone you
59:08worry since K races so upstream,
59:10but they're going to be so
59:12many bypassed pathways there.
59:13Will it have a median duration of
59:15response of at least six months or more?
59:18In fact, if not,
59:19I probably have to be combined
59:21so my phone is that very nice
59:23that we have these agents.
59:25the Q 12 see not as good in colon cancer,
59:28of course,
59:29but that's that's a smoking
59:31related KRS abnormality.
59:31Now we do have data that K Rasputin
59:34patients to respond to immunotherapy.
59:36But I think that combination is
59:38something that hopefully we're
59:40already doing here at yeah.
59:41So Sarah Goldberg already is running trials.
59:44Rick Wilson Patton.
59:45Navid have fares as a trial in the face.
59:48One group.
59:49These are all things were studying
59:51here and then. Final question from David.
59:53Rim is a diagnostic test needed to see
59:55who will benefit in the admin setting
59:58or should every mutation patient get?
60:00I guess those emergent OSI here, right?
01:00:02So I imagine I was hurt.
01:00:05And at this point, no.
01:00:07I think everyone who's EGFR Mutant.
01:00:09You know, you know.
01:00:10Again, you know there are going to be
01:00:12some who say we don't have survival data.
01:00:14I can share if I were giving
01:00:16this talk a week from now.
01:00:17I think I could put the nail
01:00:19in the case because you know,
01:00:21certainly if when we're not
01:00:22to metastasized to the brain.
01:00:24I think that's a good thing,
01:00:25but I think that yes,
01:00:27you know we're going to
01:00:28have to learn from this.
01:00:29I can't wait till dawn when gets
01:00:31those samples and he can sequence
01:00:33them and tell us who's going
01:00:34to metastasized to the brain.
01:00:36So we know that advance.
01:00:37We can look at the cell free DNA and
01:00:39know that someone is developing early
01:00:41resistance and maybe we get Katie.
01:00:43Some tumor actually can
01:00:44develop an animal model.
01:00:45There's still room to to do better,
01:00:47but I think right now,
01:00:49assuming approval, I think will use this.
01:00:51Then one of our surgeons right here.
01:00:53I have to convert him that he should
01:00:55send the sample for each year from
01:00:57Mutation and hopefully will do that.
01:00:59And hopefully David will help me with that.
01:01:02Alright,
01:01:02thank you, I know we're out
01:01:04of time is a fantastic talk.
01:01:06Great, great work.
01:01:07Thank you for all that you're doing
01:01:09in your leadership. And again,
01:01:11thank you for a fantastic presentation.
01:01:13Thanks for all your support. Again.
01:01:15It's it's the Cancer Center that supports
01:01:17the teams that really can make the
01:01:19difference that can help the patients.
01:01:22Eventually everyone have a good
01:01:24day and will see you next week.