Smilow Shares CME: Neoadjuvant Therapy and Cutaneous Malignancy

January 07, 2026

Presentations by:

Aarti Bhatia, MD, MPH

Associate Professor of Medicine (Medical Oncology); Clinical Research Team Leader, Head and Neck Cancers Program

Kelly Olino, MD, FACS

Assistant Professor of Surgery (Oncology); Leader, Skin Cancer Surgery, Melanoma Program; Clinical Director of the Smilow Melanoma Program, Yale Cancer Center; Co-Director Cutaneous Malignancy Tumor Board, Yale Cancer Center; Medical Student Clerkship Liaison for Division of Surgical...

Ansley Roche, MD, BA

Assistant Professor of Surgery (Otolaryngology)

Kathleen Cook Suozzi, MD

Associate Professor Term

Thuy Tran, MD, PhD

Assistant Professor of Medicine (Medical Oncology)

Information

ID: 13720
To Cite: DCA Citation Guide

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00:00Welcome, everyone. We have a
00:01wonderful
00:02session
00:03where we've decided to group,
00:06multiple diseases under one
00:08important theme, that being the
00:11growing importance of her cutaneous
00:13malignancies,
00:15giving our patients who seem
00:17to have advanced
00:18disease
00:19consideration for neoadjuvant treatment. So
00:22today you'll hear first from
00:23from doctor Kathleen Souzy about
00:26the role that she plays
00:27as a as a highly
00:28talented Mohs surgeon and seen
00:30many of these advanced cases
00:31and setting the stage
00:33for our high risk cutaneous
00:35squamous cell and really highlighting
00:37who those patients are
00:39that fit into that category,
00:41which can be a little
00:42complicated to begin with. And
00:44then Doctor. Ansely Roche has
00:46joined us as a as
00:47a head and neck surgeon,
00:48one of our main cancer
00:49surgeons here at the Smilow
00:50Hospital,
00:51to again talk about some
00:52of her experience and give
00:54us some cases
00:56with Doctor. Bhatia
00:57then joining us from medical
00:59oncology for many of these
01:01high risk patients,
01:02explaining the role not only
01:03of immunotherapy in general, but
01:05that in the new adjuvant
01:07setting where there's an increasingly
01:09important role.
01:10And then we have doctor
01:11Thuy Tran, who's one of
01:13our
01:13senior medical oncologists and an
01:15expert in cutaneous malignancies, particularly
01:18that in melanoma,
01:19who will, along with me,
01:21take us through our journey
01:22of where we've arrived
01:24towards,
01:25the role of new adjuvant
01:26treatment in cutaneous high risk
01:28melanoma.
01:30So with that, I'll
01:31have doctor Susie begin.
01:33Sure.
01:35I'm just,
01:36share my screen here.
01:48Hold on. Something happened there.
01:51There we go.
01:52Okay.
01:54Good evening, everyone. My name
01:55is Katie Swozzi, and I'm,
01:58section chief of dermatologic surgery
02:01and specialize in Mohs micrographic
02:03surgery. And today, we're gonna
02:04talk about high risk cutaneous
02:06squamous cell carcinoma.
02:07So,
02:09why does accurate staging matter?
02:11Well, we know that overall,
02:13cutaneous SCC has a very
02:14favorable prognosis.
02:17The incidence
02:18is about a million cases
02:20a year, so it's a
02:21very common tumor. And so
02:23the risk of unfavorable
02:24outcomes is low,
02:26less than five percent for
02:27local recurrence,
02:28less than four percent for
02:30nodal metastasis, and less than
02:31three percent for disease specific
02:33death. But when you have
02:35a tumor that is so
02:36common,
02:38you know, when we look
02:38at,
02:39annual estimated deaths with cutaneous
02:41squamous cell carcinoma,
02:43it's actually greater annually than
02:45melanoma. And there is, you
02:46know, some overlap with head
02:47and neck cancer where sometimes
02:49the lines are blurred between,
02:50you know, what is a
02:51cutaneous,
02:52SCC versus a head and
02:54neck SCC when we're talking
02:55about areas
02:56like the lip or sometimes
02:58for tumors,
02:59that arise,
03:01you know, within the parotid
03:02where we're not sure where
03:04the original primary was. So,
03:06really, the key is how
03:07do we predict these bad
03:08actors at diagnosis? So I'm
03:10gonna start just, with,
03:12case I actually shared with
03:14doctor Bhatia. So this was
03:15a patient who presented with
03:16a very routine
03:19cutaneous,
03:21swim cell carcinoma on the
03:22scalp,
03:23for Mohs micrographic surgery. So
03:25this is something that I'll
03:27see in my practice, walk
03:28in the door, you know,
03:29more than twenty times a
03:30week. And so this tumor
03:32was less than two centimeters.
03:33It was cleared on two
03:35stages and repaired linearly.
03:38About
03:39one month later, the patient
03:40presented,
03:42with,
03:43he called saying that he
03:44had a nodule on the
03:45scalp, and we thought maybe
03:46it was a spitting suture,
03:47hadn't come in and saw
03:49this. Still thought maybe this
03:50was just a suture reaction,
03:52but was suspicious enough for
03:54a recurrence that the lesion
03:55was biopsied.
03:56And it showed,
03:58and the biopsy confirmed recurrent
04:00SCC that was infiltrative histology
04:03with a depth of seven
04:04point five millimeters. So we'll
04:06pause that case for a
04:07second, and let's just talk
04:08about our staging criteria for
04:10cutaneous SCC.
04:11So AJCC
04:12eight,
04:13is our current staging criteria,
04:15for, tumors of the head
04:17and neck. And it is
04:18important to note that these
04:19staging criteria is specific for,
04:21head and neck cutaneous SCC.
04:23And,
04:24the really, this is a
04:25big advancement,
04:27from AJCC seven,
04:29now about, over seven years
04:31ago,
04:32where
04:33the two the tumor criteria
04:36moved from not just a
04:37designation by size, but also
04:39to include other high risk
04:41features.
04:42So this,
04:43t three group now includes,
04:45any tumor that has minor
04:47bone erosion
04:48or perineural invasion
04:50or deep invasion. And so
04:52deep invasion is defined as
04:54beyond subcutaneous
04:55fat or greater than six
04:57millimeters from the tumor,
04:59or from the, base of
05:00the adjacent normal epidermis to
05:03the base of the tumor.
05:04And perineural invasion is defined
05:06as,
05:07nerve caliber of greater than,
05:09point one millimeters
05:10or deep nerves below the
05:12dermis or radiographic evidence of
05:14nerve involvement, which is rare.
05:16And so,
05:18this really helped,
05:20to stratify,
05:21risk as in AJCC seven,
05:24the,
05:25the biggest proportion of poor
05:27outcomes occurred in t two,
05:29and this was a very
05:29heterogeneous
05:30group. So now, the greatest
05:32proportion of,
05:34poor outcomes
05:35occurs in t three as
05:37t four, you know, which
05:38is, gross bone invasion is
05:39a relatively restricted group.
05:42So the second staging criteria
05:44is the Brigham and Women's
05:45staging criteria, and this one's,
05:47relatively simple and straightforward.
05:49It's based, strictly on risk
05:51factors. So the risk factors
05:53that are considered are tumor
05:54size greater than two centimeters,
05:57tumor invasion beyond subcutaneous fat,
06:00again, perineural invasion with that
06:01point one millimeter cutoff, and
06:03poorly differentiated histology. So if
06:06you have zero risk factors,
06:07your t one, one risk
06:09factor t two a,
06:11two to three risk factors,
06:12t two b, and greater
06:14than,
06:15four risk factors for your,
06:16would be, t three. And
06:18so when we look at
06:19how the staging criteria compare,
06:22against each other,
06:24so note, Brigham and Women
06:25does not have a t
06:26four stage, so their t
06:27three tracks,
06:29along with, t four in
06:31AJCC eight. But Brigham and
06:33Women does have a little
06:34bit of a better differentiation
06:35in terms of outcomes here
06:37looking at local recurrence and
06:38nodal metastasis between the t
06:40two a and t two
06:41b,
06:43categories where, you know, in
06:44AJCC eight, those t two
06:46and t three still track
06:48pretty close together.
06:49But, you know, you can
06:50see here when we're looking
06:52for risk of nodal metastasis,
06:53it's, you know, less than
06:54ten percent in t two
06:55a jumping up to, greater
06:57than twenty percent in t
06:58two b. So this t
06:59two b category is really
07:00where our antenna is going
07:02up,
07:03you know, in terms of,
07:04you know,
07:05getting imaging for these patients,
07:07thinking about coordination
07:08for,
07:10recommendations for
07:12adjuvant radiation,
07:13or, you know, getting our
07:15other colleagues on board.
07:17But this is based at
07:18staging on biopsy, and I
07:19think that's really important because
07:21when we look at depth
07:23of invasion, this is not
07:24always gonna be reported. And
07:25sometimes we don't know the
07:26depth of invasion just on
07:27the biopsy alone because we're
07:29taking superficial shapes.
07:31So,
07:32you know, going back to
07:33our patient, if we put
07:35him in staging criteria,
07:37he would fit, t three
07:38based on that depth of
07:39invasion of seven point five
07:41millimeters.
07:42But with Brigham and Women,
07:43he'd be t two a.
07:44He really only had that
07:45one risk factor of depth.
07:46So you can see here
07:47that there's still discrepancy between
07:49our staging systems, and we're
07:50not always
07:51able to put our patients,
07:52you know, in in one
07:54box. And so in addition
07:56to so staging criteria take
07:58into account tumor factors only,
08:00but we know that patient
08:01factors are highly important when
08:03we're stratifying high risk squamous.
08:05And so,
08:07things here,
08:08like lesions, you know, off
08:10the head and neck, which
08:11AJCC
08:12eight does not, take into
08:14account.
08:15But also is the lesion
08:16recurrent?
08:17Is the patient immunosuppressed?
08:19This is a a key,
08:20patient risk factor.
08:22You know, sites of prior
08:24radiation, a rapidly growing tumor,
08:27also important, but not taking
08:29into account and staging criteria.
08:30And we're thinking back to
08:31this patient.
08:32He's hitting these categories as
08:34well as that depth of
08:35invasion. So by eight by
08:37NCCN,
08:38this patient would be in
08:39a very high risk category.
08:40In addition,
08:41you may give him immunosuppression
08:43too because of history of
08:44follicular lymphoma.
08:46So, and this histology question
08:48is also important because, you
08:50know, really, that poorly differentiated
08:52histology is the only risk
08:53factor that counts, but there
08:54are other high risk subtypes
08:56of cutaneous SCC. So when
08:58I see infiltrative histology, again,
09:00my antenna is up that
09:01this is a high risk,
09:03tumor even if
09:05it's not upstaging them,
09:07based on that criteria.
09:09So, here, I just wanted
09:11to show the, frozen section
09:13histology from this patient's,
09:15MOSE surgery, and you could
09:16see this was, on the
09:18second MOSE when he came
09:19back for that recurrence. And
09:20here, you can see that
09:21this tumor is set down
09:23below the subcutaneous
09:24fat,
09:26in the galea here,
09:28and the muscular layer of
09:29the scalp. And when we
09:30look up close, you can
09:31see, this I would call
09:33poorly differentiated histology with the
09:35high, nuclear to cytoplasmic
09:37ratio and almost forming these,
09:39like, pseudo glandular like structures
09:41and clearly losing, its differentiation
09:44pattern.
09:45So,
09:46you know, this patient,
09:48after the second mose, again,
09:49repaired linearly, and then within
09:51weeks presented again,
09:53with
09:54nodules here. And at this
09:55point here where you're seeing
09:56nodule along the scar line,
09:58but then outside the scar
09:59line, this is,
10:01a clinical representation of satellite
10:03ptosis or in transit METs.
10:06And so
10:08for satellite ptosis, you know,
10:10here, this is really where
10:11multidisciplinary
10:12discussion is important.
10:15And, you know, for operable
10:16disease,
10:17where you really feel like
10:18those in transit METs are
10:20still contained within a region
10:21where wide local excision is
10:22an option, Here's where you
10:24may be considering the adjuvant
10:26therapy, and, I'm sure we're
10:27gonna talk about this later,
10:29versus for unresectable disease where
10:31really then you're looking into
10:33systemic options. And so here
10:34was this patient,
10:36While we were discussing what
10:37to do with him, this
10:38is how his tumor exploded
10:40really within,
10:41you know, within
10:43a couple weeks' time.
10:46So I just wanted to
10:47put in a plug for,
10:48this risk calculator. So this
10:50was developed
10:51by some of my colleagues
10:53in the Mose College, in
10:54conjunction
10:55with, colleagues in head and
10:57neck surgery and,
10:59radiation oncology,
11:01and med onc as well,
11:02I believe.
11:03And this, was just published
11:05in
11:07JAMA Dermatology
11:08in,
11:10February of this year.
11:12The QR codes here, if
11:13you wanna download it, it's
11:14an app, and it's really
11:15nice because it takes into
11:17account the staging criteria that
11:19I just just reviewed as
11:20well as many of the
11:21features that are in the
11:22NCCN guidelines
11:24to, to,
11:26give you personalized
11:27risk profiles for your patient.
11:29So I think it's really
11:30easy to use for anyone
11:32to have on their phone,
11:32and,
11:34I've found it very helpful.
11:35And the initial, data on
11:37this very large cohort multi
11:39multi institutional
11:40cohort shows that actually the
11:42predictive,
11:45the predictive ability,
11:47outperforms either staging criteria alone.
11:51So that's what I wanted
11:52to talk about. So now
11:54I'm gonna turn it over
11:56to doctor Badia. Is that
11:57right?
11:59Let me stop my share.
12:05I wasn't sure if doctor
12:06Roche was going next. Oh,
12:07sorry. Doctor Roche. I'm sorry.
12:09I missed.
12:11All good. All good. Alright.
12:13Let's see.
12:15Alright. I will share my
12:16slides now.
12:18Okay.
12:21Great. Can set you guys
12:23can see my slides?
12:24Great. Okay.
12:26So I'm Ansley Roche. I'm
12:27a head, neck,
12:29cancer and reconstructive surgeon here
12:30at Yale.
12:31I
12:33take care of patients with
12:34cancers of the oral cavity,
12:35oral pharynx, the upper airdigestive
12:37tract, but also cutaneous malignancies,
12:41salivary gland tumors.
12:42So I'll be talking about
12:44sort of the clinical some
12:45of the clinical,
12:46scenarios that we,
12:48come run into and the
12:50role of,
12:51neoadjuvant treatment for these patients.
12:54So I'll present a case
12:55and then I'll just discuss
12:56sort of the basis for
12:58how these how this treatment
12:59sort of came to be,
13:01generally quite well accepted for
13:03head and neck cancer patients.
13:05Let me there we go.
13:07Okay. So this is a
13:08patient,
13:09AR,
13:11I saw about a year
13:12and a half ago.
13:13Fairly sick gentleman, older, eighty
13:15six year old, with a
13:16pacemaker on eliquis, congestive heart
13:18failure, multiple medical comorbidities, had
13:21had multiple cutaneous malignancies, all
13:23basal cell, carcinoma of the
13:25torso,
13:26that were excised with Mose
13:28who developed the sort of
13:29rapidly growing mass in the
13:31left preauricular area, had been
13:33present for just a couple
13:34of months and just kept
13:35increasing in size sort of
13:36by the day,
13:37right in front of the
13:38family's eyes. They were quite
13:39troubled by it. So he
13:41had a biopsy of this,
13:42and it demonstrated squamous cell
13:43carcinoma.
13:46Of note on physical exam,
13:48his,
13:49facial nerve, was fully intact
13:51and really no other kind
13:53of significant findings, no cervical
13:55lymphadenopathy on exam.
13:58Cross sectional imaging,
14:00she can see this left
14:01preauricular lesion,
14:03two two sections here. This
14:05first one on the left,
14:06you can see it's, you
14:07know, superficial,
14:09the superficial extent of it.
14:10And then on the right,
14:11you can see that there
14:12is this sort of projection,
14:14of tumor heading into the
14:15deep lobe of the parotid,
14:18adjacent to where the facial
14:20nerve, leaves the skull base
14:22and heads into the parenchyma
14:23of the parotid.
14:25No cervical lymphadenopathy was visualized
14:27on CT.
14:29He then underwent,
14:31a PET scan as well
14:32that redemonstrated this lesion. And
14:34then you can see here
14:35it has this kind of
14:37crescent like
14:38projection
14:39and distribution.
14:41And no cervical lymphadenopathy was
14:44noted on the pet, nor
14:45any distant metastasis.
14:49So, I talked to him
14:50about what surgery would be.
14:53It would have obviously involve
14:54a wide local excision.
14:55Due to the location of
14:57this being
14:59superficial to the parotid gland,
15:02he would need a total
15:03parotidectomy
15:04Depending on the the relationship
15:06of this cancer to the
15:07facial nerve, he would potentially
15:09need facial nerve sacrifice, and
15:11we would you know, that
15:12happens from time to time,
15:13and we reconstruct that with
15:14nerve grafting or
15:17static and dynamic facial reanimation
15:21techniques,
15:24and potentially free tissue transfer,
15:26meaning, taking, you know, tissue
15:28from one part of the
15:29body and and kind of
15:31revascularizing
15:32it in the head and
15:33neck, to give a blood
15:34supply.
15:35All in all, a surgery
15:36that would take probably on
15:37the order of ten to
15:38twelve hours.
15:40So we presented him as
15:41always at our multidisciplinary
15:42head and neck tumor conference,
15:44and he was evaluated by
15:46all members of our multidisciplinary
15:48team.
15:49And considering his comorbidities,
15:52and the extent of what
15:54his surgery would be, the
15:56recommendation was to at least
15:58consider,
15:58neoadjuvant samiplimab.
16:00And so he and his
16:01family,
16:02agreed to proceed with this
16:04method of treatment.
16:05And he,
16:08was initiated.
16:09And we have the baseline
16:10picture on the left. And
16:11then after just two months
16:12of samiplimab,
16:14you can see
16:15a pretty dramatic
16:17response here of the lesion.
16:22And six months later, you
16:23can see a photograph here
16:25on the left.
16:26Really just essentially complete resolution.
16:27There's, you know, obviously some
16:28residual complete
16:30resolution. There's, you know, obviously
16:31some residual scar. And a
16:33PET scan done around that
16:34same time, showed no evidence
16:36of disease,
16:37kind of,
16:39FDG resolution of this lesion.
16:43At one year, he has
16:45essentially just a scar in
16:46this area and a PET
16:47scan that, again, continues to
16:49show no,
16:50evidence of disease.
16:53So he remained on samiplimab
16:54for an additional year, so
16:56two years total. And,
16:58he was felt to have
16:59developed a complete at least
17:01a complete clinical and radiographic
17:02response.
17:05Since this is sort of
17:06a novel
17:08strategy to treat these types
17:09of cancers, I
17:11recommended that he get just
17:12an excisional biopsy, so sort
17:14of confirm complete pathologic resolution.
17:18He and his family have
17:19refused. Again, I think having
17:21to do predominantly with his,
17:23multiple medical comorbidities.
17:25But as of now, he
17:26remains without evidence of disease.
17:30So just a little bit
17:32of background of this therapy.
17:34So, in twenty twenty two,
17:36a group at MD Anderson
17:37published,
17:39a phase two,
17:42non randomized
17:43trial in
17:45the New England Journal
17:46where they selected
17:48about twenty or so patients
17:51to
17:52receive samiplimab.
17:54These were for resectable cutaneous
17:56squamous cell carcinomas
17:58squamous cell carcinomas of the
17:59head and neck that were
18:00stage two to four.
18:02And,
18:03they received
18:05neoadjuvant zenlopimab.
18:07They followed them both clinically
18:08and radiographically.
18:10And then they ultimately did
18:11have them all undergo,
18:13biopsy or excision of the
18:15remaining or, remnant lesion.
18:18And what they found was
18:19a pretty remarkable,
18:22response.
18:23The dark green here in
18:24this waterfall plot shows the
18:26number of patients
18:27that had, complete,
18:29pathologic
18:30response. Meaning, they they received
18:32samiplimab, they went to the
18:33operating room, excised the remaining
18:35lesion or what's left or
18:37the scar, and,
18:39quite the majority of them
18:40had complete pathologic response.
18:43And then, you know, more
18:44had major pathologic response, meaning
18:46there's still some tumor remaining.
18:49And, a very small portion
18:51had no kind of pathologic
18:53response and even smaller portion,
18:55patients did not agree to
18:57go to the operating room
18:58for excision.
18:59So this is sort of
19:00the foundation for kind of
19:02the next iteration
19:03of,
19:05what is we're trying to
19:06learn about this this new
19:07medication,
19:09fairly new.
19:10We are have we've just
19:13opened,
19:14as a site for a
19:15multi institutional
19:17trial,
19:19featured or funded by or
19:20sponsored by the NRG,
19:22where patients will be randomized
19:24to receive, neoadjuvant immunotherapy
19:27versus not. And then go
19:29on to receive a response
19:31adapted
19:31treatment modality.
19:33So this is just a
19:33quick diagram of the schema.
19:37Patients will be stratified whether
19:38they're immunosuppressed. And actually this
19:40protocol allows for patients to
19:42be on, if they're on
19:43a low dose of steroids
19:44for other medical issues, they
19:45are still eligible for involvement
19:48in the study.
19:50And then they'll be, and
19:51then also looking at their
19:52nodal disease and then they'll
19:53be randomized
19:54either to arm one or
19:56arm two where arm one
19:57is the standard of care
19:58surgery,
19:59being the standard of care
20:00for these cutaneous malignancies
20:02followed by adjuvant radiation is
20:04indicated from the final pathology.
20:06The second arm or the
20:10study arm is
20:11receipt of neoadjuvant salmiplumab.
20:13And then
20:15patients undergo what's been described
20:17as a response adapted oncologic
20:19surgery,
20:21meaning
20:22a surgery that is
20:25reflective of the response that
20:26patients have had to treatment.
20:28And so for the gentleman
20:29that I presented,
20:31we wouldn't go in and
20:32do a a wide local
20:33excision, total parotidectomy,
20:36you know, neck dissection reconstruction.
20:38We'd essentially excise the scar.
20:40So wherever there is clinical
20:42evidence of disease, you know,
20:43if he would get a
20:45CT scan before surgery, wherever
20:47there's clinical evidence of disease,
20:49including radiographic, that's what we
20:50would excise.
20:52And then those patients would
20:53go on to receive adjuvant
20:54radiation based on their final
20:55pathology.
20:57And, also additional,
20:59samiplimab.
21:00Of note, if patients have
21:02a complete pathologic response, they
21:04will not receive any additional
21:05samiplimab.
21:08And this is just sort
21:09of a description of what
21:10response adapted oncologic surgery is.
21:12It's controlling for margins, as
21:14we always do.
21:16Gross viable or visible tumor
21:18and any abnormality,
21:20that's seen at the time
21:21of surgery.
21:22We address the nodal basin
21:24based on the baseline imaging.
21:27And then where there's an,
21:29any sort of concern about
21:30function. So in this gentleman,
21:32the facial nerve being at
21:33high risk,
21:35you know, the study encourages
21:37that we not do the
21:38original surgery, which would have
21:40been a potential radical tonsillectomy,
21:42facial nerve sacrifice.
21:43And essentially for this gentleman,
21:45would have looked something like
21:46a wide local excision, possibly
21:47a superficial parotidectomy,
21:49where we would just peel
21:50the the parotid off of
21:51the facial nerve.
21:53So a lot of promise
21:54with this, study and we
21:56are,
21:57opening or if not, have
21:59already opened,
22:00and will start enrolling, very
22:02soon.
22:04But just a quick question
22:05just for both for doctor
22:07Swozier and for doctor Roche.
22:09When you're determining
22:11kind of the margins for
22:12for those, either patients with
22:14us today or providers,
22:17at the community. How are
22:18you determining what you're considering
22:21to be clinically viable disease
22:23besides,
22:24you know, the wealth of
22:25experience that you've accumulated over
22:27the years
22:28about ensuring then that you're
22:30you're getting an adequate resection
22:33and again and how you
22:34think that these responses are
22:35different than sometimes patients who
22:37may have historically been treated
22:39with other modalities that are
22:41not immune therapy.
22:46Kathleen, you wanna take that
22:48one first?
22:49Sure. I would say that
22:51in the,
22:53in the neoadjuvant
22:54setting so using it upfront
22:56in,
22:57high risk cutaneous SCC, this
22:59is pretty novel for us.
23:00So in
23:01most of in most of
23:02those cases, then the patients
23:04have already been sort of
23:05referred to our head and
23:06neck surgery
23:07colleagues for potential wide local
23:09excision afterwards. Right? For for
23:12most micrographic surgery, right, in
23:13that tissue sparing sense,
23:15once we're no longer
23:18in those low risk SCC
23:20types there, you know, we're
23:21thinking more wide local margin
23:22where,
23:24I'm I'm not necessarily gonna
23:25need that MOSE to be
23:27really particular about our margin
23:28or marginal control where we
23:30wanna more take, like, a
23:31wider two, three centimeter
23:33margin around the area when
23:34we're worried about those in
23:35transit
23:37in transit meds. But I
23:39think, you know, I didn't
23:40show an after picture of
23:41my patient, but,
23:43in that case, that patient
23:44did not have had a
23:46complete,
23:47clinical response
23:49to, samiplimab
23:51and
23:52did not have, further surgery
23:54after, similar to doctor Roche's
23:56patient.
23:57But there aren't clear guidelines
23:59of, like, for example, how
24:00many centimeters outside of their
24:02scar,
24:03you would go at this
24:04point.
24:06Right. I mean, the standard,
24:07you know, for surgery being
24:09the first modality of treatment
24:10for these patients, it's generally
24:12a a good centimeter,
24:14kind of in the cutaneous
24:15direction for wide local excisions.
24:19We you know, for deeper
24:20structures, we try to maintain
24:21that as well.
24:24It's often a a conversation
24:26intraoperative conversation about, well, here's
24:29a palpable tumor that's, like,
24:30right up against the facial
24:31nerve. It's not invading the
24:33facial nerve. And so in
24:34those cases, we do try
24:35to spare, you know, preserve
24:37function and spare. You know,
24:39we we kind of
24:40overlook our ideal one centimeter
24:42margin in all directions for
24:43these cases.
24:45And then for the neoadjuvant,
24:47you know, as kind of
24:49what's described in this,
24:51study schema,
24:53I think just the appearance,
24:55we start with just the
24:56appearance. Like, if it looks
24:57like scar, if it's not
24:59friable, if it's not kind
25:00of angry looking, then then
25:02we kind of treat that
25:03as scar.
25:05But I would typically go
25:07about a centimeter outside of
25:08the scar and then, you
25:10know, send that to the
25:11pathologist for real time frozen
25:12section analysis.
25:15All the more, interest and
25:16excitement about the the trial
25:18besides some of these magnificent
25:19responses that we see. So
25:21on that note, doctor Bhatia.
25:25Thank you.
25:26Good evening, everyone, and thank
25:28you for attending this very
25:29timely discourse.
25:31I am a medical oncologist
25:33at Yale, and I treat
25:34my focus is on head,
25:36neck, and skin squamous cell
25:37cancers.
25:39And I will be reviewing
25:40the literature around immune checkpoint
25:42therapy to date in cutaneous
25:44squamous cell cancers.
25:48So I'm just gonna go
25:48ahead and share my slides.
25:50You
25:51can see my screen.
25:57Okay.
25:58So,
26:00oops. Yep. As doctors,
26:03Susie and Roach have already
26:05outlined before me, surgery followed
26:07by radiation for high risk
26:08disease is the mainstay for
26:10treating these locally advanced high
26:12risk tumors.
26:14But despite intensive local therapy,
26:16about thirteen to forty one
26:17percent of these patients can
26:19still go on to develop
26:21either local regional recurrence or
26:22distance spread of disease.
26:25And, additionally, surgery and radiation
26:27can be physically deforming.
26:29It can lead to facial
26:30droop. It can involve loss
26:31of digits.
26:33It can affect speech and
26:34swallow, especially in the head
26:35and neck region.
26:36Many of these tumors occur
26:38in elderly patients as doctor
26:39Roach pointed out, and surgery
26:41can be demanding, if not
26:42impossible
26:43for them.
26:44So, there is or was
26:46a critical unmet need for
26:48effective systemic therapy in this
26:49disease, and there were, actually
26:51no FDA approved treatments,
26:53as recently as until twenty
26:55eighteen.
26:57So simiplamab,
26:58which is something we've been
26:59talking about this evening, is
27:01an anti PD one agent,
27:02and it was approved for
27:04the treatment of locally advanced
27:06unresectable
27:06and distant metastatic cutaneous squamous
27:09cell cancers in twenty eighteen.
27:11And that approval came on
27:13the basis of an early
27:14phase trial. It was a
27:15phase one, two trial,
27:17in about a hundred patients
27:18with locally advanced and metastatic
27:20cohorts.
27:22About fifty percent of patients
27:23had response to treatment in
27:25both these cohorts,
27:28and many of them had
27:29very durable responses.
27:30There was another paper published
27:32subsequent to this one in
27:33the NEJM
27:35with a longer follow-up time,
27:37and in a bigger in
27:38a slightly bigger patient cohort.
27:40And the median duration of
27:41response,
27:42for that cohort for the
27:43entire patient cohort was determined
27:45to be about forty one
27:46months.
27:47So, you know, that kinda
27:48correlates with what we're seeing
27:50clinically with these patients who've
27:51received one year, two years
27:53of systemic treatment,
27:54and many of who were
27:55just following in surveillance
27:57either with or without scar
27:58excision surgery,
28:00and many of them do
28:01stay cancer free for years
28:03afterwards.
28:04Around the same time as,
28:06the simiclumab paper about a
28:08couple years later, keynote six
28:09two nine, which evaluated the
28:11efficacy of pembrolizumab,
28:14another anti PD one agent
28:15in a hundred and five
28:16patient cohort,
28:18also with advanced cutaneous squamous
28:20cell cancers,
28:21showed a response rate of
28:22about thirty five percent, and
28:24that led to, the approval
28:26of pembro in twenty twenty
28:27for this disease.
28:29And more recently in, I
28:31think, about four or five
28:32months ago, casibelumab,
28:34which is a PDL one
28:35inhibitor,
28:36was also approved. So that's
28:38the third agent now, for
28:39people with advanced cutaneous squamous
28:41cell cancers and based on
28:43very similar efficacy data.
28:46So the success of immune
28:48check point agents and advanced
28:49disease,
28:50led to trials being conducted
28:52with these agents in the
28:53curative setting.
28:54And, actually, two key adjuvant,
28:57anti PD one trials,
28:59are gonna be presented at
29:01ASCO next month.
29:02One of them is keynote
29:04six six thirty, which enrolled
29:06five hundred and seventy patients
29:07with high risk locally advanced
29:09cutaneous squamous who first underwent
29:11upfront surgery,
29:13then followed by adjuvant radiation
29:15and were randomized to receive
29:17either pembro or placebo for
29:19a total of one year.
29:20And the primary endpoint was
29:22recurrence free survival.
29:24On the other hand, enrolling
29:26simultaneously
29:27was the c post trial,
29:29which enrolled patients also with
29:31high risk locally advanced disease
29:33who underwent surgery followed by
29:35radiation and were then randomized
29:37to receive simoplumab or placebo
29:39for one year.
29:40And their primary endpoint was,
29:42DFS, disease free survival.
29:45And we don't have the,
29:47official presentations
29:49from these trials. They're gonna
29:50be at ASCO next month,
29:52but there were press releases,
29:54recently for both these studies.
29:57The the keynote six thirty
29:58trial was reported to be
30:00a negative study, by by
30:02Merck, And while the c
30:04post trial, which was by
30:05Regeneron,
30:06was a positive study and
30:07actually demonstrated a sixty eight
30:09percent reduction in the risk
30:10of disease recurrence.
30:12So it will be interesting
30:13next month, to contrast the
30:15patient characteristics,
30:16median time from RT completion
30:18to immune checkpoint therapy,
30:21maybe other clinical and pathologic
30:23factors that may have accounted
30:24for the differences, the stark
30:26differences in outcomes,
30:28using very similar agents and
30:30what seems like a similar
30:31patient population.
30:34And then in twenty twenty
30:35two, as doctor Roach pointed
30:36out, came this paper from,
30:38doctor Neil Gross's group at
30:39MD Anderson.
30:41This was a phase two
30:42trial that explored, samiplimab in
30:44the neoadjuvant
30:45or pre op space,
30:46for patients with locally advanced
30:48receptacle disease.
30:50Seventy nine patients were enrolled,
30:52and they all received, four
30:54doses or twelve weeks of
30:56samiplimab,
30:57and seventy of them underwent
30:58surgery.
31:00About fifty one percent of
31:01the samples, so forty patients,
31:03had a pathologic complete response
31:06and ten additional patients, so
31:07another thirteen percent of the
31:09cohort, had major pathologic response,
31:11which was defined as residual
31:13tumor in less than ten
31:14percent of the surgical specimen.
31:17Post op treatment was at
31:18physician discretion,
31:20and at the eighteen month
31:21follow-up,
31:22paper,
31:23that was published a year
31:24later in twenty twenty three,
31:26half the patients had chosen
31:28or were
31:29recommended by their physician,
31:31observation post op. About a
31:33quarter continued to receive adjuvant
31:35samiplimab,
31:37and only a quarter
31:38received adjuvant radiation.
31:41Importantly,
31:41none of the forty patients
31:43who had a PAT c
31:44r,
31:45and only one of the
31:46ten patients who had a
31:47major pathologic response had recurrence
31:49at that eighteen month time
31:51point,
31:52or by that eighteen month
31:53time point. And the twelve
31:54month disease free survival for
31:56the entire cohort was ninety
31:57two percent.
31:59So very, very encouraging data.
32:02And given our experience with
32:04anti p d one agents
32:05in this disease, perhaps,
32:07the best way to harness
32:08the full potential of these
32:10agents is to administer it
32:11in the neoadjuvant space.
32:14That's the direction the field
32:15is moving in.
32:16The hope is that it
32:17would decrease the recurrence risk,
32:19which,
32:20you know, seems likely with
32:22these agents being effective in
32:23the adjuvant and in the
32:24advanced space,
32:26but more importantly, might actually
32:27decrease the morbidity of surgery,
32:30at least for the majority
32:31of patients who do end
32:32up having a treatment response.
32:34So with that intent, we're
32:36excited to support,
32:37NRG h n zero one
32:39four, which is, very soon
32:40gonna open at Yale.
32:42It will be led by
32:43doctor Roach, and this is
32:44a randomized cooperative group trial
32:46as she pointed out. It
32:48will be offered to patients
32:49with locally advanced cutaneous squamous
32:51at any body site. Patients
32:53will be randomized to receive
32:55either upfront surgery,
32:57followed by adjuvant radiation, which
32:59is the current standard of
33:00care, or neoadjuvant
33:01simoplumab.
33:03It's gonna be similar to
33:04the phase two study design.
33:05So patients will receive four
33:07doses followed by response adaptive
33:09surgery,
33:11adjuvant radiation if indicated, which
33:13at our site we offer
33:14to people with residual disease,
33:16but not necessarily otherwise,
33:19and adjuvant simiplimab,
33:20again, only if there is
33:21residual disease for twenty four
33:23additional weeks. And four hundred
33:25and twenty patients are expected
33:27to be enrolled.
33:29These are the key eligibility
33:31criteria.
33:32So patients should have resectable,
33:34stage three or four cutaneous
33:36squam,
33:37or they could have regional
33:38lymphadenopathy
33:39suspected to be from a
33:40cutaneous primary,
33:42or in transit METs.
33:44Disease should be measurable by
33:46resist.
33:47And importantly, patients with CLL,
33:49so immunosuppressed,
33:51who are not on active
33:52treatment
33:53and with HIV, who are
33:54on, entry retroviral therapy and
33:57with controlled viral loads will
33:59be eligible to enroll.
34:01And that's all I have,
34:03from the Medanquin immunotherapy perspective.
34:06I'm happy to take any
34:07questions.
34:08Thank you.
34:12Doctor
34:14could you comment on how
34:16we think about the use
34:17of checkpoint inhibitors and solid
34:19or organ transplant
34:21recipients? Because,
34:22you know, traditionally, that's been
34:24a was a hard no,
34:25but now,
34:26you know, that's being relooked
34:28at. So I'd be curious
34:29on your perspective of that.
34:31Yeah.
34:32So we're obviously
34:34wary about using immune checkpoint
34:36therapy in solid organ transplant
34:38as well as in allogeneic
34:39stem cell transplant patients because
34:41the risk is of graft
34:42rejection.
34:44There have been retrospective series
34:46that have, tried to assess,
34:48a a risk sort of
34:50like a risk assessment for
34:51these patients, and,
34:53there has been a reported
34:55forty to forty five percent
34:56risk of graft rejection,
34:58with using immunotherapy,
35:00in solid organ transplant recipients.
35:03Having said that, there was
35:05recently a small,
35:06prospective trial. I think it
35:08enrolled eleven or twelve patients
35:10at Dana Farber.
35:12One of the cohorts was
35:13in cutaneous
35:14squam, and it was in
35:15patients who've had renal transplants.
35:19And along and they were
35:21given immunotherapy.
35:23I think it was simiplimab,
35:25along with pulse dose steroids
35:27and an mTOR inhibitor.
35:28And, they did demonstrate a
35:30forty to forty five percent
35:32response rate, so very similar
35:34to what we see in
35:35non immunosuppressed,
35:36non transplanted patients.
35:39And, you know, interestingly, none
35:41of those patients had a
35:42rejection of their graft.
35:45Now are we ready to
35:46translate this into other organ
35:48transplant recipients?
35:50Probably not ready for prime
35:51time yet.
35:53The risks are obviously lower
35:54for renal transplant patients who
35:56have dialysis as a backup,
35:58but not necessarily for other
36:00transplants. So,
36:02you know, we have considered
36:04cautiously using immunotherapy
36:06in renal transplant patients,
36:08but haven't yet, you know,
36:10made that switch to liver,
36:12you know, cardiac lung transplant.
36:14That would just be too
36:15high risk.
36:17Yeah. And then that was
36:18the,
36:19recent study that I was
36:20alluding to, and I think
36:21that, like you said, of
36:22course, the organ matters.
36:24But also the patients who
36:26have that catastrophic carcinomatosis
36:28tend to be those patients
36:29who have cardiac transplant or
36:31higher immune suppression. So Mhmm.
36:34But I think being able
36:35to consider it for patients
36:37who have renal transplant,
36:38is where we're moving, it
36:40seems.
36:41Yes. Exactly.
36:44I think to add along
36:45those points, too, we always
36:46just try to work with
36:48the transplant
36:50physician about minimizing their immunosuppression
36:52as well because that in
36:53and of itself sometimes
36:55can help reactivate,
36:56reinvigorate the immune system to
36:58provide a clinical response
37:01particularly in these earlier stage
37:02squamous cell carcinomas
37:04to try to avoid all
37:06systemic therapy altogether.
37:10That's a great point.
37:11Again, our our q and
37:12a is open if if
37:14anyone in the audience wants
37:15to, send us any chats.
37:18We keep asking each other
37:19very hard questions so someone
37:20someone needs to help us
37:21save us from ourselves.
37:24On on that note,
37:26doctor doctor Tran will begin,
37:29our, segue into the world
37:31of melanoma.
37:33Alright. So just building upon
37:35already kind of the excellent
37:36response data that we've already
37:38seen from our colleagues here
37:39in cutaneous gramisocarcinomas.
37:41I I think the next
37:42set of questions that Doctor.
37:43Alina and I will discuss
37:45are basically how to select
37:47the populations that would benefit
37:48the most
37:49while minimizing
37:50overtreatment
37:52and toxicity
37:53from the systemic immunotherapies.
37:55And while our colleagues have
37:57eloquently reviewed kind of cutaneous
37:58gramin cell carcinomas, Doctor. Lina
38:00and I will kind of
38:01focus now
38:02specifically on melanomas.
38:04And so whenever we think
38:06about
38:07utilizing systemic therapy for a
38:09disease that's surgically
38:11technically curative, although may be
38:12morbid,
38:13we have to stop and
38:15ask the question about risk
38:16and benefit ratio
38:18per the patient. You know,
38:19what is in the patient's
38:21best interest, the individual in
38:22front of us? So as
38:24with their a lot of
38:25other main therapies,
38:27irreversible toxicities,
38:29as you all know, can
38:30occur,
38:31which can be life altering.
38:33So to give someone a
38:35permanent endocrinopathy
38:37or even more severe toxicity
38:39such as myocarditis,
38:41in something that is potentially
38:43just curative with surgery alone,
38:45that can be particularly devastating.
38:49So generally, we're able to
38:50accept more of a risk
38:52profile when we think about
38:53treating more aggressive cancers or
38:55recurrent cancers in the hopes
38:56that we can kind of
38:57balance out the side effect
38:59ratios to avoid impacting an
39:01individual's quality of life.
39:04And so there are a
39:05lot of factors that get
39:06integrated into how we approach
39:07and treat skin cancers.
39:10Even for melanoma, certain types
39:11are much more responsive to
39:13immunotherapy
39:14than others.
39:15For example, kind of one
39:16of our classic scenarios is
39:18desmoplastic
39:19melanomas of the head and
39:20neck. Those are particularly even
39:22more responsive to single agent
39:24immune therapeutics, and sometimes that's
39:26all patients need,
39:28versus things that are more
39:29refractory that don't carry the
39:31typical UV induced mutational signature.
39:33So things like mucosal April
39:35melanomas.
39:37Additionally, there is other risk
39:38factors, including
39:40where the mass is, you
39:41know, is it a large
39:42axillary mass that's pressing on
39:44the brachial plexus
39:46that could potentially lead to
39:47loss of function and over
39:48the next few months,
39:50where we need rapid cytoreduction
40:05the lytic virus therapy is
40:07already approved. I mean, checkpoint
40:08inhibitors, we all know about.
40:10Adoptive T cell transfer therapies
40:13have also now been FDA
40:14approved.
40:15And under investigation
40:17currently are cancer vaccine therapies,
40:19in which we'll discuss
40:29classically high dose IL-two is
40:30fairly toxic. How can we
40:32kind of redesign these cytokine
40:34drugs to make them more
40:35tolerable,
40:36while maintaining efficacy.
40:40And so because these treatments
40:42can be quite effective in
40:43melanoma, the next question is
40:45how can we optimize sort
40:46of the sequencing of these
40:48therapies
40:49to maximize
40:50response and also durability of
40:52response?
40:53So when we think about
40:55melanoma, we like to talk
40:56about melanoma
40:58specific
40:58survival.
41:00And then over on the
41:01right here is the table
41:02by stage of the five
41:04year and ten year
41:05melanoma specific survival. And as
41:07you can see, most of
41:08this data correlates.
41:10You know, individuals with lower
41:12risk, lower stage melanomas
41:14have improved survival overall.
41:16And generally, in the higher
41:17risk,
41:18melanomas, so those that are
41:20stage IIBs and beyond,
41:22the five and ten year
41:23overall
41:24melanoma survival
41:26can be between,
41:27the low 80s to twenty
41:29four percent.
41:30This is also kind of
41:31with exception of the stage
41:33three a population,
41:35which actually
41:36performs better than a standard
41:38two b or two c.
41:42So what we wanna do
41:43is now that we have
41:44these adjuvant therapies approved for
41:46high risk melanomas,
41:49now we're trying to kind
41:50of hone in on the
41:51subpopulation
41:53that would potentially benefit for
41:54new adjuvant consideration.
41:57And the rationale is that,
41:59you know, for a long
42:00time, there was very little
42:02to offer for individuals with
42:03metastatic melanoma.
42:06It's really been over the
42:08past twenty years that we've
42:09seen
42:10a vast proliferation
42:12of available
42:13therapeutics,
42:14both immune checkpoint inhibitors,
42:16but also targeted therapy,
42:19and T cell therapies that
42:21have been approved.
42:22And it's kind of like
42:24a trickle down effect. If
42:25you have a medication
42:26that works so well in
42:27individuals with metastatic disease,
42:30how can we move and
42:31make these therapies available for
42:33individuals at higher risk for
42:34recurrence to try to prevent
42:36relapse in the future?
42:38And so, as a consequence
42:40to that, a lot of
42:41these same medications have then
42:43since been approved for adjuvant
42:44therapy.
42:45And so now the real
42:46question is, you know, how
42:48can we further optimize on
42:49this? Because
42:50there are still real limitations
42:53of adjuvant treatment.
42:55So, for stage two melanoma,
42:58so high risk stage twos,
42:59these are the two Bs
43:00and two Cs,
43:01There's two separate clinical trials,
43:04phase three studies, the CheckMate
43:06seven sixty,
43:08I'm sorry, seven,
43:10seventy six ks and keynote
43:12seven sixteen
43:13that had led to the
43:14approval of nivolumab and pembrolizumab
43:14respectively. And as you can
43:15see, based on these early
43:17respectively.
43:18As you can see, based
43:19on these early readouts from
43:22these studies,
43:23there is a slight improvement
43:24in recurrence free survival and
43:27metastatic
43:27distant,
43:28free disease for survival,
43:31but there really is no
43:32data on overall survival.
43:36When we think about stage,
43:38three melanomas,
43:39so these are kind of
43:41three
43:42a's in some studies, primarily
43:44three b's and beyond in
43:45most other studies,
43:47looking at
43:49first initially like does ipilimumab
43:51work? Yes. The answer is
43:52yes. But with significant toxicity
43:54in some studies,
43:56forty one percent depending on
43:58the dose. If you give
43:59ten of epi, then it
44:00can be as high as
44:02fifty eight percent with grade
44:03three toxicities.
44:04And really also, you're still
44:06not seeing a terrible significant
44:08improvement in overall survival.
44:11With CheckMate twothirty
44:13eight,
44:14which compared ipi versus nivo,
44:16Clearly, ipi was less toxic,
44:18fourteen point four percent compared
44:20to forty five point nine
44:22percent.
44:23But, again, really no clear
44:25difference in overall survival between
44:27these two groups.
44:28And then with the
44:30approval of pembrolizumab
44:32two
44:33and candidate
44:34zero fifty four,
44:36again, really no reported overall
44:39survival difference,
44:41but,
44:41slight, you know, increase in
44:43toxicity with even single agent
44:45pembrolizumab.
44:48Combi AD, I just included
44:50here, but it's actually a
44:51targeted therapy,
44:53for individuals who have a
44:54BRAF e six hundred e,
44:56E or K mutation.
44:58This was really the only
44:59study that demonstrated
45:01a trend towards an improvement
45:03in overall survival. And this
45:05is the latest eight year
45:06updated data,
45:08whereby with all the preexisting
45:10adjuvant immune therapy options,
45:13improvement.
45:15And then also just
45:17as a side here, ongoing
45:19clinical trial of an adjuvant
45:21mRNA
45:22vaccine. So this is a
45:23personalized mRNA vaccine that encodes
45:26up to thirty four different
45:27neoantigens
45:28associated with an individual's tumor
45:31that's given in combination with
45:32pembrolizumab
45:33versus pembrolizumab
45:35alone.
45:37Again, there's some improvement in
45:39relapse free survival
45:41and distant metastasis
45:42free survival.
45:43There's still no clear OS
45:45data that has yet to
45:46be reported,
45:48and hopefully updates will be
45:49forthcoming.
45:51And so all of these
45:53prior therapies have really focused
45:55on, you know, this paradigm
45:56of, okay, let's get this
45:58tumor out and then let's
46:00determine whether or not this
46:01patient
46:02can get additional immune therapy
46:04versus targeted therapy if they
46:06have a BRAF mutation.
46:08And again, a lot of
46:09these studies with adjuvant immune
46:11therapies have demonstrated no improvement
46:13in overall survival, which is
46:15our gold standard
46:16for how we want to
46:17measure
46:19significant improvements in patients' outcome
46:21over time.
46:22So the new shift is
46:24trying to evaluate whether we
46:26can utilize some of these
46:27therapies upfront,
46:28sort of like that mRNA
46:30vaccine study whereby
46:32instead of a very costly
46:34and expensive way to reintroduce
46:36tumor antigens
46:37in the context of concurrent
46:39immune therapy,
46:40basically to use the patient's
46:42in situ tumor
46:43to reinvigorate
46:44and restimulate the immune system
46:46with the added neoadjuvant immune
46:48therapy,
46:50and determine whether that improves
46:52response.
46:54So basically giving patients treatment
46:56upfront followed by surgery
46:58and then kind of a
46:59risk stratification
47:00whether that patient needs any
47:02additional therapy based on pathologic
47:04response.
47:07And so I'll hand it
47:08over to Doctor. Alino to
47:10lead the next section of
47:11the discussion.
47:13Again, just to reiterate some
47:14of the points brought up
47:15earlier. So
47:17why would we shift from
47:18the adjuvant
47:19paradigm that served us so
47:21well to this neo adjuvant
47:23paradigm? So
47:25one is we can actually
47:27now determine responses to therapy.
47:29So if we're going to
47:30do something different, some of
47:31these conditional trials,
47:33it's really valuable information.
47:36What began with kind of,
47:37I think, you know, biomarker
47:39driven studies, I think, was
47:40really surprising what people found
47:42even during some of our
47:44early new adjuvant studies in
47:45melanoma.
47:47In some cases, it can
47:48actually markedly reduce the size
47:50of a tumor before surgery,
47:51although we don't begin with
47:52that as our expectation.
47:55And if you look kind
47:56of at the tumor immunology
47:57or true immune system level,
48:00there's a lot of thought
48:01that if you have a
48:02tumor in place, you're gonna
48:04have a greater chance to
48:05be encountering different types of
48:07parts of that tumor. We
48:08call those tumor antigens
48:10that then may be useful
48:12to prevent recurrence later.
48:14It's also
48:15thought that we may have
48:16those T cells
48:18better activated and actually having
48:20them lasting longer and leading
48:22to better memory response is
48:24the same reason why when
48:25you get your measles vaccine
48:27that you're, you know, you
48:28get a booster, but you
48:30won't get measles. Right. So
48:31having that memory in your
48:33immune system is really key
48:34and really the holy grail
48:36for a lot of us
48:37in cancer treatments.
48:39And the thing that becomes
48:40really incredibly
48:42unique is much of what
48:43we study in oncology
48:45is based upon our failures.
48:48When we actually combine these
48:50neoadjuvant approaches and then combine
48:52them actually with surgical resection,
48:54we can actually learn from
48:55our successes.
48:57What happens in this circumstance
48:58that this patient actually had
49:00a great response? We have
49:01tumor tissue available for that.
49:03So it actually
49:05globally also helps us advance
49:07the field. Next.
49:10And this is a cartoon
49:11rendition of some of those
49:13principles. In the upper left,
49:14you can see kind of
49:15what our old paradigm was.
49:16You send the person to
49:18to myself, doctor Swozi, doctor
49:20Roche, and, you know, a
49:22surgeon removes the tumor lesion,
49:24but what's left behind is
49:25quite minimal. So the thought
49:27is, what are we mounting
49:28that immune
49:29response against? Where is the
49:30tumor that we're supposed to
49:32where's the antigen?
49:33What is the immune system
49:34there to recognize and attack?
49:36However, if we leave that
49:37in the bottom panel,
49:39maybe we'll activate more t
49:41cells. Maybe we'll give ourselves
49:42a better opportunity.
49:44Then the surgeon goes in,
49:45removes the tumor, and what's
49:47left behind, we're hoping, is
49:49a greater
49:50diverse pool.
49:51And, again, when the immune
49:53system at these earlier nodal
49:55stages before the body is
49:57ravaged by multiple metastatic sites
49:59that we usually are studying
50:00our patients in,
50:02you know, we'll have less
50:03dysfunctional
50:04cells around. So maybe, again,
50:07we can have that investment
50:08upfront
50:09and actually have durable, curative
50:11responses
50:12that may actually truly have
50:14a long term survival benefit.
50:15We're not there, but that's
50:16the hope and the rationale.
50:18Next.
50:21So why did we think
50:22that? Well, historically,
50:23you know, if you flip
50:25things around, when you have
50:26effective treatments
50:28and then you give a
50:28patient
50:29to a surgeon and you
50:30say, take out this area
50:32that's not responding.
50:34Those patients you can see
50:35here with the with the
50:37use of adjuvant surgery
50:39and doing a metastaticomy
50:40following systemic immunotherapy. This is
50:42some data from Danielle Bella,
50:44who's a Yale graduate, unfortunately
50:45went to Memorial, but She's
50:47wonderful. You know, our data
50:48at Yale, if you look
50:49at the data from Duke,
50:50if you look at all
50:51of our institutions, we're seeing
50:52the same thing. So if
50:54we're consolidating
50:55patients with systemic immune therapy
50:57and then going out and
50:58removing the tumor
51:00in those folks that are
51:01responding that we can get
51:02them to very limited disease.
51:04These patients are doing quite
51:05well, and we're separating that
51:07biology
51:08actually from those folks that
51:09are having
51:10multiple areas of progression where
51:12maybe surgery is not the
51:14the ideal, but we've identified
51:16those patients and perhaps spared
51:17them from an operation.
51:19Next.
51:21So, again,
51:22I'd like to people to
51:24think about there's a big
51:25difference in when we're comparing
51:27with who these patients are.
51:29So if you look at
51:30people if we look at
51:31our historical outcomes in patients
51:33who present with clinically apparent
51:36nodal disease,
51:37still stage three, but these
51:38are not the patients that
51:39were doing a central node
51:41biopsy and detecting microscopic disease.
51:43This is a much different
51:45patient population.
51:46Right? So this is, again,
51:47historical before our advent of
51:49immune therapy. But even having
51:51one clinically enlarged nose, when
51:54you're looking at that survival,
51:55right,
51:56forty percent is not ideal.
51:59Four lots of nodes in
52:00that basin, right, that is
52:01almost that is the equivalent
52:03of what we see many
52:04times from metastatic
52:05disease. And the same thing
52:07for some of our thicker
52:08tumors. So, again, we have
52:09to make sure when we're
52:10looking at these patients that
52:11we're looking at the correct
52:13patient population. These are not
52:14the same stage threes,
52:16even though they may fall
52:18into the same category
52:19on our card there on
52:20the right when they're presenting
52:22that way to us in
52:23our clinics. Next.
52:26So a lot of those
52:27initial works were done with
52:29small trials, and we've kind
52:30of I've divided this table
52:32into some different sections. So
52:33if we look at the
52:34anti PD-one monotherapy, again, some
52:36early trials that were done
52:37just to get a semblance
52:38of safety And, actually, as
52:40I said, really biomarker
52:41driven. The biggest one was
52:43the,
52:44the the phase two trial
52:45done, the swag eighteen o
52:47one. I'll highlight that in
52:48a little bit. But that
52:49was giving patients, you know,
52:51a sandwich approach. You get
52:52three cycles of neoadjuvant
52:54therapy,
52:55and then you have surgery,
52:57and then you're still gonna
52:58continue to get adjuvant therapy.
52:59And they compared that to
53:00our typical paradigm, which was
53:02upfront surgery for these patients
53:04with clinically apparent nodal disease
53:06or resectable stage four disease,
53:08enrolled, you know, over three
53:10hundred patients.
53:12Again,
53:12things to highlight the pathologic
53:14response in those patients who
53:15got the neoadjuvant
53:17therapy was only about twenty
53:19percent,
53:21but they only had about
53:23a twelve to fourteen percent
53:24toxicity. So that neoadjuvant
53:26group really wasn't harmed any
53:28more than they would have,
53:29and that's kind of our
53:30typical acceptable rates of what
53:31we would see with monotherapy.
53:34Again,
53:35OPDUALAG, that's the anti PD
53:37one, LAG three dual therapy,
53:38a very small trial.
53:40Regeneron has a bigger trial
53:41that we're we're working towards
53:43opening here at Yale. Again,
53:44looking to see, again, a
53:46doublet therapy in the neoadjuvant
53:48setting. Again, a small setting.
53:50Again, seeing overall response rates,
53:52much higher path response rates
53:54that over fifty percent,
53:56but with the
53:58almost twice the the toxicity
54:00about twenty six percent when
54:01we look at grade three
54:03and four. And again, those
54:04patients got,
54:05a couple of months upfront
54:07of treatment.
54:08Next.
54:09Now a lot of the
54:10initial work and ongoing work
54:13has been really done with
54:14the combination
54:15of anti PD one with
54:17anti CTLA four.
54:18Most of that beginning and
54:20building upon the APOCEN and
54:21then the APOCEN NEO trial,
54:24which began with small numbers.
54:26The APISEN NEO trial highlight
54:27in a moment really tried
54:28to say, well, where is
54:29where does our Goldilocks dose?
54:32Where do we get the
54:33most amount of response with
54:35the least amount of toxicity?
54:37We'll also highlight the PRADA
54:39trial that tries to look
54:40at things similarly to what
54:41many may be accustomed to
54:43with breast cancer surgery, where
54:44we're giving neoadjuvant treatment. We're
54:46testing the nodes and then
54:48saying, do we have to
54:49do more node surgery? That's
54:50not quite ready for prime
54:51time, but that's something people
54:53are gonna be hearing more
54:53and more about. And then
54:55the other study to highlight
54:56is the Nadina trial, which
54:58is our largest trial done
54:59in the neoadjuvant setting using
55:01doublet therapy that for many
55:03people,
55:04has led to practice
55:06changing patterns worldwide.
55:11So for PD one monotherapy,
55:12again, the swag eighteen o
55:14one, the sandwich approach, either
55:16you're gonna have your surgery
55:17up front followed by your
55:18adjuvant standard of care, or
55:20you're gonna get three cycles
55:21of PD one, and then
55:22you're gonna have your surgery.
55:23And again, this trial was
55:24designed that no matter what
55:26your response was, you were
55:27going to then continue to
55:28get adjuvant therapy. Now a
55:30couple of things for this
55:31trial, again, in the neoadjuvant
55:33setting, sometimes your endpoints have
55:35to be a little bit
55:36different because you have to
55:37take into account if someone
55:38gets a toxicity, the preclusion
55:40from surgery, do they progress
55:41in the time period before
55:43surgery? So they had to
55:44create a composite
55:45called an event free survival.
55:47So not a recurrence free
55:49survival,
55:50not overall survival, not melanoma
55:52specific survival. But again, if
55:53you look at this at
55:54least superficially, you could see
55:55those those are curves that
55:56are quite far apart from
55:58each other.
55:59And in follow-up, they've actually
56:00maintained that separation.
56:02But again, if you look
56:03at the patients themselves,
56:05for patients who potentially had
56:07curable, resectable disease, you knew
56:09about twelve out of a
56:10hundred and fifty four of
56:11those patients, you had to
56:13have a very difficult conversation
56:15that none of us love
56:16to have, which is with
56:17this therapy,
56:18you're no longer a surgical
56:20candidate. And most of that
56:21was actually due to local
56:23and not actually distant metastatic
56:25progression. But that's, you know,
56:26one of the things that
56:27becomes important and maybe
56:29better judged and said, you
56:30know, maybe that person
56:31didn't need that operation anyway.
56:33So, again, you can look
56:34at it both sides of
56:35the coin. Next.
56:39Now, again, the office in
56:40the trial was one of
56:41the first doublet treatments that
56:42had come out. And, again,
56:43this was the Goldilocks trial.
56:45How do you determine
56:48in a group of patients
56:49who, again, could be cured
56:50with surgery, only experience about
56:52fifteen percent toxicity in the
56:54adjutant setting, how do we
56:56pick the right dose to
56:57get the most amount of
56:58a response
56:59and then use that information
57:02for
57:04decision making?
57:05So in this case, if
57:06you look at the treatment
57:07r and b, that became
57:09kind of our Goldilocks dose.
57:11That was Nivo three ipi
57:12one, which again first for
57:14systemic treatment is for many
57:16people, the preferred option of
57:17doing doublet where you have
57:19the benefit of having the
57:20ipilimumab,
57:21but at the lower dose
57:23where we have less toxicity
57:25and those the opposite neo
57:27when that's been updated,
57:28those responses have been quite
57:30durable.
57:33Next. Now, again, an an
57:35idea of, you know, how
57:36do we
57:37deescalate
57:38surgery? So, again, following a
57:41paradigm similar to what was
57:42seen in breast cancer, again,
57:44you had patients these are
57:45just three b and c,
57:46so not heavy nodal burden
57:48disease. Three d's were not
57:49included in here. And, again,
57:51the patients got the best
57:52dose, the Goldilocks dose of
57:54ipi one nivo three
57:56and got their cycles. And
57:57then instead of doing as
57:59an opposite NEO and when
58:00we talk about the NEDENA
58:01trial, a full completion nodal
58:03dissection,
58:04a fiducial was placed and
58:06just that fiducial marked
58:08lymph node removed,
58:10leaving everything in the rest
58:11of the nodal basin. And
58:12in this study, then they
58:13said, okay. Based upon that
58:15one lymph node, we're going
58:17to commit to making treatment
58:18decisions. So if you had
58:20a complete or near
58:22pathologic response,
58:24you did not then undergo
58:25a therapeutic node dissection again
58:27similar to the paradigm that
58:28we have in breast cancer.
58:30And also you didn't get
58:31additional systemic treatment.
58:34For the pathologic response, you've
58:35got a therapeutic node dissection.
58:37Those patients then,
58:39if they had no distant
58:40disease were observed, if there
58:41was greater than fifty percent
58:43of those non responders, they
58:44then got a therapeutic node
58:46dissection
58:47and then went on to
58:48have,
58:49the investigator have a choice
58:51about what adjuvant treatment then
58:53they wanted to give.
58:55Next.
58:57So, again, if if one
58:58looks and this is some
58:59of the earlier information, the
59:00updates have not come out
59:02yet,
59:03but there were about sixty
59:05patients out of the ninety
59:06that did have a complete
59:08response, and they had a
59:09ninety eight percent distant metastasis
59:11free survival. Again, none of
59:13them had adjuvant treatment. Less
59:15of a number had just
59:16partial responses,
59:18but their recurrence free survival
59:20was less as well as
59:21their distant metastasis free survival.
59:22So, again, identified a different
59:24patient population here. And the
59:26same thing with those patients
59:27who were non responders.
59:29Next.
59:31So
59:32the largest trial by far
59:33that's been done and again,
59:35the one that many of
59:36us feel has been paradigm
59:37shifting is the NEDENA trial.
59:39So this was a phase
59:40three trial again using the
59:42same
59:43ipilimumab
59:44one mg per kg with
59:45enivolumab three mg per kg
59:47dose.
59:48And
59:49this was
59:51randomized
59:52where
59:53patients either got upfront nodal
59:55dissection and then got adjuvant
59:57therapy
59:58Oregon had a conditional
60:00treatment based upon
01:00:02their pathologic
01:00:03response
01:00:04following
01:00:05surgery.
01:00:12The primary endpoint was event
01:00:14free survival. Again, a composite
01:00:16score and secondary endpoints included
01:00:18overall recurrence free survival, distant
01:00:20metastasis free survival, the pathologic
01:00:22response, adverse events and quality
01:00:24of life, which was also
01:00:25important for this patient cohort.
01:00:27Next.
01:00:29So you can see in
01:00:30the upper left, if we
01:00:31look at
01:00:34our neoadjuvant versus adjuvant
01:00:36curves,
01:00:37you know, for
01:00:39recurrence free survival.
01:00:41Again, those event I'm sorry,
01:00:43event free survival. Again, you
01:00:44see a similar separation of
01:00:45curves that you did see
01:00:46for the swag eighteen o
01:00:47one trial. If you look
01:00:48at the the left lower
01:00:50area again, if you actually
01:00:52stratify them by pathologic response,
01:00:54those patients with major pathologic
01:00:56response who are then just
01:00:57observed,
01:00:59you know, those are
01:01:01it's, you know,
01:01:02spectacular,
01:01:04you know, greater than ninety
01:01:05percent of those patients having
01:01:07durable,
01:01:08recurrence free survival benefit, not
01:01:11recurring. And those curves actually
01:01:12draw them out now a
01:01:14couple of years out and
01:01:15those curves has maintained themselves.
01:01:17The partial pathologic response patient,
01:01:19again, we're seeing seventy, seventy
01:01:21six percent
01:01:23recurrence free survival.
01:01:24But again, those patients who
01:01:26are not pathologic responders,
01:01:28these are a different patient
01:01:29population. We have to think
01:01:31of them differently. Those are
01:01:32patients you're gonna highlight for
01:01:34maybe early clinical
01:01:35trials. Those are not your
01:01:37immune therapy responders.
01:01:39And again, just the two
01:01:39panels on the right shows
01:01:41that, you know, we saw
01:01:42similar,
01:01:43responses
01:01:44to the new adjuvant treatment
01:01:46regardless of your BRAF mutation
01:01:48status.
01:01:49Next.
01:01:50This is just,
01:01:52a smaller trial too that
01:01:53really then pushed the limits
01:01:55a little bit more and
01:01:55said, what if we combine,
01:01:58targeted therapy with,
01:02:00neoadjuvant
01:02:01immune therapy? Again, a smaller
01:02:03study, just a total of
01:02:04thirty patients.
01:02:05And what you can see
01:02:06is, you know, not surprisingly,
01:02:09if you combine patients who
01:02:10have,
01:02:11BRAF mutations, so v six
01:02:13hundred e mutant folks, if
01:02:15you combine immune therapy along
01:02:17with targeted therapy, you're going
01:02:18to have more pathologic
01:02:20responses,
01:02:21that did come at the
01:02:22cost of toxicity
01:02:24compared to your BRAF mutant
01:02:25patients, where you really didn't
01:02:26see, in my mind, any
01:02:28additional benefit of adding one
01:02:30of your targeted therapies
01:02:32to your,
01:02:34your monotherapy with immune
01:02:37treatment. So, again, only seeing
01:02:38about
01:02:42thirteen percent of your patients
01:02:43having a pathologic response rate.
01:02:45So I think you could
01:02:46probably, on the basis, even
01:02:47though it's a small trial
01:02:49for your BRAF wild type
01:02:50patients, really not add that
01:02:52selection in,
01:02:54as a choice. But again,
01:02:55if you really needed to
01:02:57have a patient with super
01:02:58bulky
01:02:59disease,
01:03:00you
01:03:01did see really some really
01:03:02impressive early responses in this
01:03:04trial for patients. Next.
01:03:08All right. So thank you,
01:03:10Doctor. Alina. So we're just
01:03:11going to highlight a few
01:03:13examples of where new adjuvant
01:03:15therapy has led to, you
01:03:16know, good responses, but maybe
01:03:18also kind of mitigated by
01:03:20toxicity. So
01:03:21the first example I wanted
01:03:23to highlight was
01:03:24a lady with a right
01:03:26abdominal melanoma that arose from
01:03:28a congenital mole. So she
01:03:30presented to see Doctor. Alino
01:03:32and myself with a bulky
01:03:34right axillary
01:03:35lymph node,
01:03:37which we which was a
01:03:39stage three b.
01:03:41No other distant metastatic disease,
01:03:43fortunately.
01:03:44She did have a BRAF
01:03:45B600E
01:03:46mutation.
01:03:47And so what we did
01:03:48was given the size of
01:03:50that lymph node and also
01:03:52additional concurrent medical core morbidity
01:03:54such as just optimizing her
01:03:56cardiac performance status, given a
01:03:58history of CHF
01:03:59and a concurrent diagnosis of
01:04:01an early stage endometrial
01:04:03adenocarcinoma,
01:04:06We offer her new adjuvant
01:04:07nimvolumab.
01:04:09So she got two doses,
01:04:10had a fantastic clinical response
01:04:13in that right axillary lymph
01:04:14node but then developed myocarditis,
01:04:16was hospitalized for that.
01:04:18Troponin's in the hundreds.
01:04:21She was given large doses
01:04:23of Solumedrol
01:04:25followed by cardiac oncology,
01:04:27eventually had to be,
01:04:29you know, given Cellcept and
01:04:31tofacitinib
01:04:32as well.
01:04:34However, given
01:04:36improvement in her myocarditis
01:04:38and stability of that right
01:04:40axillary lymph node, she eventually
01:04:42was able to make it
01:04:43to surgery. And so these
01:04:44are just,
01:04:45CT scans
01:04:46at baseline showing that large
01:04:48right axillary lymph node, probably
01:04:51representing
01:04:52a group of matted lymph
01:04:53nodes in that area. And
01:04:54after just two doses,
01:04:57about a greater than fifty
01:04:58percent reduction in the mass
01:05:00of that lymph node.
01:05:03You know, ideally, we would
01:05:05have taken to her to
01:05:06surgery, you know, if we
01:05:07were going by the swag
01:05:09eighteen o one trial after
01:05:10that third dose of anti
01:05:11PD one.
01:05:13However, given her myocarditis
01:05:15and the fact that that
01:05:16left right axillary lymph node
01:05:18had been stable
01:05:19while despite all the immunosuppression
01:05:21she got for treating her
01:05:22myocarditis,
01:05:24we kind of held study,
01:05:25you know, and made a
01:05:27judgment call to do this
01:05:28as safely as possible.
01:05:30So
01:05:31eventually, she was able to
01:05:33get surgery,
01:05:34about
01:05:35six, seven months after
01:05:38her last dose of anti
01:05:39PD one.
01:05:41And throughout this entire time,
01:05:42her CT scans had been
01:05:44stable,
01:05:45and her immunosuppression
01:05:46was,
01:05:47weaned down significantly.
01:05:49But when Doctor. Alina went
01:05:51in to remove that lymph
01:05:52node, what she found was
01:05:55mainly necrotic tissue, lots of
01:05:57lymphocytes,
01:05:59that were holding any viable
01:06:01melanoma towards the center of
01:06:03that lymph node. Unfortunately,
01:06:05she did not have a
01:06:06major pathologic response. There was
01:06:08still some viable melanoma
01:06:10at the core.
01:06:12And so subsequently given her
01:06:14BRAF mutation, we kind
01:06:16of then,
01:06:18determined, you know, it was
01:06:19gonna be probably best to
01:06:21treat her with an additional
01:06:23year of adjuvant
01:06:24BRAF MEK inhibitors,
01:06:26given the fact that she
01:06:27would be ineligible
01:06:29to receive any further immune
01:06:30checkpoint therapy in the future
01:06:32given her myocarditis.
01:06:34So
01:06:35despite she completed a year
01:06:36of adjuvant, arafniv, trametinib.
01:06:39And despite this, after two
01:06:40years, her scans remain
01:06:42negative.
01:06:44So, again, great response,
01:06:46but we paid a price
01:06:47for that.
01:06:49The second case example I
01:06:50wanted to highlight,
01:06:52follows more closely the NEDENA
01:06:54trial.
01:06:55So here and we tried
01:06:57ipi one and nivo three
01:06:58instead.
01:06:59So this is a gentleman
01:07:00with cutaneous
01:07:02melanoma of the scalp, and
01:07:03you can see his picture
01:07:04at baseline
01:07:05with those multiple in transit
01:07:07lesions adjacent to that. He
01:07:09actually had a third one
01:07:10that was biopsied to demonstrate
01:07:12and verify in transit metastases.
01:07:15He also did have a
01:07:16BRAFV600E
01:07:17mutation.
01:07:19So he received
01:07:20two cycles of ipi one
01:07:22nivo three,
01:07:24and then given his fantastic
01:07:26clinical response, and as you
01:07:28can see, after two cycles,
01:07:29that lesion really flattened out.
01:07:31It was not
01:07:33nodular
01:07:34any longer.
01:07:35He actually opted to delay
01:07:37surgery
01:07:38a little bit. And so
01:07:40we gave him additional doses
01:07:42of nivolumab.
01:07:43And eventually, when he decided
01:07:45he was ready for surgery,
01:07:47because he didn't want any
01:07:48downtime from any post lock
01:07:50healing given his work schedule,
01:07:52it showed a pathologic
01:07:54complete response. And so,
01:07:56further immunotherapy
01:07:58was stopped and he's been
01:07:59monitored with just surveillance,
01:08:02continues to be NAD
01:08:04on on clinical examine and
01:08:06restaging scans.
01:08:10So in conclusion,
01:08:11you know, neo adjuvant immune
01:08:12therapy,
01:08:14has really
01:08:15shifted the paradigm for care,
01:08:17particularly with the NEDENA trial,
01:08:18which was a large phase
01:08:19three study,
01:08:21kind of advocating for improved
01:08:23responses with doublet therapy for
01:08:24individuals with macroscopic
01:08:26stage,
01:08:273b and above disease.
01:08:30There's ongoing clinical interest in
01:08:32trying to improve this treatment
01:08:34paradigm, maybe make it less
01:08:36toxic. And as Doctor. Alluded
01:08:37to kind of that Goldilocks
01:08:39approach, trying to find the
01:08:40right regimen, the right dose
01:08:42with the while trying to
01:08:44all the time minimize any
01:08:45toxicity.
01:08:48You know, a lot of
01:08:49times when we have individuals
01:08:51presenting with bulky disease,
01:08:53disease that could
01:08:55present as functionally limiting disease.
01:08:58We oftentimes, you know, will
01:09:00try an adena style approach,
01:09:01but then it's very good
01:09:04to have our surgeons on
01:09:05hand as well because if
01:09:06things do not clinically shrink,
01:09:08we can always
01:09:09abort and proceed to surgery
01:09:11sooner before there is any
01:09:13compromise of function,
01:09:15or any further growth in
01:09:17the disease.
01:09:19And it'll be interesting with
01:09:20our ongoing vaccine trials too
01:09:22whether
01:09:23any,
01:09:24adjuvant vaccine is gonna be
01:09:26better than kind of leaving
01:09:27the tumor in situ for,
01:09:29again, trying to immunize and
01:09:31promote,
01:09:32T cell responses to those
01:09:34tumor neoantigens.
01:09:37So
01:09:38on go there's a lot
01:09:39of ongoing research, a lot
01:09:41of development of new targets,
01:09:43and therapeutic strategies,
01:09:45in addition to kind of
01:09:46playing with the sequencing of
01:09:48all these effective immune therapies
01:09:49to try to improve responses.
01:09:51And ultimately
01:09:53our endgame that improvement in
01:09:55overall survival for our patients.
01:09:57So that being said, I
01:09:59think, any closing remarks, Doctor.
01:10:01Alino? Otherwise, we'll open it
01:10:03up for further questions.
01:10:08And thank you, everyone. That
01:10:09was kind of a tour
01:10:10de force of the evolution
01:10:12of the last twenty five
01:10:13years in cancer treatment across
01:10:15the spectrum. So
01:10:17and in only
01:10:19sixty minutes. So,
01:10:21thank you to to all
01:10:22of the panelists.
01:10:24I don't see any other
01:10:25additional questions in in the
01:10:27q and a. So,
01:10:29I thank everyone who tuned
01:10:31in and everyone who will
01:10:32watch this in the future.
01:10:34We are all available as
01:10:35well as our teams for
01:10:36some of these really tough
01:10:37cases,
01:10:39and for the clinical trials
01:10:41that we do have open
01:10:42for this unique patient population.
01:10:44So thank you so much
01:10:46to everybody.