Head and Neck Cancer DART: Head and Neck Cancer Research at Yale

June 24, 2021

Yale Cancer Center Grand Rounds | June 22, 2021

Drs. Barbara Burtness, Aarti Bhatia, and Melissa Young

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00:00Welcome everyone, I'm right here.
00:03Still be the moderated today.
00:06Just as we started this remind
00:08everyone that this Friday from 8:00
00:11to 12:30 is our annual review of ASCO.
00:14And I'm very excited this is the 10th
00:16year I'll be doing it, but we had it
00:19in place a number of years before that.
00:21Eddie used to run it and it should
00:23be very nice of you, Barbara.
00:25Already one of you are probably
00:27speaking on heading that cancer.
00:29So, uh, another chance to hear,
00:31hear them, and then it'll be very special.
00:343540 minutes around 11:00 o'clock,
00:36where Vince Devita and his daughter Elizabeth
00:38and a few questions for myself as well.
00:41We'll discuss a little bit about the 50th
00:43anniversary of the National Cancer Act,
00:46so that should be very excited.
00:48So now I'm going to introduce today's
00:50speakers on introduce all three of you,
00:53and then I'll let Barbara moderate
00:55through the the presentations,
00:56and then we'll have questions at the end.
00:59And one of the things we've been
01:01doing is we've been highlighting
01:03our darts or disease teams at these
01:06grand rounds and it's a great way to
01:09develop multi modality discussions.
01:10An interaction between the disease programs
01:12and the research programs with Cancer Center.
01:15So we're very excited.
01:16We have a group today,
01:18a tremendous team.
01:19First speaker will be Doctor
01:21Barbara Burtness,
01:22Barbara Professor of medicine and
01:24medical in country and disease
01:26aligned research team leader for
01:28head and neck cancer.
01:29She was recently named as interim
01:31Associate cancer Director for Diversity,
01:34Equity and Inclusion.
01:35Congratulations Barber Chief Medical
01:37degree from SUNY at Stony Brook
01:39completed a residency at Yale and our
01:42Fellowship at Memorial Sloan Kettering.
01:44Is that on faculty?
01:46Of course that yeah,
01:47she left in and she's come back.
01:50Doctor Bernice is an internationally
01:52recognized leader in the treatment of head
01:55and neck cancer and as chair of the Ikago,
01:57Akron and Therapeutics Committee since 2006.
01:59Pioneering biomarker,
02:00guided treatment and treatment at the
02:03intensification studies in this disease.
02:04She also leads the Yellowhead
02:06and explore recently awarded.
02:07Finished just finished the first year,
02:09which addresses critical barriers to
02:11treatment of head and neck squamous cell
02:14carcinoma due to resistance to immune.
02:16DNA damaging and targeted therapy
02:19so welcome Barbara.
02:20And also on the panel this morning
02:22or this afternoon is already Bhatia.
02:25Doctor Bhatia is an assistant professor
02:27of medicine and medical oncology.
02:28She received her medical degree
02:30from Toccoa National Medical College
02:32and her MPH from the University
02:34of Texas School of Public Health.
02:36She played her residency at Johns
02:38Hopkins University Sinai Hospital and
02:40I fell asleep at Temple University,
02:42Fox Chase Cancer Center.
02:43Dr Bhatia treats patients with head
02:45and neck cancers and a research
02:48interest include exploring novel
02:49therapies for patients.
02:50She designs and conducts clinical
02:52trials and also serves as a site
02:55Pi for several multi center studies
02:56and then last but not least from
02:59radiation oncology.
03:00We have Melissa Young and Doctor
03:01Young is an assistant
03:03professor of therapeutic radiology and chief
03:05of the head and neck radiotherapy program.
03:08She completed her MD PhD training as
03:09part of the Medical Scientist Training
03:12program at the University of Texas
03:14Southwestern Medical Center in Dallas.
03:16She then continued her training
03:18in radiation oncology, yeah,
03:19and stayed and joined our faculty in 2015.
03:22Doctor Young treats patients as part
03:24of their head in their cancers.
03:27Multi disciplinary clinic at the
03:29Smile Cancer Hospital Care Center
03:31in Trumbull and also specializes in
03:33breast and gynecological agencies.
03:34So finally, just a quick word.
03:37The head and neck cancers dark
03:39provides expert multidisciplinary care
03:41for head and neck cancer patients.
03:43Names to advance new research and the
03:45force of the next generation of hedex
03:48cancer translational researchers through
03:49a developmental research program.
03:51Career enhancement program.
03:52An interaction in collaboration with the
03:54wider spore and head and neck squamous
03:56cell Cancer Research communities.
03:57So what an amazing team.
03:59I've used up five of your
04:00minutes introducing you.
04:01You're also qualified.
04:02I'm going to stop by to turn over to you.
04:05Barbara,
04:05one of the best things that ever happened
04:07here at yell for me in my 10 years,
04:09is when you came and joined us and
04:11you know Barbara and I worked together
04:1320 years ago in the early ages,
04:15so Texas map.
04:16So Barbara thank you for all
04:18you've done and the floor is yours.
04:27OK, well thank you for that
04:29very kind introduction and for
04:31recruiting me back and I'm also very
04:34grateful to have the opportunity to
04:36talk about what we've been doing in the
04:40in the head neck DART. As you heard,
04:43the way we're going to do this is.
04:47My team I'm gonna spend about half an
04:51hour trying to do a world whirlwind tour
04:54of some of what our dart has been up to,
04:57then turn it over to Doctor Bhatia
05:00to talk about some of the clinical
05:02trials she's been developing in
05:04her collaboration with the sporlan,
05:07then to Doctor Young,
05:09who leads our therapeutic radiation
05:11efforts in this area.
05:12So just a brief introduction to
05:14our clinical membership.
05:16The nature of of head neck cancer.
05:18Given its anatomic complexity,
05:21its tendency to treatment resistance.
05:24It has been that very clearly outcome
05:27is improved when patients get surgery
05:30and radiation at high volume centers,
05:33and so we have a dedicated focus
05:35on trying to have pockets of
05:38excellence around the state.
05:41So in addition to the program, it's Milo.
05:44There are hubs for head and neck cancer,
05:48multidisciplinary care,
05:49including at Trumbull Ann Lawrence Memorial.
05:51I know Emily Collier is going to be.
05:55Joining us at Saint Francis.
05:57So it's a it's a terrific team.
06:00A lot of fun to work with with everybody.
06:04The patients who present with
06:06with head neck cancer often come
06:08with locally advanced disease,
06:10so local,
06:11regionally invasive and not meta
06:13static and may present many times
06:15in a curative state or cure,
06:18potentially curable stage.
06:19But these tumors are located in areas
06:22that are very critical for speech and
06:25swallowing and taste and appearance and.
06:27And many of the things that we do
06:30to interact with with other people.
06:33So having a conversation,
06:35sharing a meal,
06:36singing all of these things can
06:38be impacted by either the cancer
06:41or the treatment for the cancer.
06:43Treatments are further constrained
06:45by some anatomic peculiarities,
06:46like the carotid artery in the
06:49base of the skull,
06:50and even patients who are
06:52successfully treated may be left
06:54with very significant impairment,
06:56functional restriction, and actually.
06:57May succumb to the consequences of their
07:00treatment even when they are cured.
07:02So there is a lot of work to do
07:04to improve our standard of care
07:06even when its curative an as well.
07:09There are a lot of of I think areas of
07:11difficulty in the science underlying or
07:14the biology underlying head neck cancer.
07:16So Roy mentioned that he and I first
07:19worked together in the context of
07:21cetuximab and it was a thrill when we
07:24saw that lead to responses as a as
07:26a single agent in head neck cancer.
07:29But it's clear that both constitutive
07:32resistance and adaptive resistance
07:34greatly limit the utility of
07:36EGFR inhibitors and another.
07:38Her family inhibiters the genome
07:40of head neck cancer is dominated by
07:43mutations in tumor suppressor genes,
07:46so this has been very difficult
07:48to target there.
07:50There are not a lot of successes
07:53with kinase inhibitors of activated
07:55oncogenes in this disease.
07:57Although we have activity for immune
08:00checkpoint inhibition and I'll
08:02briefly show you some of those data.
08:05The effective immunotherapy is more
08:07modest in head and neck cancer
08:09than in many other solid tumors.
08:12And part of this story certainly
08:14lies in the tumor microenvironment,
08:16which is hostile to immune
08:18effector cells because of hypoxia.
08:20Expression of Ido macrophage polarization.
08:22Very high abundance of Milo
08:24drive suppressor cells,
08:26an lymphocyte excluded phenotypes
08:28of the cancer.
08:30We have a new kind of head neck cancer.
08:33Over the past 1520 years which is
08:36driven by human papilloma virus,
08:38which gives us both an immune target and
08:42and and maybe also a way to interfere with.
08:46The signaling that drives these cancers,
08:48but there has been pretty low
08:51success in targeting HPV as a driver
08:53of head neck cancer.
08:55We see very grave disparities
08:57in outcome in HPV.
08:58Negative cancers between black
09:00patients and other groups,
09:01and although much of this is is
09:04explained by socioeconomic factors,
09:06it's becoming clearer that their
09:08ancestry based differences in
09:09treatment response as well,
09:11and these have kind of been lossed in
09:14a pool of trials that did not include
09:17a lot of patients of African ancestry.
09:21And then the field as a whole
09:23has historically suffered from
09:25underinvestment in clinical trials
09:26and low access to new patients
09:29to new agents for our patients.
09:31So what I'd like to quickly do
09:33is talk a little bit about
09:35multidisciplinary clinical care here,
09:37how we address problems in
09:39our catchment area,
09:40afew highlights of our
09:42clinical research portfolio,
09:43some of the correlative and
09:45translational science that is going on.
09:47Some of our translation to the
09:50cooperative group network.
09:52Engagement with policy and then career
09:54development and then part of career
09:56development will be turning it off to
09:58my two very talented junior colleagues.
10:00Multidisciplinary care I mentioned
10:02that high high case volume is
10:05important and so you see here,
10:06at least from the pre pandemic numbers
10:09are surgical volumes for oral cavity,
10:11pharynx and larynx cancer.
10:13We have a multidisciplinary tumor board.
10:16That brings together surgery,
10:18radiation, medical oncology,
10:20neuro radiology,
10:21pathology and speech language pathology
10:24which helps us to make treatment
10:27recommendations that optimize both our
10:30drive for cure and the need to think
10:32about the functional consequences
10:34of treatment for our patients.
10:37We've rolled out chemoradiation
10:39supportive care order sets
10:41across that the health system.
10:43We work very closely with
10:45speech language pathology.
10:47And function preservation beginning
10:49with pre him before the surgery or
10:53or chemoradiation even begins and we
10:55have dedicated social work to help
10:58with many of the problems with employment.
11:01That and and other socio economic problems
11:04that this group of patients encounters.
11:07Several marijuana var or the leader of
11:10our head and neck surgical oncology
11:13program introduced to clinic clinical
11:16care pathway for reducing ICU.
11:18Usage in head neck cancer microvascular
11:21reconstruction and you can see here
11:23these absolutely stunning data not
11:25only lowering the average length of
11:28stay to a week for very complicated
11:30large reconstructive surgeries,
11:32but also bringing ICU stays from
11:34100% to 6% and dramatically reducing
11:37unplanned 30 day re admission.
11:40Within our catchment area,
11:42New Haven County is well documented
11:44to have excess rates of tobacco use
11:47relative to national rates and in
11:49lower income adults in New Haven
11:51uses twice as high oral cavity.
11:54Cancer is increasing dramatically.
11:55In Connecticut, Ann is 50% higher in
11:58the Latin X population in the state,
12:01so we have a very significant focus on
12:03the on the tobacco associated malignancies.
12:06We have trials and Artie
12:08Patio will speak later about.
12:10About one of them,
12:12but moving forward in the cooperative groups,
12:15international trials focused
12:16on HPV negative disease.
12:18Two of the projects in our
12:21head and explore focus on HPV,
12:24negative disease and in the E con Akron
12:27health Head Neck Committee that that I lead.
12:31We are now developing HealthEquity
12:33coast studies with many of
12:36our larger clinical trials.
12:38I mentioned that the outcomes disparities.
12:41For HPV negative head neck cancer
12:43are among the most dramatic for
12:45any solid tumor and a collaborator
12:47of mine from my time at Fox Chase.
12:50Camille Reagan, who is now part of our spore,
12:54has demonstrated that African ancestry
12:56informative markers are associated with
12:58overexpression of DNA polymerase beta
12:59and that this in turn is associated
13:02with platinum and radiation resistance.
13:04She's got a large collection of patients
13:06in the temple system that she's sequencing.
13:09It's highly enriched for African American
13:11patients and we're collaborating with her.
13:13To bring forward.
13:16Patient drive tissue resources for
13:18studying alternative therapies to
13:21platinum and radiation in these patients.
13:23We have a large clinical trial portfolio.
13:26I don't want to go through it in detail,
13:30but I'll just emphasize that we always
13:33prioritize investigator initiated trials.
13:34Doctor Bhatia will talk about the Phantom,
13:37so tuck some AB work.
13:39I'll talk a little bit about a trial
13:42for pembrolizumab in primary radiation
13:44resistance and the five Aza work we have
13:47phase one trials particularly focused on HPV,
13:50therapeutic vaccines for HPV.
13:52Associated cancer.
13:53Have participated or LED some
13:56practice changing trials including.
13:58Not that we let it,
14:00but contributed to the cabins
14:02antonym in radioiodine.
14:03Refractory thyroid cancer study that
14:05was presented at ASCO this year and I
14:08think is really going to change the
14:10standard of care for Len Bat neighbor
14:13factory disease and on going late phase
14:16trials in the chemoradiation setting.
14:18So let me tell you a little bit
14:20about this radioresistance trial.
14:23This was started by Zen Hussain when
14:26when he was here before he left for
14:29Toronto and the idea was that we
14:32had patients in our practice HPV.
14:35Negative cancers predominantly,
14:36who had presented with very advanced
14:39disease and had primary radio
14:41resistant disease.
14:42At that time there was no standard of care
14:45with immunotherapy for those patients,
14:48and so he put together a.
14:50Phase two trial for moving them
14:53right on to Pember Lizum app with
14:55the advantage that we would have
14:58baseline tissue tissue from the biopsy
15:01that prove persistent disease and
15:03if the patient had become resectable
15:05by the end of four cycles of
15:08Pember lism and they would,
15:10they would go on to reception.
15:13So we are doing immuno profiling on
15:16the specimens from this trial and
15:18also started sequencing them in the
15:21first two cases that we sequenced.
15:23Both had this.
15:25Very unusual finding of whether
15:29new emergence or enrichment for
15:32mutation in tenascin R1 of the.
15:35Tenascin family proteins that
15:37controls EMT and can be involved in
15:39an immunosuppressive microenvironment.
15:41So we have just gone back and received
15:44funding to finish sequencing.
15:46All the cases here and think
15:48that this is potentially a very
15:51interesting lead into the biology
15:53of primary radioresistance.
15:54The pictures at the bottom just show
15:57you one of our patients who had a CR.
16:01He's now four years out.
16:05Just to switch gears now to some of
16:08the correlative work along time ago,
16:11the Kaag committee had demonstrated
16:13that for patients who had undergone
16:15margin negative resection,
16:17but who had disruptive mutation of
16:19TP 53 that they continued to have a
16:23pretty poor outcome despite getting
16:25risk based appropriate postoperative therapy.
16:28And that was done with older sequencing
16:31technology as next Gen sequencing came
16:34on and a number of new algorithms
16:37for calling P53 mutation became available.
16:40We undertook a comparison of all of
16:43these different classifying schemes
16:45in the specimens from that ekonk trial,
16:48finding that our original rule,
16:50which was DNA binding domain
16:53mutations or truncation mutations,
16:55somewhat supplemented with
16:56information about splice variants,
16:58really was the best predictor of bad outcome.
17:01And since.
17:02P53 mutation is quite prevalent
17:05in head neck cancer.
17:07And difficult to target this has,
17:09I think,
17:10really helped us focus on the
17:12importance of understanding the
17:14biology of these people.
17:32Barbara
17:36did we lose Barbara?
17:48Yeah, look. Her Internet is down.
17:56OK, well these things happens.
17:58It's the storms.
18:00Who's ready to step up?
18:02Oh, here she is. Barbara
18:07you're muted.
18:22Sorry about that. So we sequenced
18:25these or characid sequenced over
18:271000 HPV negative cancers.
18:29We classified the P53 mutation using
18:32a variety of different schemes ever.
18:35You need to share your slides again, sorry.
18:41Will give you 2 extra minutes at
18:42the end of the hour, don't worry.
18:47Alright, am I doing better now?
18:50There's this better perfect looked
18:52at CDK into a mutations and then
18:55calculated tumor mutation burden
18:57and So what was quite interesting
18:59here was that either P53 or CDK
19:02into a mutation was associated
19:05with higher tumor mutation burden,
19:07with the exception of when that P53
19:10mutation was a gain of function,
19:12not loss of function mutation,
19:15but that the Co occurrence of P53,
19:18CDK and 2A.
19:19Mutation was associated with the HYEST
19:22tumor mutation burden and this came
19:25into the 15 mutations per megabase range,
19:29which has been informative
19:31for response to immunotherapy.
19:34But it's been understood for a long
19:36time that there's a range of TMB
19:39across different kinds of both HPV
19:41positive and HPV negative head,
19:43neck cancers,
19:43both smokers and nonsmokers that
19:45this is associated with response to
19:48pembrolizumab and more recently in a
19:50randomized trial of development that
19:52was actually negative for all comers.
19:54If you focused on the group with high
19:56TMB there was a survival advantage
19:59for the use of immunotherapy,
20:01so I think one thing this points us
20:03to is the early use of immunotherapy.
20:06In P53 mutated head neck cancer
20:09and I'll maybe take a brief detour
20:12here because this is.
20:13This is work that Yale investigators
20:16participated in before I arrived here.
20:18And then I've been very involved
20:21with the keynote 012 trial,
20:23which was the first large scale study
20:26of immune checkpoint inhibition
20:28in head and neck cancer was done
20:31with pembrolizumab.
20:32We had a big focus on including both
20:35HPV negative and HPV positive cancer,
20:38and you can see.
20:39That durable responses were seen
20:41in both types of head neck cancer
20:43and looking at the spider plot,
20:46I think that you see.
20:48Really,
20:49what the next five years of research
20:51into immunotherapy in head neck
20:53cancer has has played out as because
20:55there are early and deep responses,
20:57there are somewhat slower responses,
20:59but that are deep and very durable.
21:02But there's a subset of patients who
21:04not only don't respond to immunotherapy,
21:06but appear to almost have accelerated.
21:10Disease growth and so we need to
21:12understand what's suppressive in the
21:14tumor microenvironment that leads
21:16to this resistance and what it might
21:18be in the tumor microenvironment
21:20that's PDL one expressing that
21:22it's actually bad to turn off.
21:24So I think there's there's some.
21:27Some work to be done there,
21:29but given the strong signal with 18%
21:32response rate and durable CRS in
21:34the treatment refractory setting,
21:35we move this forward as a first
21:37line trial in metastatic recurrent
21:39disease and this had a little bit
21:41of a complicated design because we
21:43recognized that the standard of care
21:46which was chemotherapy with Cytoxan
21:47Mab actually had a higher response
21:49rate than pembrolizumab monotherapy,
21:51but it didn't have the same duration
21:53of response and it didn't have
21:56the same complete response rate.
21:57So we had to experimental arms.
22:00One was Pember Lism AB alone and one
22:02was purple is made with chemotherapy,
22:05each of them independently compared
22:07to the standard of care
22:08of chemotherapy with cetuximab and
22:10then we undertook a biomarker driven
22:13analysis because the hypothesis was
22:15that those cases that express PD,
22:17L1 the most richly might be
22:19the most likely to respond,
22:21and there the advantage over chemo cetuximab
22:23would would be more readily apparent.
22:26Actually, Pember Lism had
22:27performed better than.
22:28Then we could have imagined,
22:30but so this is the CPS 20 group,
22:32the highest PDL one expressing an
22:34you see here a hazard ratio of
22:36.61 in favor of Pember Lism AB.
22:38We now have four year data showing that
22:41this group has over a 20% for your survival.
22:45This is all PDL one.
22:47Expressing cancers,
22:47hazard ratios of 0.78 and this was
22:50also statistically significant
22:51compared with the control arm.
22:54And then if you took all comers so
22:57that includes the 15% that are PDL,
23:00one negative Pember Lizum app was
23:03noninferior to chemotherapy cetuximab.
23:06Going back and looking at that PDL
23:08one subset they do substantially
23:11worse with Pember Lizum app then
23:14with chemotherapy cytoxan and so
23:16they should not get pember lism in
23:19monotherapy and then Pember Lizum
23:21app plus chemotherapy superior to the
23:23reference regiment across all regiment,
23:25across all biomarker subgroups.
23:27So this study has has been very fruitful.
23:31Subsequent publications coming out
23:32about patient reported outcomes.
23:34The PDL one subsets.
23:36In long term survival.
23:39I would like to introduce you to
23:42our head export team so spores are.
23:46Programs of research excellence
23:49usually centered around a given disease type.
23:53They they need to have at
23:55least three projects and cores
23:58and developmental projects,
24:00and we received very generous support
24:04from the Cancer Center in the medical
24:09school to jumpstart these projects and.
24:12The first review had some some
24:15comments that we had to address,
24:17but we were funded late last year,
24:20so we have three projects,
24:22one on targeting the EGFR family.
24:24An artifact will talk about that
24:26more in a couple of minutes,
24:28one on synthetic lethal therapy for
24:31predominantly P53 mutated cancer.
24:32I'll speak about that a little bit,
24:35and then Karen Anderson and Del Yarbrough,
24:38leader project.
24:39Looking at demethylation to trigger
24:41a pevec induced synthetic lethality,
24:44and I'll introduce them briefly as well.
24:48So I've been talking about P53 mutant
24:51cells really being sort of one of
24:54the last bastions of undruggable
24:56head neck cancer,
24:58and we know that these cells exhibit
25:01impaired regulation of G1 S checkpoints,
25:04increasing their dependence on the G2
25:07M transition to repair replication damage,
25:10creating vulnerability to inhibitors
25:12of these processes through DNA damage,
25:15G2 checkpoints,
25:16restrictive mitotic entry and we have had.
25:19An interest in in this for a long
25:21time going back to work when I was
25:24at Fox Chase demonstrating that
25:26Aurora kinase overexpression in the
25:28nuclear compartment was associated
25:30with worse overall survival,
25:32we know that Aurora is regulated by P53,
25:35and so if you look across these
25:37commonly used P53 mutated or null
25:40head neck cancer cell lines,
25:41they all over expresser or relative
25:45to normal tissue.
25:46And so we began to look at
25:48using Aurora as an inhibitor.
25:50Both preclinically and in the clinic and
25:53the clinic it hit a 9% response rate,
25:56so that was obviously pretty disappointing.
25:58And what we found when we gave
26:00it clinically and this is with
26:02an agent called ellisor tip is
26:04that it it did actually aggregate
26:06phosphorylation of Aurora.
26:08It did change the function of Aurora,
26:10so we got these.
26:12Try and quadripolar spindles.
26:16And and yet what happened was that the cells,
26:20I'm sorry, but the cells entered
26:22really a cell cycle arrest that was
26:24mediated through phosphorylation of CDK.
26:27One is, you see here that that inhibitory
26:30phosphorylation is placed by we won,
26:32and so we combine the Aurora inhibitor
26:35with the wee one inhibitor we want is a
26:38regulator of mitotic entry and you see
26:41here when you give the wee one inhibitor,
26:44you accelerate mitotic entry
26:46and find these cells that are.
26:48Sort of held up in late mitosis,
26:50but when you give the two agents together,
26:53you precipitate mitotic catastrophe and the
26:56cells undergoing a pup tatic cell death.
26:58As you can see here with the Nixon
27:015 and Cliff Park,
27:02we treated animals with the combination.
27:05Their survival was markedly improved compared
27:07to either of the amount of therapies,
27:09and tumor growth was really controlled.
27:11If you looked at these mirroring
27:14tumors under the microscope,
27:15you saw that the combination increased
27:17cleaved caspase reduced proliferation.
27:19Looking in the leading edge
27:21of these tumors using Aqua,
27:22we could count phospho CDK one
27:24and it was markedly reduced.
27:26We've now moved to a more selective
27:28second generation Aurora inhibitor,
27:30which we think will be easier
27:32to use in the clinic,
27:34'cause it's not as myelosuppressive and
27:36been able to replicate these findings
27:38and so part of our score is to take this
27:41combination forward as a window trial in HPV,
27:44negative disease,
27:45going for resection with those escalation,
27:47and then an expansion cohort.
27:50Collaborating with the Glamis lab,
27:52we've done a high throughput screen
27:54to identify additional synergistic
27:56pairs or additional partners for agave,
27:58assertive and our strongest hit
27:59was with the check.
28:01One check two inhibitor prex assertive.
28:03When I first saw saw that come out,
28:06I was pretty discouraged.
28:07'cause that's a pretty
28:09myelosuppressive agent in the clinic,
28:10and I was fearful that we wouldn't
28:13be able to use it in combination.
28:15But if you look here,
28:17you can see that even at 25 nanomolar we get.
28:21Clonogenic survival effects in combination,
28:23so these pairs are going to be tested in
28:26animal models as part of our sport project.
28:29I think in the interest of
28:31time I will skip this.
28:33This sort of side branch story that
28:35we have trying to explore these
28:38therapies for patients with Fanconi
28:40anemia who developed head neck cancer
28:42at very high rates in adulthood.
28:44But let me introduce you to Karen Anderson
28:47and Dell Yarbrough's project in the spore.
28:50There's a.
28:51Observation from the TSJ that
28:53they're striking differences in
28:55metalation between HPV negative
28:56and HPV positive head neck cancers,
28:59and else lamp had done work
29:02demonstrating that this metalation
29:03induces immune silencing and if you
29:06give a demethylating agent like 5 Aza,
29:09you downregulate HPV and MMP expression.
29:11You stabilize P 53 and you induce a
29:14pop ptosis so we ran a window trial
29:17of Viveza siding and HPV negative
29:20and HPV positive cancer.
29:22No effects in the HPV negative cancers,
29:25but in the HPV positive cancers. We saw.
29:31That there was activation of.
29:35Type One interferon signaling.
29:37Upregulation of the gene editing
29:39protein apobec 3B which increased
29:41double strand DNA breaks and there
29:43was activated T cell infiltration
29:45within tumors and you see here.
29:48Photomicrographs before and after
29:49that were stained in David Rims Lab,
29:52looking for CD4 CD 8 and CD 20
29:54cells and I just Representative
29:56Lee have shown you the CD eight
29:59counts within the tumor mask before
30:02and after five days of siding.
30:05So we are taking this.
30:08Forward now in a store window,
30:11trial either 5/8 sided,
30:14being alone nivolumab alone
30:16or the combination in the new
30:19edgmont setting and are.
30:22Also hoping to add to this 18 F energy
30:25pet for noninvasive quantitation
30:26of activated T cell infiltration
30:29across the course of the new engine
30:32therapy and collecting samples
30:34for tumor neoantigen expression.
30:39The cooperative groups are, I think,
30:41an important venue for asking
30:43questions that are closer to practice,
30:46and I've talked a lot about HPV,
30:48negative disease in HPV positive disease.
30:51Are questions center more on?
30:53How can we enhance function
30:55preservation and these are data we
30:58just presented at ASCO this year,
31:00showing that if you take patients
31:03with resectable stage HPV
31:04associated cancer to transoral
31:06resection and then you have that.
31:09Pathologic staging from the surgical
31:11material in hand that really permits
31:14much more dramatic treatment.
31:16The intensification than if
31:18you have to rely on.
31:21Clinical variables and so here you see
31:23that for favorable risk surgical staging
31:26without any post operative therapy,
31:28we have three year progression
31:30free survival approaching 97%
31:31for the intermediate risk group.
31:33So this is node positive but
31:35no extranodal extension.
31:36Whether we gave 60 Gy of radiation
31:39or 50 grey Anne Frank,
31:41the fields we maintain three year
31:43progression free survival of about
31:4594% and then even the very high
31:47risk patients we were able to be
31:50intensify therapy by going to.
31:52So weekly chemotherapy in the
31:54post op setting.
31:55You'll see here that about a third
31:57of the patients on the trial ended
31:59up needing Tri modality therapy
32:01that is not the goal of treatment.
32:03The intensification and so one question is,
32:05how can we better identify the
32:07patients who have higher risk of
32:09let's say any or positive margin
32:11from going on to a surgical trial
32:13because they ought to probably
32:15go straight to chemoradiation.
32:17Ben Khan,
32:18who's now a junior faculty
32:20member at the Farber but was a
32:22radiation oncology resident here,
32:24undertook a machine learning project
32:26where he developed a deep neural network
32:29algorithm for identifying extranodal
32:30extension from a baseline CT scan.
32:33We've now validated that on the
32:35cooperative group trial in 76 patients,
32:37and this has moved on to part of the
32:41University of Pittsburgh head next door
32:43that I'm a Co investigator on where
32:46we're going to be linking radio MIC.
32:49To genomic signatures so that we hopefully
32:51can have a better means of identifying
32:54these high risk patients at baseline.
32:57In terms of policy there,
32:59I think have been.
33:03Really,
33:03a paucity of FDA approvals
33:05in head neck cancer.
33:07The approvals of pembrolizumab in Nevala
33:10map in 2017 were the first in over a decade.
33:15And these trials have become more difficult.
33:18Certainly for the HPV associated cancers,
33:20where the event rates are quite low,
33:23and designing randomized trials where
33:25you're looking to have something
33:27happen that's better than 94% at
33:29three years really becomes prohibitive
33:30in terms of size and duration.
33:33And although we see many ways that
33:36immunotherapy and targeted therapy
33:37could allow us to D intensify trials,
33:40there is no accepted regulatory strategy
33:42for demonstrating that that's the case.
33:44So the goals of Project 2025.
33:47Are to find harmonized surrogate
33:50endpoints that the FDA will accept they.
33:56You know want to have public meeting
33:58with all the stakeholders present
34:00that that will kind of refine PFS?
34:03Probably looking better
34:04than local regional control.
34:05What's the role of following
34:07each PV circulating DNA?
34:08How do functional endpoints get
34:10defined to permit approval in the D
34:13intensification trial and then the
34:15last thing that I think is really
34:17important for us is career development.
34:19And before I turn it over to RT,
34:22I just want to highlight that
34:23the sport does have developmental
34:25research and career enhancement.
34:27Programs that offer up to 50K pilot funding.
34:32Our pay line is pretty good.
34:34We give out seven awards a year.
34:35We just had a cycle but please
34:37think about us next year.
34:38So with that I'm going to.
34:42I think not introduce my two Co
34:45speakers 'cause Roy Herbst did very
34:47nice job with that just mentioned
34:48that obviously this work was done
34:51by many many people besides myself.
34:53Thank my funding agencies and
34:54stop sharing so that I can turn
34:57it over to Doctor Bhatia.
35:15Good afternoon everyone. Thank you for
35:18the opportunity to present here today.
35:20I'll be talking briefly about research
35:22strategies that we have undertaken
35:24at Yale to overcome cetuximab
35:26resistance and head neck cancers.
35:29As we all know, so toxic members in
35:32monoclonal antibody against EGFR an it's
35:34the only approved targeted therapy for
35:36patients with head and neck cancers.
35:38This approval was based on improved
35:41locoregional control and survival
35:43when it was given concurrently with
35:45radiation in the locally advanced setting
35:47and do to improve PFS and OS when
35:50administered in combination with chemo
35:52in the recurrent metastatic setting.
35:53However, these effects are modest
35:55and the definitive setting in the
35:58definitive settings attacks map.
35:59In radiation is proven inferior
36:02to chemoradiation.
36:03Its clinical utility is limited
36:05primarily by either inherent or
36:07acquired resistance to therapy,
36:09like and binding of EGFR needs to
36:12**** and Heterodimerization with
36:15other her family receptors or other
36:18receptors in kinases such as met and
36:21subsequent downstream signaling of
36:23MAP kinase K3 kinese mtor pathway
36:26rest Ref Mac or Pathway or Jack stat.
36:29And resistance can be mediated
36:31either by over expression of EGFR,
36:34or it's like ends as we see in hidden
36:37cancers and in response to smoking it can
36:40be mediated by nuclear translocation of EGFR,
36:44where it stabilizes P CNA and
36:46enhances DNA repair and synthesis,
36:48or increase headers.
36:49Dimerization with other members
36:51of the her family,
36:53her two and her three,
36:55or with cross talk with other
36:57receptors in kinases such as Seemeth.
36:59In bed rest and identifying effective means
37:03of sensitizing hidden cancers to EGFR
37:05inhibition is an important goal for us.
37:08An important part of our sport
37:11project to prior research at Yale.
37:13Done on tissue microarrays that
37:15were constructed from oropharyngeal
37:17cancer specimens showed a significant
37:19association of nuclear EGFR with
37:21membranous EGFR expression.
37:23An with nuclear P CNA,
37:25and that suggested that EGFR
37:27functions as a tossing pennies in
37:30the nucleus where it stabilizes PC na.
37:33The nuclear activity will could therefore
37:36constitute a novel therapeutic target.
37:39Subsequent to that,
37:40we designed a phase two trial using a
37:44chemo backbone and dual EGFR blockade
37:46with cetuximab and or lachnit.
37:49The rationale was that dual EGFR blockade
37:51would overcome EGFR overexpression,
37:54and it's like an independent downstream
37:56signaling an show improved responses.
37:58The tumor biopsies were planned
38:01at baseline font treatment,
38:02an at disease progression.
38:04An encore native analysis,
38:06we found that nuclear PC na staining.
38:10A decrease in the standing actually
38:12correlated with clinical response to
38:14treatment for several patients who had
38:16matched pre and post treatment biopsies
38:18and that suggested that nuclear EGFR
38:20may also be inhibited with this combination.
38:23As a follow up to that study,
38:26we proposed and received an CC and
38:28funding for a phase two trial of
38:31cetuximab and afatinib in patients
38:33with platinum and mostly immune
38:35checkpoint inhibition had neck
38:37cancers were really no effective.
38:39An approved treatments exist.
38:41This trial is ongoing for a
38:43target accrual of 50 patients.
38:45We have already approved 38 tissue for
38:48correlatives is being obtained both pre
38:51pre and post treatment for most patients.
38:54An existing funding from NC, CNN,
38:57the Patterson Foundation will support
38:59quantitative immunohistochemical
39:00assessment of the known biomarkers
39:03of resistance to EGFR inhibition,
39:05namely P-10, Phosphoric,
39:06Phospho, AKT and PCN.
39:08A tumor biopsies from patients on
39:11this trial will also be used in
39:14project one of the sport to establish
39:17PDX is an immune deficient mice and
39:21recent structural insights into TKI
39:24binding have shown that stabilization
39:26of receptor activation states.
39:28For instance,
39:29after Heterodimerization with her three
39:32produces EGFR confirmations that do
39:34not bind inhibitors like Patna benefit
39:36net and that could lead to resistance.
39:39So the goal is to identify TK eyes
39:42that bind to EGFR confirmations
39:44that are occurring in head,
39:46neck cancers or those that are
39:49not restricted by confirmation.
39:50State dependent binding and to
39:52test the effectiveness of these
39:55compounds in head neck cancers.
39:57So PDX is derived from.
39:59Biopsies from patients on the trial will
40:02be treated with EGFR directed TK Eyes,
40:05which retain efficacy against her three
40:08an EGFR heterodimers We also received
40:11a recent Department of Defense funding
40:13to a define the relationship between
40:16TP 53 genotype Aurora kinase expression,
40:19an response to EGFR inhibition using
40:22patient samples from the same NSN trial.
40:25In the absence of TP 53,
40:27or in the presence of TPX 2 Aurora
40:30kinase is highly expressed and it
40:33provides an alternative mechanism of
40:36downstream signaling of EGFR using
40:38the tissue samples from the trial.
40:41We will be able to determine
40:43if the combination.
40:45I'm sorry whether TP 53 mutation
40:47will predict for baseline or
40:49post treatment resistance,
40:51an weather Aurora kinase and
40:53TPX 2 levels are predicted.
40:55Biomarkers of non response to
40:58dual EGFR inhibition and correlate
41:00with a shorter survival.
41:01Also using posttreatment biopsies,
41:03we can determine whether a rise in
41:07Aurora kinase levels will predict
41:09for disease progression following.
41:11Progression clinical progression
41:12on treatment.
41:14Yale is also participated in a multi
41:17institutional IIT of an hepatocyte
41:19growth factor cement pathway inhibitor
41:21similar to the map in combination
41:24with Cytoxan map in patients who have
41:27previously progressed onset eczema.
41:28There is cross talk between EGFR and
41:31the cement pathways and it's a known
41:34tumor intrinsic resistance mechanism,
41:36a phase one trial of this combination
41:39showed a response rate of 17% in
41:42syntax map resistant patients.
41:44And the subsequent randomized phase
41:46two trials showed a response rate
41:48of 38% in HPV negative patients,
41:50and these results were presented
41:52at ASCO this year.
41:56So while keynote over 8 has established
41:58the role of immune checkpoint
41:59inhibition in the first line,
42:01treatment of head neck cancers,
42:03so toxic map continues to hold a
42:05place in the treatment of this
42:07disease and it is one of the most
42:09frequently chosen second line treatment
42:11in combination with chemotherapy.
42:13For patients who came off keynote over
42:158 on the Pembroke monotherapy arm.
42:18We now seek to explore the best second
42:21line treatment options for head and
42:24neck cancers and multiple lines of
42:26evidence has suggested that head
42:29neck tumors are frequently hypoxic.
42:31An have elevated VEGF signaling,
42:33which is associated with immunosuppression.
42:35The object via the stat three
42:38signaling pathway or impairment of
42:39dendritic cell maturation induction
42:42of immunosuppressive populations,
42:43such as MDF, season T regs,
42:46and reduce recruitment of
42:48cytotoxic effectors.
42:49Including CD 8 cells,
42:50CD 8 positive T cells and natural
42:53killer cells.
42:54So we postulate that VEGF blockade
42:56with bevacizumab will reverse these
42:58suppressive mechanisms and lead
43:00to improved antitumor immunity and
43:02clinical responses in patients
43:04who were previously treated with
43:06in the checkpoint inhibition.
43:07The combination of immunotherapy
43:09and veg F inhibition has also shown
43:12excellent clinical efficacy in other
43:14solid tumor types, including renal,
43:16cell, lung, and hepatocellular,
43:18and was recently approved as
43:20first line treatment for HCC.
43:22Anne in head neck.
43:23We had a Phase 1B trial looking
43:25at the combination of Pedro and
43:28botnet which showed a response rate
43:30of 36% and the PFS of 8.2 months.
43:33So we designed a Phase 2 slash
43:353 trial through ekach.
43:37There will be 3 arms in the initial phase.
43:40Two portion of this study.
43:42We chose chemo and cetuximab as a
43:44control arm because that was the
43:46regimen most patients coming off
43:48of keynote over 8 went on to an
43:50the two experimental arms are chemo
43:52and Beves is a map anitys alisme
43:54AB Inbev's is a map 216 patients
43:57will be randomized in the initial
43:59phase two part of the trial and
44:01the winner of the phase two.
44:03Portion will then move to phase
44:06three against the standard chemo's
44:07attacks ARM and another 214 patients
44:10will be randomized in phase three
44:12for a total sample size of 430.
44:14Expected study duration is about
44:15four and a half years.
44:17We expect this study to actually
44:19be activated soon.
44:20We are collaborating with Jeff Ishizuka
44:23on that issue Correlatives an at
44:25the end of the phase three portion
44:27we hope to have a clear answer for
44:30best second line treatment moving forward.
44:32Uhm,
44:32that's all I have for my work here so far.
44:36I'll pass it on to Melissa.
44:40Screen sharing.
44:49Alright now and thank you.
44:50I'll try to get my screen up. Next
45:03and I am again I want to
45:05thank everyone here for
45:06the opportunity to discuss.
45:07It's such an honor to be able to
45:09speak in combination with Doctor
45:11Burtness and Doctor Bhatia,
45:13and I look forward to the years that we
45:15have in the future to continue these
45:18projects that we're all excited about.
45:20Part of what I wanted to do today in terms
45:23of my brief presentation was to really also.
45:26While we're focusing a lot
45:28on the head and neck dart,
45:30Anan the spore that we have funding for,
45:32and how we're incorporating that
45:34to the clinical trial progression
45:36at Yale didn't want to discount
45:38the the contribution that the
45:39radiation oncology Dart also does.
45:41And we work very collaboratively
45:43collaboratively between the
45:44two organizations and arts,
45:45so I wanted to kind of highlight some
45:47of the trials that we do have open,
45:50and some of the hope that that
45:52will be able to help contribute,
45:54both with supporting the head and neck dart.
45:57But also with the head and neck score,
45:59I have no disclosures and I am
46:02not going to spend a lot of time.
46:04I know we're running a little short on time,
46:07but as everyone here knows that you
46:09know head and neck squamous cell
46:11carcinoma is very common with at least
46:1364,000 cases in the United States
46:15and this is reiterating some of what
46:17Doctor Burtness had previously already
46:19mentioned is that the head and neck
46:21location of cancer is very sensitive
46:23part of the body and it's very
46:25important with how we interact with society.
46:27Maintain nutrition, communicate.
46:29Anan, it's what,
46:30especially in a pandemic.
46:31How we visualize each other to how we,
46:34how we see each other and communicate orally.
46:37So currently as we know that in
46:40order to provide curative treatment
46:41for people who are nonmetastatic,
46:44that is usually some form of local therapy
46:47which may be surgery or radiation,
46:49or sometimes a combination of both,
46:51which carries a lot of potential
46:54risk for functional impairment.
46:55Whether it's related to surgical changes,
46:58scar tissue from both, surgery radiation.
47:00I'm swallowing dysfunction pain dry mouth.
47:02You know,
47:03complications that can arise from
47:04dental health and other things that
47:06that come down the line after.
47:08As a consequence of the curative
47:10intent treatment.
47:10So while patients may be cured,
47:12they could be left with lifelong
47:15implications of their treatment and
47:16some of the goals that we have both at
47:19Yale but also across the country in
47:21the world or to understand how we can
47:23try to reduce the morbidity of that
47:25treatment without compromising cure rates.
47:27But also importantly,
47:28we still have a long ways to
47:30go in certain disease sites.
47:32We've already heard a lot about
47:34the P-16 negative population.
47:35And and disease resistance.
47:37And how can we overcome treatment
47:40resistance but also prevent further
47:42morbidity of the treatment that we provide?
47:45Some of what's been touched on already,
47:48as is the importance in recognition
47:50of immune checkpoint inhibitors.
47:52Certainly other disease sites and FDA
47:54approvals have come along showing activity.
47:56An other disease sites and we
47:58now see data showing
47:59the efficacy that immune checkpoint
48:01inhibitors appear to have,
48:03both also in head and neck
48:05cancer as well, and therefore,
48:07while a lot of initial data has indicated
48:10efficacy in the metastatic setting,
48:12we're also now looking to see
48:14how this might be incorporated.
48:16In the upfront definitive setting
48:18and whether or not that might
48:21also provide some opportunity for
48:23either reduced dose of radiation,
48:26reduced need for cytotoxic chemotherapy,
48:28but still maintaining.
48:32Equivalent cure rates as to
48:33what we already have,
48:35so a lot of these trials are now
48:37moving into the definitive setting,
48:39looking at multiple different
48:40immune checkpoint inhibitors
48:42that I've got listed here.
48:43Some of the former trials that
48:45we are now in in either actively
48:47enrolling on through the head and
48:50neck through the head and neck DART,
48:52but also previously open trials that
48:54are now in their follow-up phase,
48:56have used immune checkpoint inhibitors
48:58in the upfront setting whether
49:00it was in keynote for 12, where.
49:02Checkpoint inhibitor Kimbrough was added
49:04in conjunction with CHEMORADIATION
49:06but also in the maintenance phase.
49:09We are currently enrolling on the
49:11ikago Akron 3161 that is looking
49:13at addition of at atrovent you know
49:16therapy after an initial phase of
49:19definitive chemoradiotherapy and
49:20there have been some phase one
49:23trials including H NO3 that have
49:25looked at how immunotherapy may
49:27play some role and also safety and
49:30the adjutant setting after surgery.
49:33One of the trials that we currently
49:35have open through the radiation
49:37oncology DART is looking at how
49:40immunotherapy may perhaps improve
49:42efficacy in a high risk population.
49:44So specifically,
49:45this is looking at patients who have
49:48positive margin or extranodal extension
49:50after initial surgical resection of
49:53locally advanced head and neck cancer,
49:55and patients are currently standard
49:57of care is radiation cisplatin,
49:59but this is now heading into
50:02the phase three design.
50:04An activation and this is now exploring
50:06the combination of Docetaxel subtaxa
50:08map with radiotherapy versus cisplatin
50:10with the addition of immunotherapy,
50:12this one being a tease.
50:14Oh, and this has been.
50:16Unfortunately, I must admit,
50:17a high accruing trial. In part, I think.
50:20Again, we're seeing this.
50:24A phenomenon of increased.
50:28Higher stage disease,
50:29more locally advanced disease,
50:30especially as patients have have had maybe
50:32some delays in their care from COVID.
50:34And so we have.
50:35We have actually been accruing
50:36to this at a rather high rate,
50:38and we look forward to the results to come.
50:42We are also, as I alluded to, looking at how.
50:46We might be able to improve
50:48our definitive intent,
50:49and there's certain populations
50:50where we have some room to improve,
50:53and one of that population is
50:55a cisplatin ineligible group of
50:56patients has already been alluded to,
50:58so I won't get into the details of the data.
51:02But as was previously mentioned,
51:03so tuck some AB does have some improvement.
51:06The Bonner Trials had indicated some
51:08improvement over radiotherapy alone,
51:10but when compared to cisplatin,
51:11it is inferior,
51:12although we do have that group of
51:14patients that are ineligible
51:16for cisplatin instaed eczema,
51:17maybe that that therapy that we have.
51:20And so H&O four is now looking at
51:23whether or not we can take those
51:25patients who are ineligible for
51:27cisplatin and compare how they might do.
51:30And compared to Subtaxa ma'am.
51:32So this is using a derbe as an immunotherapy,
51:35and whether or not this might also
51:37provide meaningful outcomes help
51:38radiosensitizing those patients
51:39who are not otherwise eligible
51:41for cytotoxic chemotherapy.
51:43This is open to more advanced P.
51:4516 and higher risk P 16 positive population,
51:48but also the P-16 negative population.
51:50Both stage three and stage four cancers.
51:53I mean and also a trial that we
51:56have been enrolling on with at
51:58least about 7 patients currently
52:00on study and in its current state.
52:03And then lastly,
52:04in terms of the intensification,
52:05it is certainly one of our
52:07goals as is also been mentioned,
52:09the HPV population.
52:10Has been recognized as having a better
52:13prognosis than that of the P-16
52:15population and across the country.
52:18We're now trying to tease out how.
52:20How might we be able to safely D
52:23intensify in therapy and the ikago Akron,
52:263311, or this I should say,
52:28the COGS 3311 is kind of one
52:30example of where there might be
52:33some opportunity to reduce.
52:35Treatment,
52:36but the outcomes and the number of
52:38failures are low because this is a
52:40relatively good prognosis population,
52:42so we have to think about this
52:44meaningfully an carefully an whether
52:46or not that's some combination of
52:48reducing radiation dose whether or
52:50not it's a combination of surgery
52:52with reduced radiation dose.
52:53I'm not going to be talking about
52:55any kind of induction, you know,
52:57systemic therapy followed by your dose
52:59reduced or risk adjusted local therapy,
53:01but certainly a lot of different
53:03ways in which this could be explored.
53:06And we are going to be looking to move.
53:10We're moving to open H and 05,
53:13which is looking at our low risk.
53:16P-16 population today.
53:17Intensified protocol,
53:18kind of as a jumping point from
53:21previously published results of H
53:23and O2 that had shown reasonably
53:25good to your progression.
53:27Free survival of 90% with the instead
53:30of our typical 70 Gy of radiation.
53:33Instead 60 grave radiation with
53:36cisplatin omitting the cisplatin
53:38did did cross to lower progression
53:40free survival so.
53:41Hi,
53:42no five is looking to keep the 60
53:44Gray with cisplatin arm but also
53:46then looking at a somewhat escalated
53:48or hyper accelerated radiation
53:50delivery of 60 Gray over 5 weeks
53:53with the addition of immunotherapy
53:55to compare how that may may relate
53:57to the standard of care 70 grain
54:00cisplatin versus 60 Gray and cisplatin.
54:02So we do look forward to opening
54:05this specific population that we
54:07don't have a lot of trial opportunity
54:09in clinical trial opportunity and
54:11look forward to.
54:12To providing more options and
54:15contributing to important questions
54:17nationally and internationally.
54:19And then,
54:19in terms of the future goals for our
54:22therapeutic radiation oncology dart
54:23in combination with how we interface
54:26with all of the other
54:27darts that we work with.
54:28But today specifically the head
54:30in our head and neck dart,
54:32you know our goal is to continue
54:34to collaborate with this for a
54:35lot of the physicians that doctor
54:37Burtness had previously indicated
54:39at the beginning of her slides,
54:41there were at least six physicians just
54:43from radiation oncology faculty alone
54:45who are part of this combined effort.
54:47We have a lot of clinician scientists
54:49who are actively engaged in DNA.
54:51Repair and how we might be able to
54:53improve outcomes in this fits nicely with
54:56the purpose and an goal of the head.
54:58And next four,
54:59and will also be continuing toward
55:01to support the head and neck dart
55:03with the trials that were able
55:05to open our resources as well.
55:07Also, we want to continue to open
55:09cooperative group trials that will
55:11align with the needs of our patient
55:13population here in Connecticut and
55:15continue to assess that and make sure
55:17that we're opening trials that are
55:19appropriate for our Community efforts.
55:21And then lastly,
55:22is was also alluded to.
55:24Outcomes are better at high volume centers,
55:27so as we continue to expand an
55:29need to serve a greater,
55:31expensive community across the entire
55:33state of Connecticut and our department,
55:35we are working very vigorously of maintaining
55:37high quality at our care center specifically.
55:40Really water for Dan Trumbull.
55:42In addition to our main campus
55:44here in New Haven.
55:45So we have extensive efforts in standardizing
55:48our radiation treatment planning,
55:49ensuring we have quality across the system.
55:52How we do that is multi factorial,
55:54but certainly we have peer
55:56review of all of our cases.
55:58We've.
55:59Do them regularly whether patients are
56:01on or off clinical trial to make sure
56:03that we have and maintain quality.
56:05All the physicians that participate
56:07in any head and neck treatment under
56:09satellite through also attending
56:11these multidisciplinary tumor boards
56:12and and many of us also attend
56:14multidisciplinary clinics as well.
56:16So we're very engaged with with
56:17the head and neck team.
56:24Like any of the cooperative groups
56:26that have external review required
56:28as part of our radiation planning,
56:30have have identified no concerns
56:32with our radiation planning.
56:33And then lastly,
56:34I think one of the things that is
56:37important is that we work very hard
56:39to make sure that we have the clinical
56:42support services that are key.
56:44So the speech, language, pathology,
56:46the social work that was mentioned,
56:48the surgical resources and expert
56:50experts on site so that we can
56:52make sure to appropriately.
56:54I'm triage our patience is as
56:56they go through their treatment,
56:57but also have the same high
56:59quality surveillance and and
57:00also support as they are in their
57:02survivorship from heaven and cancer.
57:04And I'll combine.
57:05I think this will help continue to improve
57:07access as well as improved clinical trial,
57:09trial, enrollment everywhere.
57:10And with that I want to.
57:12I'll stop here.
57:13I want to thank everybody again,
57:15I I don't have an acknowledgement slide,
57:17but certainly everyone that
57:18Doctor Burtness had mentioned,
57:19plus or clinical trials team has been
57:22very critical in our ability to do
57:24what we've been able to do in serve.
57:26Our patients here in Connecticut.
57:31OK, thanks Melissa.
57:32We have time for a couple questions.
57:35Please put them into the chat or if
57:37you want will unmute you so you can
57:40speak while I'm waiting for you. I'll
57:42just say Melissa, I was very impressed
57:44by the multi modality nature of care
57:46and the fact that you're writing these
57:49trials and all the different centers.
57:51So what's the secret we need
57:53more trials like that?
57:54You know higher crewing.
57:55You know where you can can.
57:57It's a very prevalent type
57:59of disease with a trial that.
58:01I guess the eligibility criteria
58:02are quite broad to allow
58:04most patients to enroll.
58:06Yeah, I think that's part of it is as we as
58:09our darts and doctor Burtness
58:10can can attest to this too.
58:12We really try to understand
58:14what's going to likely accrue for
58:15our current patient population,
58:16and I think that that's been key.
58:18But also making sure to advertise it.
58:20And I think because our physicians
58:22have been so engaged at the other
58:24centers were able to get these opened
58:26in enrolled at the care centers.
58:27Sometimes we're able to meet
58:29these patients locally.
58:30I think that's been a huge
58:31part of our success.
58:32Is is making sure those patients who,
58:34specially if they're seeing a New Haven,
58:36are seeing all of us and and have.
58:38Have full venue and access
58:40to understanding every every
58:42clinical trial available to them.
58:44Great
58:44thanks. We have a we have a question
58:47from Tommy Tommy you want to unmute
58:49and will let you ask your question.
58:52Yes, first of all.
58:55Barbara and I you have and also others.
58:59I think that progress in this area is.
59:03Very impressed my sections to you.
59:07Is all of your services go up to
59:11the what is happening after those
59:14combination in terms of adverse effect.
59:18Is it getting worse for the same
59:22Orpik or less? And you know this.
59:25So putting index is the most
59:27important part of the treatment.
59:29One of motion.
59:30So could you come in anger and the
59:34particular you several, or you'll be
59:37involving using antibody email check.
59:40What's the impact?
59:42On the enterprise, the combination on the 88.
59:49In other words, anybody you want her?
59:51You go stand by the response.
59:54Is that like getting more or less or or what?
59:59So could you sort of comment on this so so
01:00:02maybe I'll start and then I'll pass
01:00:04it to to Melissa because I think.
01:00:07Radiation has its its whole own story with
01:00:10the toxicity in terms of the combination
01:00:13of Pember Lism AB with chemotherapy,
01:00:16it did not lead to more toxicity
01:00:19than people is made with the taxman
01:00:22and pembrolizumab alone was a lot
01:00:24less toxic than the combination.
01:00:27The there is a suggestion that there
01:00:29is a little bit of intensification
01:00:32of the myelosuppression when you give
01:00:35pembrolizumab chemo relative to the tax man.
01:00:38Chemo and although it didn't lead to a
01:00:41significant increase in the number of deaths,
01:00:44we did see more tumor bleeding when
01:00:47we used pen bro or Pembroke chemo.
01:00:51And that I think may have to do with.
01:00:56Loss of immune checkpoint at as regards
01:01:00the interaction of the activated T
01:01:02cells with the wall of these damaged
01:01:05blood vessels within the tumors,
01:01:08these are these antibodies are
01:01:11not inducing a a high rate of.
01:01:15Anti humanized antibody antibodies.
01:01:17So overall I would say our experience
01:01:19with toxicity is this the subgroup
01:01:21of patients who have high grade
01:01:24immune related adverse events and
01:01:25other than that not really worse
01:01:28than it used to be in the prior era.
01:01:31And then Melissa,
01:01:32I don't know if you want to talk
01:01:34about is we've added the immune
01:01:37checkpoint inhibitors to radiation.
01:01:41So certainly some
01:01:42of the initial patients that we've followed.
01:01:44I think there's the immune,
01:01:46so we talk about potentially using.
01:01:48I mean therapies is something
01:01:49to avoid cytotoxic,
01:01:50but certainly there's the immune
01:01:52concern and we certainly are seeing
01:01:54activation of psoriasis skin conditions.
01:01:56You know anything underlying those
01:01:57are the things that I think we're
01:02:00still learning to manage in terms of
01:02:02toxicity during radiation have not
01:02:04necessarily seen any worse toxicity
01:02:05during the actual course of radiation
01:02:07and these initial patients that have
01:02:09been on these combined modality.
01:02:11Therapy, but there are different things
01:02:13that we're having to think about.
01:02:14You know when do we,
01:02:16you know we're having to determine
01:02:18whether or not we're needing to add
01:02:20steroids at any point along the way.
01:02:22Different toxicities that we didn't
01:02:23necessarily have to think about
01:02:24checking for during radiation
01:02:25for definitive intent treatment,
01:02:27but I think that is what we
01:02:28are continuing to learn.
01:02:30And for these trials,
01:02:31the information we get from these
01:02:32trials and toxicity assessments will
01:02:34be very important in determining.
01:02:35Is this a way of the intensifying?
01:02:39That's the way we're going to.
01:02:42So I'll go ahead
01:02:43with just about overtime, but I know
01:02:44my car, which has a question too,
01:02:46but you can do a quick follow up time.
01:02:49OK. In terms of skin, **** city.
01:02:53Your EGFR inhibitor,
01:02:56but it caused skin.
01:02:59And also the other antibody,
01:03:00also called skin.
01:03:02So what happens if you use combination as?
01:03:05I think it was mentioned it's getting
01:03:08worse as that is a quite a very
01:03:11unpleasant this toxicity patient app.
01:03:13If you have a skin issues.
01:03:19So I don't know if if
01:03:21Artie wants to address The
01:03:22Phantoms to talk.
01:03:23Samantha has been associated
01:03:24with a fair bit of skin toxicity
01:03:27that responds to steroids.
01:03:28So talk some ampem Bros.
01:03:30Been reported now in head neck
01:03:32cancer to be quite active without
01:03:34really much of a difference in
01:03:36the safety signal so you know,
01:03:39I think there's there's obviously still
01:03:41a lot to learn with these regiments
01:03:43that are reported with patients,
01:03:45but I think we're all quite
01:03:47intrigued by the possibility of
01:03:49the IO anti EGFR combinations.
01:03:55OK, and then the final question
01:03:56Micro it's you've had your
01:03:58hand up along time.
01:04:02No, not always. Mark Horowitz,
01:04:06yes, so fresh ham it number one.
01:04:10I had an HPV positive tumors that I was
01:04:14she at yeah portion is actually bad.
01:04:18Yeah I was my holiday since actually yeah,
01:04:22'cause my radiation allergist and
01:04:25Schumer was eventually recessive as
01:04:28absolute treasure and who oppose
01:04:30them by Sasha Mirror and tell you
01:04:33that I received superior hair?
01:04:35I just change and your experience
01:04:38is just fantastic.
01:04:40So I'm a year and a half out tumor free.
01:04:46Couldn't be happier.
01:04:48I'm back in my lab in the Department of
01:04:52Voice appears looking away so thank you.
01:04:57I work with pleasure.
01:05:01They have voted, but you see,
01:05:04an influx of mafic ages fo a
01:05:08positive cells in or around HPV.
01:05:11Positive tumors in the presence of
01:05:15patients who are treated with the.
01:05:19Checkpoint inhibitors versus intros.
01:05:26So I think less so than the
01:05:29infiltration of T cells.
01:05:31It is well understood that,
01:05:33particularly in the more hypoxic
01:05:36and HPV negative head neck
01:05:38cancers there is at baseline.
01:05:41Quite a lot of.
01:05:46Extensive macrophage population and
01:05:47that it's sort of M2 polarized and make
01:05:50correspond to the macrophage populations
01:05:52that have been defined in preclinical
01:05:55models for predicting hyper progression.
01:05:57For example in non small cell lung cancer.
01:06:00So I think still a lot of
01:06:03work to be done there,
01:06:05but the the response when someone
01:06:08is responding seems to be that
01:06:10we're seeing in ingress of T cells.
01:06:15Well, thank you. Thank you for
01:06:17your wonderful comment and for
01:06:19telling the whole world what how
01:06:21lucky I am to work with these two.
01:06:24It's just issue,
01:06:25yes issues. Well, well, you
01:06:28know that's a great way to end
01:06:30and you know with the patient,
01:06:31care comes first and the the
01:06:33amazing work that you're all doing.
01:06:35And we have an example right here.
01:06:37So keep it up.
01:06:38Lab to clinic clinical lab.
01:06:39You know multi modality care.
01:06:41It's exactly what we all aspire to.
01:06:42So thank you all for coming to grand
01:06:45Rounds today and we'll see you next week.