John Murren, MD Memorial Lecture: 15 Years of Advances in EGFR Mutant Lung Cancer

November 18, 2020

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Yale Cancer Center Grand Rounds | November 3, 2020

Heather Wakelee, MD

ID5899

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00:00Fortnight yeah we can see out
00:03the window behind you looks
00:05nice. So why don't we get started?
00:08And I know there's still people joining us,
00:11so to all those in attendance,
00:14since those logging in welcome to a
00:16special Cancer Center grand rounds
00:18where you know very privileged to
00:20honor the legacy of Doctor John Murnan,
00:23have a very special guest as our
00:252000 two 1020 Memorial Lecture,
00:28and I want to introduce where I
00:30herbs whose everyone knows is
00:32our chief of Medical Oncology and
00:34Associate Cancer Center director
00:36for a translation of science and.
00:38Leader of our lungs.
00:40For, among other things,
00:41to speak about the lectureship
00:43and introduce our speaker.
00:45So Roy, thank you,
00:46thanks Charlie and thanks
00:47everyone for joining.
00:49This is a very special lecture because it
00:51honors our colleague and friend John Urine.
00:54If we can go to the next slide,
00:56please.
00:59Emily. So many people who are on the line,
01:05new John I see John Sister Mary
01:07Kay is on and his wife Nancy and
01:10perhaps others are the family.
01:11One of the special things about
01:13this lecture is we usually can get
01:16together and talk and in person.
01:18Hopefully that will happen again next year.
01:20But no, John was a very special person
01:23and as many of us know he passed away in
01:262005 of Melanoma at the young age of 47.
01:29He was an associate professor
01:30of medicine at the at Yale.
01:32He was the director of the outpatient
01:34center director of the Lung Cancer Clinic.
01:36I wouldn't probably be here at Yelp,
01:38not for John and Co.
01:40Leader of the Experimental Therapeutics
01:41program at the Yale Cancer Center.
01:44He was survived by his wife Nancy,
01:46his son John,
01:48his mother Jean and I know that
01:50Nancy is here and maybe Gene no.
01:53Many new new John even better than me.
01:56I knew him from from the clinical
01:59trials and from meetings.
02:01He was really the consummate
02:03medical oncologist.
02:04Academically, he was just the most caring,
02:06position and active laboratory
02:08working to develop new treatments.
02:10Very insightful and really the
02:12top program that we have today.
02:15Is in large part due to John in his effort.
02:18He had some efforts to his family
02:20with in Las Vegas and Yell had some
02:23interactions there for awhile,
02:24but really he just was someone that
02:27we all knew and loved and one of
02:29the reasons we've invited today's
02:31speaker is not only is she an amazing
02:34researcher and clinician lung cancer,
02:36but she knew him as well through the
02:38cogs where John was a major person.
02:41So really very glad to have this lecture.
02:43I gave this lecture 11 years ago
02:46so it's really a pleasure to
02:48introduce today's speaker.
02:49We can go to the next slide, please.
02:51So in thinking about this,
02:54you know this is the second time
02:56we've scheduled this with Heather
02:58and we just decided we would do this
03:00virtually because we were so lucky to.
03:03Heather agreed to come and speak with us.
03:06Doctor Heather Wakelee is a professor
03:08of medicine and the interim chief in
03:10the Division of Oncology at Stanford
03:12University and the President elect
03:14of the International Association
03:15for the Study of Lung Cancer.
03:17PS When she received her medical
03:20degree from Johns Hopkins University
03:22and completed offer postgraduate
03:25training at Stanford University
03:27before joining the faculty in 2003.
03:29Heather specializes in the
03:31treatment of lung cancer,
03:33thymoma and mesothelioma,
03:34and had developed research programs
03:36related to lung cancer in SOMA across
03:39multiple areas including clinical trials,
03:41translation, working, population Sciences.
03:43He's the principal investigator.
03:44Numerous clinical trials that
03:46have changed the pattern of care,
03:48and as a faculty director of the
03:51Stanford Cancer Clinical Trials Office
03:52and lead investigator for Ikago,
03:54Akron Clinical Trials Group at Stanford.
03:57He also is active in many organizations,
03:59but actually I've shared many
04:01patients with her.
04:02She's also the most compassionate
04:03physician and the person that
04:05I would call whenever I
04:06have a difficult case,
04:08especially in the go far field.
04:09In fact, I did that last night,
04:12so if you go to the next slide we
04:14normally at this point I would
04:16be handing Heather her plaque,
04:18but due to the amazing efficiency
04:19of Yale Cancer Center,
04:21Heather hasn't show us.
04:23And so it already arrived.
04:26Can you see it? So here we
04:28go and then last night we actually
04:30had a little get together.
04:32Some of us on zoom and you
04:34can see Pam Kuntz there.
04:36Who we recruited out of Heathers Group
04:39and we did a little zoom happy hour
04:41and without drinks but just talked
04:43about John talked about lung cancer.
04:46So Heather it's wonderful to
04:47have you here today.
04:49Thank you to them.
04:50You're in family for your support
04:52and again and we Miss John so
04:55much but we're looking forward to.
04:57His memory to a wonderful
04:59lecture from Heather Wakelee,
05:0015 years of advances in EGFR
05:02mutant lung cancer, Heather,
05:04welcome to Yell.
05:06Thank you, thanks right for
05:08that very kind introduction for
05:10inviting me to be here today.
05:11I really wish I could be there
05:13in person to get to visit with
05:16all of you toward the campus,
05:18which I haven't seen in a few years.
05:20I know there's been a lot of lot of
05:23development an I really would have
05:25valued getting to meet with the family.
05:27As Roy mentioned, I did know John,
05:29I was pretty early in my career,
05:31but he was very welcoming when I
05:33showed up at the Kage Akron meanings.
05:36I remember having several
05:37conversations with him.
05:38And I very vividly remember when
05:40I heard of his death and how
05:43devastating that was for me.
05:45For whole lung cancer community.
05:47And so when Roy invited me to
05:49give this talk and I was thinking
05:52about what could I cover,
05:54thought about the fact that we lost
05:57John 15 years ago and thought about
05:59how much the world of lung cancer
06:02therapy has changed during that time.
06:05Ann wanted to use the story
06:07with EGFR lung cancer is.
06:09As a real example of one of the
06:11most dramatic changes that have
06:12happened during that time period.
06:14But I also wanted to weave in
06:17a different story and that was
06:19about patient communication,
06:20and so I'm also going to be talking
06:23about that and framing it a little
06:26bit around another physician who
06:28unfortunately lost to cancer and who
06:30has a connection to yell as well.
06:33And that's Paul Community and his
06:35breath when breath becomes air book,
06:37I was I was his physician,
06:40and in that book he talked a lot about
06:43his philosophy about living as a.
06:45Well, first of all,
06:47is being a care provider physician
06:49for patients facing cancer and
06:51other serious issues.
06:52But then as a patient and how he
06:54thought about living as a patient
06:57an he really captured a lot of
06:59the ways I think about things.
07:01And as we talked together and so
07:04I wanted to share that as well.
07:06So I'm going to try to do over the next hour.
07:10I'm going to go ahead and share my
07:13screen here. And give you the talk.
07:18OK, and.
07:20View slideshow OK,
07:22so hopefully you're seeing this
07:24now show I titled this 15 years of
07:27advances in EGFR mutant non small
07:29cell lung cancer lung cancer and then
07:32with the focus on patient communication,
07:34these are my disclosures.
07:36And then as I thought about
07:38a learning objectives,
07:39it was to really talk about how that
07:42EGFR Field has evolved overtime,
07:44specifically the EGFR Tkis,
07:45and then a couple of things.
07:47We're looking at adding to Egypt art
07:49therapy and then talk about communication.
07:52So when we think about advances
07:55in the treatment, EGFR,
07:56TKI eyes alone, veg F combinations,
07:59each diff are combinations,
08:01chemotherapy, immune therapy,
08:02and then the communication.
08:04So back in 2000 and I was just
08:07starting my time as a oncologist.
08:09This was the state of the art and what this
08:12is showing is survival curve from a
08:14trial where patients were treated
08:16with only things we knew to use which
08:19was just chemotherapy combinations
08:20and you can see that we hadn't
08:23made a whole lot of progress.
08:24We were helping people,
08:26but not for nearly long enough,
08:28and without really being able to
08:30distinguish what was the best
08:31treatment for any given patient.
08:33Because all of these different chemotherapy
08:35combinations looked about the same.
08:37But many people realize that there
08:39were things about lung cancer that
08:42were different than some normal tissue,
08:44and one of them was a high expression
08:46of this EGFR or epidermal growth
08:48factor receptor protein,
08:50and what this cartoon is showing
08:52is that the epidermal growth factor
08:54receptor is a protein. It's a receptor.
08:56It's on the cell surface and it's
08:59sitting out there with the GF binding to it.
09:02And then it sets off a whole bunch
09:05of signaling,
09:05which does a lot within the cell regarding.
09:08Growth of cells. Survival of cell.
09:10So it was thought that each day Fr
09:12was likely pretty important in lung cancer,
09:15and you'll notice one of these
09:17reviews was written by Roy.
09:19And so people develop different
09:21ways to target EGFR,
09:23the most common being these
09:25tyrosine kinase inhibitors.
09:26So this is the tyrosine
09:28kinase receptor ligands,
09:29binds and then you get signaling down
09:32here and the tyrosine kinase domain.
09:35So these medications that are pill
09:37drugs oral can block that tyrosine
09:40kinase activity than the first of
09:43these developed was to fit Nip.
09:45And I'm going to talk about each
09:47of these drugs a little bit,
09:49but there are other strategies
09:50to hit tyrosine kinases.
09:51One is to block where the leg and
09:53would bind and will talk about
09:55a couple of drugs that do that,
09:57and then another is to just take all
09:59the Ligue and what would be binding
10:01and turning things on and remove it.
10:03And that's a different approach
10:04that used as well.
10:05So just wanted to give this
10:07cartoon to set people in mind about
10:09thinking how the drugs work.
10:10So the first drug to fit him and
10:12you see Doctor Herbst of course
10:13was involved in that was given
10:15to patients with lung cancer.
10:17And it was noted that some people,
10:19maybe 10%, had these dramatic responses,
10:21which was really exciting.
10:22But we didn't know how to select them.
10:25And this led to a larger trial with
10:27a similar drug called or lot nib,
10:29where patients receive this drug in the
10:32second or third line or they got placebo.
10:34And when you looked at it,
10:36response rates were about 10%.
10:37Survival wasn't great,
10:38but it was better than placebo and so
10:41this was really exciting at the time.
10:43To see that two month improvement.
10:45But what was really interesting
10:47is people notice that it wasn't
10:49just random who was responding.
10:51It tended to be women attended
10:53the people with the adenocarcinoma
10:54type of lung cancer,
10:56and especially people who had lung cancer,
10:58who had never smoked,
11:00and also notice that a lot of
11:02them were of Asian ethnicity,
11:04and so this led to at the
11:06study known as the ipass trial,
11:08which was conducted in Asia.
11:10It was done in people who had
11:12very limited smoking history,
11:13but who had developed
11:15adenocarcinoma lung cancer.
11:16And this ended up being mostly women,
11:18and they were randomized to either get the
11:21EGFR pill drug you fit nib or chemotherapy,
11:24and I showed you that before the
11:26chemotherapy drugs are all about the same.
11:29When we look at them.
11:31And what was interesting is
11:33when the results came out,
11:34it was very confusing at first,
11:36because when you look at the
11:38progression free survival,
11:39which is the time either that
11:41someone is no longer alive or
11:43that their tumor has started
11:44to grow the progression time,
11:46these curves kind of crossed in.
11:48The chemo was looking better
11:49until about five months,
11:51six months and then the gym fit
11:53nib so it wasn't very clear story.
11:55And when we looked at overall survival
11:57there wasn't any different so it wasn't
11:59clear that this definitive drug was really.
12:02Do anything special but.
12:06Well,
12:06that study was being conducted,
12:08so starting at around 2005 and
12:11again this is the 15 year story.
12:14Scientists at several institutions.
12:16An realize that these patients
12:18who had these dramatic responses
12:20they did testing on their tumors,
12:22and they found that the tumors had a
12:25change in the Egypt far protein that
12:27was really related to a mutation that
12:30had happened in the cancer cells.
12:32So in the cancer cells,
12:34EGFR became mutated and became
12:35turned on all the time.
12:37Constitu Tively active,
12:38and that looked like it was
12:40what was driving the cancer,
12:42'cause none of those mutations
12:43were found in the tumors are
12:46patients who didn't respond.
12:47But they were found in almost
12:49every tumor of patient,
12:50who did respond,
12:51and so that led to sort of the
12:53ah ha moment that changed how we
12:55think about treating lung cancer,
12:57because when they went back and tested
12:59the tumor samples from the patients
13:01who had been on the I pass trial,
13:03they were able to come up with a
13:05very different story that patients
13:06whose tumors had the EGFR mutation
13:08did much better with your fitness,
13:10much higher responses.
13:11It worked for much longer than chemo,
13:13but for people whose tumors
13:15did not have that,
13:16even though they otherwise look the same.
13:19It didn't work at all,
13:20and that was the first moment for us in
13:23lung cancer to realize we needed to look.
13:25We couldn't just determine based on
13:27what the patient looked like or what
13:29their tumor look like under the microscope.
13:31We needed to test,
13:32and if we could find the EGFR mutation,
13:35then we could actually treat the tumors
13:37differently and have better outcomes.
13:38And I'm focusing on EGFR today,
13:40but we now know to think about and
13:42look for mutations in seven different
13:44genes in lung cancer is actually
13:46closer to 10 now, but we have 7 where
13:48we have FDA approved medications
13:50and we can think about using those
13:52instead of chemotherapy upfront.
13:53So this was a complete revolution in how
13:56we think about treating lung cancer,
13:58and this study really was what God is there.
14:01So I'm focusing on that quite
14:03a bit in this particular trial,
14:06by selecting the way they did,
14:08about 60% of patients had EGFR
14:10mutations and those numbers vary
14:12around the world and based on who the
14:14person is who's gotten the cancer,
14:16but it's not specific dress to women in Asia,
14:20have alot of my patients here in California,
14:22wouldn't fit that demographic.
14:24But yet there tumor hasn't EGFR mutation,
14:26and they respond as if anybody else who
14:30has that EGFR mutation in their tumor.
14:33We've now had multiple other studies
14:36that have looked at giving EGFR TK I
14:39drugs versus chemo in patients whose
14:42tumor have in Egypt are mutation
14:44and you can see that in all of them,
14:48the progression free survival time was much,
14:51much better with the Egypt far drug,
14:54but it wasn't forever,
14:56and that's because we get resistance and
14:59this is a slide goes back a little bit now,
15:03but. Was figured out was that.
15:05In order for a cancer to have an EGFR
15:08mutation that we don't know why that happens,
15:11we're still trying to figure that out.
15:13But when the tumor has
15:15that easier for mutation.
15:17The tumors respond really well
15:19to an EGFR tyrosine kinase drug,
15:21but overtime resistance develops
15:23because new mutations happen,
15:25and in the setting of EGFR with
15:27these initially developed EGFR drugs,
15:30most of the time when those stopped working,
15:33it was because another EGFR mutation
15:35developed, and that was called T790M.
15:38So we spent many years trying to
15:40figure out a way to treat T790M.
15:43I have a lot of old studies that
15:46didn't go anywhere.
15:48And many medications we worked
15:49with but then came along this drug.
15:52Oh, summer NAMM.
15:53Which is the third generation EGFR drug.
15:56And it works when T790M is there.
15:58So what these are showing is you've
16:01got the line.
16:02If you've got lines above it,
16:04that means that the tumors grew,
16:06but everything below the line means
16:08that the tumor shrunk so you can see
16:11that for most of these the tumors were
16:13shrinking when a patient received
16:16oh summerton. If after they die.
16:18Already had either the jefit neighbor
16:20alot nip those so if they've been
16:22on a first generation drug and it
16:24stopped working.
16:25And then they took this third
16:27generation drug osimertinib most
16:29of the time the tumor shrunk,
16:30and that's because we were actually
16:33getting that T790M target.
16:34So to prove that there was a trial
16:37for patients who had been found
16:39to have Egypt permutation in their
16:41tumor at the beginning,
16:43they started on a first or
16:45second generation EGFR medicine,
16:46and then when it stopped working,
16:48they were on a trial randomized
16:51to either ghetto smart
16:52nib or to get chemotherapy.
16:54And what this showed us was that
16:57progression free survival was
16:58clearly better with, uh, oh, summer.
17:00New versus the chemotherapy.
17:02So it became standard that you would
17:04test when someone was diognosed if
17:07their tumor had the EGFR mutation,
17:09you would start them on
17:11our lot nib or defend him,
17:13and when that stopped working,
17:15if the T790M mutation was there then,
17:17oh, Smyrna was a better choice
17:19than going with the chemotherapy.
17:22But finding the T790M wasn't perfect,
17:24so there were several different
17:26ways to do that.
17:28You could either look with tissue.
17:31Or in the blood with plasma testing.
17:33And we also did some urine testing,
17:35but we don't do that so much anymore
17:37and what this is showing is that most
17:40of the time you could find that T790M
17:42in the tissue and in the plasma,
17:44but there were sometimes you
17:46could only find it in that issue.
17:48And that's because it wasn't
17:50being shed out into the DNA wasn't
17:52going out into the blood.
17:54Or you only found in the plasma,
17:56and that's perhaps because
17:57when you did the biopsy,
17:59you didn't get enough of the cancer cells,
18:01or there's some heterogeneity meeting
18:03that not all of the cancer cells change
18:05at the same time in the same way,
18:08so you can have areas that are
18:10resistant because of this mutation.
18:11Other areas that are not,
18:13and so I'm not going to go
18:15into that today in one hour.
18:17You can't cover everything,
18:18but I wanted to at least mention
18:20this because it is important
18:22to know that when you have.
18:24Cancer.
18:24It's evolving overtime an the
18:26way that we find out more about
18:28it as we need to sample it.
18:29An historically that was always with tissue.
18:31But now we can look at it with
18:33these plasma tests as well,
18:34but that's all I'm going to
18:37say on that topic.
18:38OK,
18:38so we know to test we know to
18:41give a first generation drugs.
18:43We know T790M develops.
18:44So then you use the third generation drug.
18:48But of course people wondered.
18:49Why don't we just give this
18:51third generation drug 1st and
18:53then T790M won't develop?
18:55So that was this flora trial
18:57where patients who are newly
18:59diagnosed and found to have EGFR
19:02mutation either goto summer nib
19:04or got a first generation drugs.
19:06And that study clearly showed
19:08that to Smyrna was better for
19:10that progression free survival,
19:12meaning that it took longer
19:14before the cancer started to grow.
19:16However,
19:16it also led to overall survival improvement,
19:19and that's because even though
19:21theoretically if you started on
19:23a first generation drugs and
19:25then developed resistance,
19:26you could go on to Summerton
19:28if if it was T790M.
19:31There are other things that cause
19:33resistance an so delaying that time
19:35to resistance with the osimertinib,
19:36even when it's not resistance due to
19:39T790M overall survival was better,
19:41and so this has become the
19:43standard approach in the US.
19:44But unfortunately as you see,
19:46these curves eventually do come down.
19:48We're not curing people,
19:49and therefore we still need to
19:52think about better things to do.
19:54So we kind of summarize
19:55this first part about EGFR.
19:57We need to test to find the Jaffar mutation,
20:00and usually that's done
20:01with the tissue testing.
20:02But we can also sometimes find it
20:04in the plasma with blood testing.
20:06If you find the Jaffar mutation,
20:08we start on an EGFR.
20:10TKI osimertinib is what
20:11we tend to use in the US,
20:13but there are multiple other EGFR
20:15tyrosine kinase drugs which are
20:17approved in the US and globally,
20:19and so those are still used as well.
20:23And as I mentioned,
20:24we're still thwarted by resistance.
20:26So with Osimertinib,
20:27it's not such a simple story like
20:29it is with the 1st generation drugs,
20:31where we get one resistance pathway,
20:34which is that T790M resistance as
20:35the predominant one when there's
20:37osimertinib resistance are a lot of
20:39different things that can happen.
20:41You can get other EGFR mutations and C.
20:44797 and T 797 S is the most common of those,
20:47but there are a lot of other pathways
20:50that can go be abnormal as well.
20:53And so it's quite complex,
20:54and there's a lot of research
20:57being done there.
20:58And this is just a graphic showing
21:00some of those resistances,
21:02so I talked about the T790M here
21:04with first and second generation.
21:07But there's also overexpression of
21:09met and mutations in other genes and
21:11also a transformation to small cell,
21:13so it's not always straightforward.
21:15And then with Osama RNIB there
21:18can be changes in what the EGFR.
21:20Just kind of percentage of expression
21:22of the protein is it's never gone
21:24that Egypt permutations never gone,
21:26but the way it's expressed is different.
21:28But you also can have met overexpression
21:31is fairly common, or changes in BRAF.
21:33We just were talking about a
21:35case this morning.
21:36Stanford, with another patient
21:37who had been on no smart Niman,
21:40then developed in be reputation and many,
21:42many others.
21:43So again, it's quite complex as we
21:45talk about bypass tracks in Egypt,
21:47our target alterations.
21:48So then what do you do?
21:50You gotta think.
21:51Outside of that, here's the target.
21:53Hit the target.
21:54We've got to be broader that.
21:56Here's a target hit.
21:57The target is great,
21:58and it's helped people tremendously
21:59for an extended period of time.
22:01But we want to extend it even further.
22:04So what can we do?
22:05We try something else so
22:07we have anti angiogenesis.
22:08Is one of those,
22:09and that's getting at the fact
22:11that in order for some tumor
22:13cells to grow into a tumor,
22:14they need to have blood vessels to feed them.
22:17And so this is angiogenesis.
22:18And that's where we get.
22:20Drugs such as Bevis is a map and many others,
22:23and there's been a ton of trials
22:26noticing that in the EGFR setting,
22:28veg F is also very important,
22:30and so a lot of trials looking at in a
22:33patient with Egypt or mutant lung cancer,
22:36you can give the EGFR medicine,
22:38but you can also give it with anti
22:40veg F therapy and that theoretically
22:42should make a big difference.
22:44So one of the first trials was the beta
22:47trial led by Doctor Herbst an in this study.
22:50It wasn't selected for patients with
22:53EGFR mutation because this was done
22:55before we knew about the EGFR mutations
22:57and we were just giving our lot nib to
23:00people after they already had chemo.
23:02But this showed that even without that,
23:04giving the bevacizumab added to the
23:07Erlotinib improved progression free
23:08survival Anne in the small group of
23:10patients who would went back and found
23:13that they actually had an EGFR mutation.
23:15There was a signal that there might
23:17even be an overall survival benefit by
23:20adding the beva system up to her latinum.
23:23So there's been multiple other trials.
23:25This was a phase two study done in Japan,
23:28where patients with EGFR mutant lung
23:31cancer received either or lot nib
23:33the pill everyday or a lot in it.
23:35Plus the breakfast is a Babin
23:37beverages and Maps and antibody.
23:39It's given Ivy every three weeks,
23:41and this study showed a marked
23:43improvement in progression free survival.
23:45This actually led to approval
23:47of this combination in Europe,
23:49but not in the US.
23:51With longer term follow-up, though,
23:53it turned out that Despite that huge
23:55progression free survival benefit,
23:57there was no overall survival benefit,
23:59and so it's a little bit unclear what
24:02we're doing with this combination.
24:05Perhaps it's helpful to prolong the time
24:07that there are lot name stops working.
24:10It turns out that if you're on
24:12our lot nib and bevacizumab,
24:14the most common resistance
24:15pathway still is that T790M.
24:17So if you're on this combination
24:19and then resistance develops,
24:20you can go on to get the oh,
24:23Smyrna, but there are other things
24:25that happen besides T790M and
24:27then no overall survival benefit,
24:28so little bit unclear.
24:30There was a randomized phase three trial,
24:33also done in Japan,
24:34which had very similar results in Nice
24:36progression free survival benefit,
24:37but no overall survival benefit.
24:39And this is news.
24:40This just was presented at our ASCO
24:42meeting in June of 2020 show we were
24:45waiting on this and now we kind of
24:47seeing this similar story emerging,
24:49but it's more complex than that in the US.
24:52We also have this or lot inhibin
24:54Rammus serum app,
24:55so I showed at the very beginning.
24:58The different ways to target
24:59these tyrosine kinase.
25:01So the first where the tyrosine
25:03kinase inhibitors which work in the
25:05cell at the tyrosine kinase domain.
25:07But then I also showed two different
25:09strategies for antibodies,
25:10one the bevacizumab type or its
25:12binding to the leg and so sucking
25:15all the leg and away the other binds
25:18to the receptor and sort of blocks.
25:20The way the receptor works oramus
25:22serum AB is blocking veg F receptor.
25:25So you've got our Latin if the
25:27tyrosine kinase inhibitor blocking.
25:29The tyrosine kinase activity
25:30and then veg F Knotty Jeff
25:32but Jeff related is also being blocked,
25:34so you get a blockage that way and you see
25:37this nice progression free survival benefit.
25:39But we haven't seen the
25:41overall survival data yet.
25:42This combination is approved as
25:44an option in the United States,
25:46but I think that we're waiting to
25:48see what that overall survival
25:50data is going to look like.
25:52Now I've talked about her Latin appear,
25:55but you're thinking the beginning.
25:56You were telling me that Osimertinib
25:58is preferred over these.
26:00So what?
26:00Where is the oh summer nimbuses
26:03amount data will hear some of it.
26:05So this was data that Hanyu and the
26:07Memorial Sloan Kettering Group put together.
26:09This is not randomized.
26:11This is just patients getting
26:12oh smart nib and bevacizumab,
26:14and the toxicity was manageable
26:16and the response rate was very
26:18high at 80% and the median time to
26:20win the drugs combination stopped
26:22working was about 19 months.
26:24So that's interesting.
26:25It's not overwhelming,
26:26but interesting.
26:27However, there is this very confusing
26:29presentation that we saw just last month,
26:32two months ago now in September
26:34at the ESMO meeting the 2020,
26:36which was a randomized phase,
26:38two of oh Smyrna plus or minus bevacizumab,
26:41again done in Japan.
26:42And when you look at this,
26:45the blue line is actually the
26:47osimertinib alone.
26:48So in this particular trial,
26:50the combination of oh Summerton
26:51Bevis is a map looked worse
26:53for progression free survival.
26:55Then just the ocean alone.
26:57So that's a little bit confusing.
27:00The ultimate number alone progression
27:01free survival was lower than were well.
27:04I should say this was done second line,
27:06so this was for patients who
27:08had or lot nip or just fitting.
27:11It already had developed T790M
27:12and then went on Osimertinib.
27:14So it's different than the first line data.
27:17But in this trial with no smart net plus
27:20or minus bevacizumab in the second line.
27:23The awesome art never alone
27:24outperformed the combination.
27:25Now this is a randomized phase two trial,
27:28so we have to be careful,
27:30sometimes randomized phase two
27:31studies don't give us the truth.
27:33This study did show that the
27:35response to the combination was
27:37higher than the single drug,
27:39but just not that progression
27:40free survival benefit.
27:41So we're kind of confused by this result.
27:44We are moving forward with the next
27:46line of exploring this though,
27:48so this is a randomized phase
27:50study randomised three study in
27:52the Kaga Chrome network.
27:53Led by Helena, you and bless Hamas.
27:55And this is for patients who
27:57have just been diagnosed.
27:58So the one I just showed you with
28:01second line. This is first line.
28:03Patients just diagnosed with lung
28:05cancer that has an EGFR mutation and
28:07they're going to get oh smart nib
28:09plus or minus bevacizumab in the study.
28:11Just opened to enrollment,
28:13so we have no data yet,
28:15but we're excited to participate,
28:16though again,
28:17as we talk about this option with patients,
28:20it will be important to talk
28:21about the data that
28:23we've already seen.
28:24With the other combinations of EGFR,
28:26TKI plus or minus a veg F drug,
28:29so we're still kind of
28:30trying to understand this,
28:32and there's also a no smart nib
28:35romanisti remap trial ongoing.
28:36OK, so leaving that and now on too,
28:40so hopefully you're following EGFR TK alone.
28:44EGFR TK I plus or minus.
28:46These anti angiogenesis drugs.
28:48And now we're looking at Egypt,
28:50far EGFR combinations and this is
28:52where we're looking at, an EGFR,
28:55TKI pill, plus an antibody drug that's
28:57also hitting that EGFR approaching.
28:59And if you think again about that first
29:02slide I showed you or early on where
29:05you've got the different strategies.
29:07If you've got a receptor tyrosine
29:10kinase inhibitor tyrosine kinase,
29:11if you block at the tyrosine kinase domain.
29:14But you also block at that receptor point.
29:17You're hitting the same protein in two ways,
29:19and so that's the theory
29:21behind why this would work.
29:22And long ago.
29:24Before we had to simmer
29:26nib so going back in time.
29:28We had a combination of an EGFR pill drug
29:32afatinib plus in Egypt are antibody,
29:34so tux,
29:35omab and this combination was the first
29:38combination and the first thing we
29:40ever saw that worked in the setting of
29:44having been on a first generation drugs.
29:46Developing T790M,
29:47so before we add anything else,
29:50this combination worked and so
29:52this was the original publication.
29:55And again,
29:55this is a waterfall plot,
29:57so you see a few patients had
29:58there's tumors grow,
29:59but a lot of patients had
30:01their tumors shrink,
30:02and so this was an option
30:03that we had for awhile.
30:05But now we don't use it too much because of,
30:08oh, Smyrna,
30:08but we're coming back to study it.
30:11And so there are combinations.
30:12Nauvo summer nib.
30:14Plus and different Egypt
30:16for antibody necitumumab.
30:17So we are part of this California
30:20Cancer Consortium study.
30:21Jonathan Rhys has talked about
30:23some of the preliminary data at
30:25ASCO last year and more ongoing
30:28show encouraging information here,
30:29and this is being looked at for
30:32patients who have already been on oh
30:35smart nib and it stopped working or early on.
30:38There also combinations with afatinib
30:40and necitumumab and were part of
30:43that consortium which is, uh.
30:44Vanderbilt,
30:45so a lot of work still looking at this,
30:48but some toxicity issues so we'll
30:50see how that pans out there.
30:53Also,
30:53newer drugs being developed at
30:55build on this so one is this
30:57aim of antonyms drug which is
30:59a combination of EGFR antibody.
31:01It's also hitting met,
31:03so if you were paying close attention,
31:05you'll notice I mentioned met as
31:07a potential resistance mechanism,
31:09and so there's data to support
31:11looking at met.
31:12There have been a lot of trials
31:15looking at specific met inhibitors.
31:17In the Egypt Far world again,
31:19I only have an hour,
31:20so I couldn't go into all of that.
31:23They haven't really gone too far yet.
31:25We haven't changed our treatment,
31:27but we haven't forgotten about that.
31:29So we're looking at Egypt.
31:30Are met antibody,
31:31hear them if antonym in combination
31:33with the different third generation
31:35drug lizard nip and to this was
31:37dated that was just presented at Asmo,
31:39which was encouraging,
31:40showing that for patients who had already
31:43had osimertinib in this preliminary
31:44data about a third of those patients
31:46did respond to this new combination.
31:48So we'll see how that pans out.
31:51How long it works,
31:52what the toxicity is show there's
31:54there is movement in excitement
31:56about new combinations.
31:58There are also newer EGFR
32:00pathway or this is the new drug.
32:03Use U Three 1402 or projection
32:05map directed hand and this drug
32:07is looking at her three and
32:10you're confused now because you
32:12think you're talking about EGFR.
32:14Why, you talking bout her three?
32:17Well, EGFR is also called her one,
32:20so her one an heard too and her
32:23three are all in the same family and
32:26they do interact with each other.
32:29Show this antibody drug conjugate
32:31that's focused on her three there's
32:34hope and some data now showing that
32:36it could be active in the setting
32:39where there's Egypt far drive.
32:41Sorry, each of our driven lung cancer,
32:44so this is again some very preliminary
32:46data where they were looking at patients
32:49who had EGFR mutant lung cancer had
32:52previously received osimertinib or
32:54had developed resistance to or lot in a
32:57bridge of fitness and didn't have T790M.
33:00And again on this waterfall plot you can see.
33:04That there have definitely been some
33:06responses and the details here all about.
33:08Well, what was the resistance mechanism?
33:10What was the underlying you do fermentation?
33:12What resistance was seen?
33:14And so there's a lot to parse through here,
33:17which I won't go into.
33:18But encouraging new data.
33:21OK.
33:21So now we talked about Egypt Party K eyes
33:24alone veg F novelly Jeff combinations.
33:27And now I'm going to switch to chemo
33:30and talk about Egypt, Kaizen, chemo.
33:32So again, bear with me here.
33:34This is a it's a lot to go through,
33:37but there's been so much we've been
33:39exploring and trying to understand.
33:41How do we do a better job of treating
33:44patients with EGFR mutant lung cancer?
33:46So what about combining chemotherapy?
33:48Need you 40K as well?
33:49When we first learned about the EGFR Tkis,
33:52there were big trials.
33:53Combining them with chemo misses the
33:55tribute and talent studies and again,
33:57Doctor Herbs played a big role in these.
34:00And these studies were completely,
34:01absolutely negative,
34:02and this was done before we knew
34:04about EGFR mutant lung cancer.
34:06We were treating everybody the same,
34:08but totally negative studies.
34:10And so this let us to not really
34:12think about this approach for awhile.
34:15There was some work looking
34:16at this intercalation idea,
34:18where you would use the Jaffar TK.
34:20I stop it, get the cell signaling again,
34:23give the chemo,
34:24restart the EGFR TKI and this
34:26actually was encourage ING.
34:28It showed an overall survival benefit.
34:30But people don't really want
34:31to be on chemo if
34:33they can just take a pill and
34:35said this was not widely adopted.
34:37People looked at whether when you
34:39were on a first generation EGFR
34:41drug and it stopped working and
34:43you were going to go to chemo.
34:45This was before Osama Rname.
34:47Whether you could continue the EGFR drug,
34:50or if you should stop it.
34:52And this was the impressed trial
34:54and that didn't work either.
34:55There was no benefit an if anything.
34:58Survival favored stopping that Jeff
34:59it nib and just going with chemo.
35:02So we had these.
35:03Big randomized trials combinations negative.
35:05We had this trial negative.
35:07If you combine the EGFR TK I
35:09in the chemo together so not a
35:11lot of enthusiasm but a lot of
35:14questions still because the idea
35:15of stopping in EGFR TKI for tumor
35:18that was dependent on it doesn't
35:20make a lot of sense to many people,
35:23and so lots of debate on this.
35:26And then we had two trials that
35:28came out which changed again,
35:30the way that we think about this.
35:32Should this was a trial done in Japan,
35:35chemotherapy.
35:36Within Egypt Artique I so this was
35:39in patients who are newly diagnosed
35:41EGFR mutant lung cancer and they
35:44either got the EGFR drugs if it new.
35:47Or they got to fit in it plus chemo.
35:49If they got your fitness plus chemo,
35:51they stayed on maintenance and
35:52at the time it stopped working.
35:54They went on to other therapy.
35:56If they got ripped fitness alone
35:58when it stopped working,
35:59they stopped it and went to chemo.
36:01So it's sort of a.
36:02You get everything together.
36:03The chemo plus that huge.
36:05If our drug or you get it sequentially,
36:07EGFR and then chemo.
36:09Again, no summerton period.
36:10This was designed before there
36:12was oh so Barnum.
36:14An when you think about this was the.
36:17First progression free survival.
36:18So this was for patients who
36:21had chemo plus to fit nib.
36:23Versus Jeff it Nip and the chemo plus
36:25your fitness group stayed on the drug longer.
36:28It was they were still on it
36:30for like 21 months.
36:31The group only get into fitting.
36:33It only worked about 11 months.
36:35You like?
36:35OK right but what you really want to
36:37know is everybody everything together
36:39concurrent versus sequential and when
36:41you looked at everybody together,
36:42concurrent versus sequential,
36:43the sequential group cut up when they
36:46went from there drifitng it to chemo.
36:47It all ended up being the same
36:50and you think OK, negative study.
36:52Except overall survival actually
36:53showed a benefit to having gotten
36:55everything at the beginning,
36:57so this has this a little bit confused.
37:00Why would getting everything at the
37:03beginning be better than the A and then B?
37:06If the progression free
37:07Survival's were the same,
37:08so we're still trying to figure this out,
37:10but there was another study
37:12that was done in India.
37:14Similar design.
37:14That also showed that there
37:16was a progression free and
37:18an overall survival benefit.
37:19This is a little bit different
37:21'cause not everybody who
37:22started on Jefit and I've
37:24got the chemo afterwards,
37:25but it kind of supports that,
37:27and so they're ongoing trials.
37:28Now looking at this question and
37:29including a study with Osimertinib,
37:31so we'll see how this pans out.
37:34And now I'm going to shift gears
37:36again and go to immune therapy because
37:38that's the other big revolution
37:40that's happened in the last 15 years,
37:42but it hasn't changed each
37:44of our lung cancer much.
37:45When we look at the first trials
37:47that got immune therapies with,
37:49these are the PD One PD L1 checkpoint
37:52inhibitors approved in lung cancer.
37:54They were given second line to
37:56people who had already had chemo.
37:58Some of whom were Egypt Farhadi,
38:00Jaffar lung cancer, and it already
38:02had Egypt farland treatments as well.
38:04They were the only subgroup that didn't
38:06do well with the checkpoint inhibitor,
38:08so in these older trials and
38:10I'm looking here at this box.
38:12Of docetaxel,
38:14chemo versus checkpoint inhibitors.
38:17Those trials showed overall
38:19survival benefits to everybody.
38:20With the checkpoint inhibitors,
38:21except patients who had EGFR mutations.
38:23So when we got to the bigger
38:25trials in first line,
38:27patients with EGFR mutations
38:28weren't included on those trials,
38:30so we have very little data.
38:32This one study that came out
38:34of the Atlantic trial,
38:35which was a phase two study,
38:37showed that if you had a Jaffar mutant
38:40lung cancer and your PD L1 level was high,
38:42sometimes the checkpoint inhibitors
38:44worked about 12% of the time.
38:46But if you had low,
38:47any different mutation, it never worked.
38:49People have done TK.
38:51I plus immunotherapy combinations.
38:53And they've been totally negative.
38:54Alot of Texas city. No clear benefit so.
38:58We don't get too enthusiastic about
39:00checkpoint inhibitors in EGFR,
39:02but we think about it.
39:04There was one trial.
39:05This empower 150 study that was chemo
39:07plus bevacizumab plus immune therapy
39:09that allowed for patients with EGFR
39:11mutations and that study did show
39:13potential survival benefit in the subset,
39:16but we have to be really careful because
39:19this was a small subset of a bigger study.
39:22It wasn't really powered to
39:24answer the specific question,
39:25and so their ongoing trials.
39:27Now looking at this so we
39:28still have questions around.
39:30What do we do with immune therapy
39:32in the setting of EGFR lung cancer?
39:34So to put all that together,
39:36each of Arcgis improved response
39:37rate and progression free survival
39:39compared to first line chemotherapy.
39:41But you have to test.
39:42You have to know the Jaffar
39:44mutation is there.
39:45Oh, summer at numbers are preferred.
39:46First line treatment from the floor of trial.
39:49Veg F inhibition improves response
39:51and progression free survival
39:52when added DJ fourty keys.
39:54But we don't know if it
39:57improves overall survival.
39:58Chemotherapy may improve overall survival
40:00in combination with EGFR TK eyes,
40:02but we're still trying to
40:04answer that definitively.
40:06And immune therapy activity is very,
40:08very limited and there's a
40:09lot we need to explore there,
40:11and we're still dealing with the
40:12fact that resistance develops.
40:13So we've made tremendous progress.
40:15But we still have a long way to go.
40:18And that's where communication
40:20is so important because some
40:21patients do remarkably well.
40:23I was meeting with one
40:25of my patients yesterday.
40:26I've been caring for for
40:28eight years with metastatic,
40:30EGFR, mutant lung cancer.
40:31We're having to think about
40:32her next line of treatment,
40:33but she still on her last name,
40:35but it's been eight years.
40:37Some patients do remarkably
40:38poorly on another patient.
40:39I saw, I think it was last Thursday.
40:42He's never had a good response to anything,
40:44even though he has a clear EGFR
40:46mutation in his lung cancer.
40:48And so why are they different?
40:49I can't tell, just based on the age
40:52of permutations that they have there.
40:54Other factors that we're
40:55trying to understand,
40:56but it's important than that when we
40:58talk about how someone is going to do,
41:00we're never too confident in that,
41:02because we really don't know,
41:04so we can often predict outcomes
41:05that we can't always.
41:07And we have to strive to keep the
41:09trust of the patient and their family,
41:12to help them relive given this uncertainty.
41:15And so I mentioned,
41:16I'm going to leave this in a little bit.
41:19So this was when breath becomes
41:21air written by Paul Kleanthi,
41:23Yale medical student,
41:24who then went on to do his
41:26neurosurgical training at Stanford,
41:28and he unfortunately died
41:30of EGFR mutant lung cancer.
41:31But while he was living with his disease,
41:34he wrote this amazing book.
41:36One of the quotes that I.
41:38Lee love from this is that the
41:41reason that doctors don't give
41:43patients specific prognosis is
41:45not merely because they cannot.
41:48What patients seek is not scientific
41:50knowledge that doctors hide
41:52but existential authenticity.
41:53Each person must find on his or
41:56her own getting too deeply into
41:59statistics is like trying to
42:01quench a thirst with salty water.
42:04The angst of facing mortality has
42:07no remedy in probability and so.
42:09That really captures the essence,
42:11I think of what we tried to do
42:12in this communication setting,
42:14but written obviously far more
42:16eloquently than I would ever
42:18have been able to do.
42:19And obviously we miss Paul very much.
42:22So when we talk about communication tips,
42:24these are a few of the things
42:26that I like to think about.
42:28One of them is about the numbers.
42:30Just as Paul said,
42:31but numbers to get remembered.
42:32If you have an hour long conversation
42:34with the patient and you mentioned a
42:36number when they leave the conversation,
42:38that's what they will remember.
42:39So you have to be very careful
42:41how you use them.
42:43And be very careful how
42:44prognosis is discussed.
42:45Avoid codeine medians,
42:46because if you quote a median again,
42:48that's the only thing Tillman remembers.
42:50Not everything we know about
42:52what a median means.
42:53She always give a range and I talk about.
42:56The worst possible outcomes,
42:58but I also talk about the best,
43:00but whenever I talk about the best,
43:02I always make sure I can
43:04think of a specific
43:05person who was there 'cause otherwise you're
43:07just making a number up out of the air.
43:10The prognosis for any individual
43:12of course evolves overtime,
43:13so help the patient to
43:14understand that and their family,
43:16and then try to guide the patient
43:18in making life decisions.
43:19They need to make based on probabilities
43:21of how much time they have,
43:23knowing that there's that uncertainty
43:25encouraging patients to think
43:26about the things they need to do,
43:28and also about what they want to do.
43:31It's really a terrible thing if
43:33someone assumes that they have
43:35many years left when they don't,
43:37and therefore they don't do the things
43:39they would have done if they had known
43:42that they didn't have alot of time.
43:44But it's also terrible to take
43:46away hope from someone because
43:48there always is that uncertainty,
43:49so you try to guide but
43:51leave uncertainty on going.
43:53Dialogue is obviously critical.
43:54I would bring up the concept of risk and
43:57benefit in regard to therapy fairly early,
43:59and I frequently talk about that when I'm.
44:02Reviewing things because at some point
44:04we are going to get to that point where
44:06the risk of ongoing therapy is going
44:09to outweigh the potential benefit.
44:10And if you bring that up for the first time,
44:13then it's a much more difficult conversation.
44:16It's also really critical as you
44:18engage the patient who is the
44:20key person in all of this.
44:21You've got to make sure the family also
44:24knows what's going on and is aware of
44:26the information that you're talking
44:28about because the family is going to
44:30live with the memory of the patient.
44:32Forever.
44:33And it's really important that there are
44:35part of those decisions as much as possible,
44:38not to guide the patient 'cause it
44:40needs to be the patients choices,
44:42but to understand how the patient was making
44:45those choices and to be a part of that.
44:47I think that really helps with the piece
44:49for the family as they continue living,
44:51having lost an important loved one.
44:54When having a Frank conversation,
44:55pay careful attention to how you're being
44:57heard harder now in the world of zoom.
45:00Much easier when you're in a room
45:02with someone and you can watch the
45:04body language in their faces and
45:05and make sure that everyone is
45:07engaged in an understanding so that
45:09you can back up and rephrase as
45:11necessary to get everyone together.
45:13Really important to check back in
45:14with the family and the patient.
45:16If you're making a decision.
45:19To have everybody understand
45:20why that decision was made.
45:21While we're choosing a particular
45:23therapy or another,
45:24because it's not always going to work,
45:26and it's important that everybody knows how
45:28we ended up making that decision together.
45:30If you hear a really strong
45:32objection to a particular treatment,
45:34it's always good to ask why there are
45:36a lot of stories that people have
45:38based on their own experiences of
45:40family members experiences someone
45:42they heard about bad experience.
45:44To understand why what the particular
45:46patients facing is either similar or
45:48different that can help a lot too.
45:50If it all possible,
45:51never answer your phone or pager
45:53when you're in with the patient.
45:55100% attention really matters,
45:56no matter how crazy are
45:57busy things are in clinic,
45:59and for those of us who are commissioned,
46:01you walk out of the exam room.
46:03We got five people talking with
46:05you about different things you're
46:06trying to process all of that,
46:08but when you go back in the exam room,
46:10you just have to be there 100%.
46:12Com you're listening and that
46:14really makes a big difference.
46:15Also, because the really the key
46:17is being sure that the patient
46:19and the family know that you care
46:21about your patient as a person.
46:22And that you are guiding them
46:24to make the best decisions that
46:26can help them live as long as
46:28possible with good quality of life.
46:30And I'm going to and then with
46:32a quote from Joe Feldman,
46:34who's amazing patient advocate
46:36within the EGFR world.
46:37And she does a lot with the ice,
46:40else she is a frequent speaker
46:42at our conferences,
46:43including our North America conference.
46:45And we were just there together
46:47a few weeks ago,
46:48and she talked about treating the
46:50whole patient on an intellectual,
46:52physical, and emotional level.
46:54We need to know that the doctor
46:56caring for us as a patient cares
46:59about us what we patients value
47:01can't be quantified in a curve.
47:03Hazard ratios and clinical trial
47:05numbers don't translate to real
47:06life or capture the une quantifiable
47:08meaning of a person's life show.
47:10I thought she really,
47:11really captured summed it up well with that.
47:14OK, so overall summary.
47:16Over the last 15 years,
47:18we know that Egypt artique eyes
47:20alone or the standard of care in a
47:23patient with EGFR mutant lung cancer,
47:25but you have to find the mutation.
47:28Veggie combinations.
47:29Encouraging,
47:29but so far we haven't seen that
47:32translate into overall survival benefit.
47:35EGFR combinations look really promising,
47:37but not standard yet.
47:38Chemotherapy combinations maybe
47:39will move into first line,
47:41seemed to have improved overall survival,
47:43but we haven't really bought that
47:45concept yet. Immune therapy.
47:46That's a promise for so many
47:48patients living with lung cancer
47:50and other cancers now.
47:52But in the world of EGFR therapy,
47:54there's a lot we don't understand yet.
47:56And that brings us to the fact
47:59that for all of these advances
48:01and wonderful things that we do.
48:04We still aren't caring people.
48:05We still have a lot that we need to do.
48:08I have intentionally not gone into.
48:10What do we do in early stage?
48:12Lung cancer therapy today?
48:14'cause there's been some tremendous
48:15advances there or with Theodore
48:17trial and other ways of looking
48:19at bringing in Egypt or therapy
48:20earlier to those patients who
48:22can theoretically be cured.
48:23Today,
48:23I wanted to really focus on
48:25metastatic disease and the fact
48:27that with all that we can do,
48:29it still about communication
48:30and really to help our patients
48:32make the right choices for
48:33themselves and to live.
48:35Despite facing the uncertainties
48:36of cancer, so thank you.
48:43Oh, you're on mute Roy.
48:46Thanks thanks Heather.
48:47That was wonderful and really great to see.
48:50The progress made in 15 years.
48:52You know a lot of it, you know,
48:54stimulated by the work of John and
48:57others were open for questions now I
48:59guess we do questions in the chat room.
49:02I see Charlie here.
49:03Maybe we'll start with a few.
49:05Well, while you get while they come
49:07in for the EGFR mutated lung cancer.
49:10Of course you know you see a lot of it,
49:13especially where you live because
49:15it's so prominent in Asians.
49:17Do we know yet why has anyone looked
49:19at the genetics of that to understand
49:22no other certain sequences or or
49:24genetics that can explain that? So
49:27it's a great question,
49:28so there are multiple efforts on
49:31going to try to answer that question.
49:33So my last international trip before
49:35travel ended was last January.
49:37I was in Taipei, Taiwan.
49:39James Gang had invited me to the National
49:42Taiwan University and there are some.
49:45There's amazing work being done there
49:47in in multiple other Asian countries
49:49trying to look at the nuances subtleties.
49:52They've done a lot of screening as well.
49:55That involves screening and non smokers
49:57trying to figure out you know what
49:59what's happening and they've very
50:01clearly shown as significant increase
50:03in adenocarcinoma of the lung in non
50:06smokers and it's both in men and in women.
50:09I'm actually working with the group
50:11that's from UC Davis University,
50:13California Davis University of California,
50:15San Francisco and then Stanford.
50:17We have a narrow one that's finding a
50:19case control study that we're doing.
50:22Looking at Asian never smoking women
50:24who have developed lung cancer,
50:25almost all of whom have EGFR mutants
50:27mutations and then doing a match control
50:30of very similar people who don't have
50:32lung cancer and trying to see if what
50:34we are able to find there and that of
50:37course involves sample collections as well.
50:39And there are a lot of
50:41similar ongoing efforts,
50:42but we don't know an for me here
50:44in Northern California though,
50:45a lot of my patience with you from you and
50:48lung cancer are never smoking Asian women.
50:51I also have a whole lot of.
50:53People have multiple different ethnicities,
50:54men and women.
50:55Different age ranges who also have
50:57each of our mutant lung cancer show.
50:59It's not just that group,
51:00but there's gotta be something 'cause
51:02it does seem to be increasing and were
51:04still baffled as to what that is.
51:07Great, thanks for the next question.
51:09We have a special guest 15 years
51:10ago a young Scott Guettinger
51:12came to Yale to work with Sean.
51:14Sadly they only work together
51:16for know about a year,
51:17but if Scott turned out OK,
51:19Jonathan done OK with you.
51:21So Scott, I'm going to move over so I put
51:23my mask on Scotts gonna ask alive question.
51:26These are Dart leader in lung cancer.
51:29To see you. Very talk I'm.
51:31I don't think you got into it too much,
51:34but I'm just curious.
51:35For your patience to progress at multiple
51:38sites while getting closer mitted,
51:40do you continue who are not trial candidates?
51:43Do you continue the those fermented
51:45with the chemotherapy to stop it
51:47along the lines of the impress trial
51:49where we didn't see a benefit from
51:52at least first generation TK eyes?
51:54How do you handle that situation?
51:56That's a great question, so obviously
51:58it's different for different folks.
52:00So first answer the first part of
52:02question you didn't actually ask which
52:04is if someone is progressing in a single
52:07or a couple areas, we will continue.
52:09Oh Smyrna bandu radiation.
52:11Or other local ablative
52:12therapy whenever possible,
52:13and try to extend the time
52:15that they're on that treatment.
52:17If we get to a point where they
52:20are definitely needing to switch
52:22to a different systemic therapy.
52:24Looking for trials first and foremost,
52:26but if we can't and they're going
52:28to switch to chemo, not on a trial.
52:31It will depend on the patient.
52:33If they have significant amount
52:34of brain disease,
52:35I will continue the OCE myrnam and
52:37start them on the chemotherapy.
52:39Continuing osimertinib for some
52:40of the other patients.
52:41I will stop it and part of my rationale
52:44behind that is I watch them closely.
52:46I do believe that flare can happen,
52:48but it's pretty rare.
52:49So if a patient suddenly gets drastically
52:51worse when we stop the jiffi drug,
52:54their back on it,
52:55they stay on it.
52:56I've had that happen more in people
52:58with bone metastases and interesting Lee.
53:00I think if you read when breath becomes air.
53:03Paul was one of the people I continued
53:05on and he never got to Summerton,
53:07but I can't because he was his
53:08disease was before that,
53:09but I continued him on 'cause he was
53:11someone who as soon as we stopped he
53:13had bone pain so he was definitely
53:15someone who flared so he never stopped.
53:17But for other patients I will stop.
53:19And part of the rationale is that by
53:22stopping the EGFR TK on the patients
53:24where you can and doing with chemotherapy,
53:26the resistance that develops at that
53:28point after they've been on chemo
53:30for awhile tends to be much more
53:32responsive to restarting and EGFR.
53:33TK I in the context of a study
53:35or some combination,
53:37so that's while I'll think about it,
53:39but a lot of my longer term patients
53:41right now we don't stop because they've
53:43had things where they've had bone,
53:45Mets, or other problems so.
53:48Thank you yeah. Great thanks Scott.
53:51We have a few questions in the chat room.
53:55Um? It's from Sarah Goldberg.
53:59Hi Sarah, was with us last night.
54:02You see any promising avenues
54:04for using immunotherapy in each
54:06year from you in lung cancer
54:08patients beyond PD one agents? Oh,
54:11great question Sarah.
54:12So I'll again into the first part of that.
54:17So with the checkpoint inhibitors
54:19I've had a couple of patients who
54:21have done very well with them.
54:23They were patients tending to
54:25VL 858 are not deletion 19 and
54:27that's something that in Taiwan.
54:29They've been looking at.
54:30A lot also tended to have high PD,
54:33L1, and so a couple folks
54:36have done well and we are.
54:38Participating in a study looking
54:40at chemo with carboplatin.
54:42Pemetrexed said bevacizumab
54:43plus or minus a Tezos.
54:46This is a multi site study.
54:49So I think there might be room there,
54:52but it's not something I'm doing
54:53is often off trial as far as other
54:56immunomodulatory modulators, yes,
54:58but I'm not a good enough immunologist to
55:00tell you exactly what that's going to be.
55:03I think that it's something that
55:05a lot of us are watching really
55:07closely to try to understand what is
55:10it that the simple explanation is EGFR?
55:13Mutant lung cancer doesn't
55:14have that many new antigens,
55:16'cause it's not very complex tumor,
55:18but then,
55:18overtime.
55:19Theoretically it gets more complex,
55:20so there should be more NEO
55:22antigens but really knew antigens.
55:24Not all Neo antigens are the same,
55:26and so I think that if we can figure
55:28out what is it that can make that
55:31cancer more identifiable to immune,
55:33system will have ways to move forward.
55:35But I don't think we've figured
55:37that out very well yet,
55:39so.
55:41Great, we have one from Katie
55:44Palitti who you know as well.
55:46When I don't know if we can have
55:48Katie give it live or question,
55:50I don't know how to do that,
55:52so I'll just ask it.
55:53She, she says she's only at
55:55one of the other leaders of
55:57our sport program in EGFR.
55:58Resistance does thank you for great lecture.
56:00Heather grey talk.
56:01I was wondering what you think
56:02we should be thinking about to
56:04address the heterogeneity of
56:05resistance mechanisms that can
56:06emerge in individual patients.
56:08Great question Katie.
56:09So I think that as much as the targeted
56:12story is a beautiful story and to
56:15be able to say we found the deletion
56:1719 and we treat it with their lot
56:20nib and then the T790M developed and
56:22then we treated with those summerton.
56:25If that only gets a so far and I
56:27don't think we're ever going to
56:29be able to really get completely
56:31around that because as time goes on
56:34there's more and more heterogeneity
56:36in the resistance pathways.
56:37Should we have to be?
56:39Thinking about it,
56:40you know the straightforward
56:41answer right now.
56:42Is chemotherapy 'cause that
56:43doesn't really care so much about
56:44what the resistance pathway was,
56:45but it gets back to Sarah's question
56:48that eventually we've got to figure
56:49out how to get the immune system
56:51to be able to recognize the cancer
56:53and all of its various iterations.
56:54As it becomes more resistant
56:56and be able to tackle it.
56:57I don't have an answer as to
56:59how we're going to do that,
57:00but to me that's really the only
57:02way we're really going to get at it,
57:04because were to get it early
57:06enough that it hasn't had time to
57:08develop all of the resistance,
57:09and that's where the.
57:10Earlier stage therapy is helpful so,
57:12but even there I think that I don't
57:14know that we're going to cure with
57:16that approach because I think that
57:18it only takes a few cells that become
57:20resistant to then grow up again,
57:22and so I think we've all got a lot of
57:25years left of work that we need to
57:27get doing to be able to make the impacts.
57:30We'd like to make.
57:32Right, and certainly by working
57:34through the cooperative groups and
57:36the societies and collaborating.
57:38Given that this is a worldwide
57:40disease so important.
57:41We I don't see too many
57:43more questions in the chat,
57:45just about the end of the hour I see
57:47Nancy nearing joined and I just want
57:50to acknowledge her Johns wife and I'm
57:52sorry we can't talk in person Nancy,
57:54but next year hopefully will see
57:56you in the front row and we can.
57:58Zoomed Heather inferred picture but Curly
58:01any any final thoughts before we end?
58:04No, there was a fantastic talk.
58:06I mean, get really outlines the
58:08but so exciting in lung cancer,
58:11both with respect to targeted
58:13therapies an hopefully integrating
58:15IO with these things.
58:16Overtime.
58:17So thank you is really powerful work.
58:20And thanks for taking the time.
58:22Thanks to everyone who joined.
58:24We had a very large crowd today,
58:26both because of you Heather and because
58:29of John and we remember him fondly
58:31and in his memory will continue to
58:34take good care of our patients and
58:36which was always number one goal
58:38with the most innovative therapies.
58:39Which is exactly what both are.
58:41Cancer centers are trying to
58:43do so thank you everyone and
58:45see you soon. Thank you.