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

Transcript

• 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.