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

Transcript

• 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.