Expert Perspectives on TGCT & the Outcomes of the Phase 3 MANEUVER Study of Pimicotinib Presented at ASCO and ESMO 2025

00:00:00: You are listening to an ADIS Journal podcast.

00:00:06: Welcome to this podcast titled Expert Perspectives on TGCT and the Outcomes of the Phase III Maneuver Study of Pinnocottinib presented at ASCO in Esmo in twenty-twenty five, a podcast discussion.

00:00:19: In this podcast hosted by Advances in Therapy we will provide an overview of tennis synovial giant cell tumor or TGCT, current treatment options for patients with TGCD and patient care journey.

00:00:30: We'll also share our perspectives on the maneuver data for penicotinid presented at ASCO and ESMO in twenty-twenty five, and clinical significance of these data.

00:00:41: I'm Dr Dale Shepherd a medical oncologist and co director of the sarcoma program.

00:00:53: Hi, my name is Sydney Stern and you can call me Sidney.

00:00:56: I'm the Senior Director of Programs at TGCT Support.

00:01:14: Really excited for this podcast.

00:01:16: I am uh, i'm the chair of orthopedic surgery at UCLA and i'm an orthopedics oncologist Uh who has the privilege of taking care of a lot of patients with tgct.

00:01:26: Excellent so why don't we jump in?

00:01:27: So we're going to talk a little bit first about um The tgc-t itself clinical presentation diagnosis.

00:01:34: So TGCT is rare locally aggressive neoplasm that affects joints tendon sheath and bursa and it's driven by colony stimulating factor or CSF-I overexpression that promotes tumor growth, by recruiting an inducing local accumulation of inflammatory macrophages.

00:01:53: This is a disease that typically affects younger adults around twenty five to fifty years of age on its associated with either monoarticular or idiopathic pain swelling stiffness limitations in mobility end impacts on social emotional physical well being patients TGCT.

00:02:12: it could be characterized by two subtypes, the localized or nodular and diffuse.

00:02:17: And there's distinct incidents in prevalence rates of each of these.

00:02:21: on The incidence of tgct regardless if subtype is about forty three cases per million person years um...and that includes localized TGCT ranges from thirty to forty five cases per Million persons per year Or diffused TG Ct That's About Five To Eight Cases Per Million person years.

00:02:42: Localized disease is about eighty to ninety percent of cases, and diffused diseases would be ten-to twenty percent.

00:02:50: so Nick maybe you could tell us a little bit about localized versus diffuse TGCT in how they vary with radiographic appearance growth presentation.

00:03:02: Yeah, thanks Dale.

00:03:03: I really do...I think most of us think of localized and diffused TGZT as is really two different disease processes that have the same driver biologically but they're really are distinct in a localized diseases something that generally appears very well defined.

00:03:23: it's fairly encapsulated, but you can draw a circle around it.

00:03:28: I mean, you see on imaging allusion that exists oftentimes commonly in the hand and wrist, But can be anywhere And It is single nodule of disease That You Can really associate as independent Of The rest of the synovium.

00:03:49: whereas diffused TGCT is infiltrative, has really poorly defined boundaries.

00:03:55: Often it's focused in intraarticular and extracurricular spaces meaning that grows in-and out of joints even though comes from there and far more destructive to the joints as an inflammatory process over time.

00:04:13: Dr.

00:04:14: Bernthal can you go on for the recurrence rate like what separates them?

00:04:19: While we think often of these diseases historically were treated with surgery, We talk about recurrence rate.

00:04:25: How often does it come back if you remove it?

00:04:31: this is a problem solved, it's very straightforward.

00:04:34: Whereas diffuse type while published rates say that recurrences are up to seventy percent I think most of us who live in this space know that recurrence rate really probably even higher than that if we actually follow these patients with MRI.

00:04:51: Diffuse TCT is very hard to clear surgically.

00:04:55: All right thanks Nick.

00:04:56: so Sydney, when we think about symptoms you know impact of the patients of TGCT.

00:05:03: tell us a little bit about how this disease impacts patients.

00:05:07: Patients with tgct have similar symptoms to more prevalent diseases which often potentially leads to the delay in diagnosis.

00:05:15: And according to the TGCT support analysis that was recently published, approximately fifty percent of all patients are misdiagnosed at some point in their journey and differential diagnosis typically range from sarcoma to benign tumors like lipomas, sports injuries.

00:05:30: Anything under the sun essentially can mimic the nonspecific symptoms of TGCT and this contributes to a delay where thirty-seven percent patients are really diagnosed within the first year.

00:05:41: we do see that shifting but main point is majority patient's not immediately diagnosed to the experience of fatigue and pain that they experienced long-term.

00:05:53: And nonspecific symptoms like pain, swelling stiffness joint instability in limited range of motion all impede the ability for optimal treatment.

00:06:03: So it's really important to get someone you Dr.

00:06:05: Shepard or Dr.

00:06:06: Bernthal as quick as possible even just a monitor properly so your not over treated with this disease.

00:06:12: I guess that kind points to need awareness.

00:06:16: It points to multidisciplinary care.

00:06:19: You know, Nick when we think about diagnosing this disease how do you go by doing that?

00:06:25: Yeah I think Dr Stern brings up a really important piece of this which is that were often acknowledged it were often engaged in this process at very late stage of people.

00:06:40: patients journeys the reality.

00:06:45: single joint monoarticular swelling and pain is an extremely common symptom in our society.

00:06:53: And so we often want to start with a physical exam, it's really important to recognize that the history of swelling for patients with TGCT.

00:07:13: TCT leads to swelling that's not connected to activity levels.

00:07:17: It's an intermittent swelling, and it is really independent of that.

00:07:22: so That's often the first clue when we don't have that classic morning swelling of rheumatologic diseases or that late in-the-day postactivity swelling of osteoarthritic processes.

00:07:34: But then we go to MRI pretty quickly, that's the gold standard for soft tissue mass diagnosis.

00:07:40: Often patients get radiographs but if were getting x-rays and seeing joint erosions weren't a very late stage TGCT.

00:07:49: so often times it is an MRI at nodular synovitis.

00:07:59: There are some advances in MRI technology that let us get closer to a sort of pathognomonic diagnosis with this sort of blooming artifact, but the reality is-is that we need a tissue diagnosis.

00:08:13: so if we go from MRI to biopsy ,we make a tissue mononuclear infiltrate with the giant cells and the hemocittering deposition that's characteristic for TGCT will form our diagnosis.

00:08:33: So Nick, just really quickly doubling back.

00:08:35: you know delay diagnosis.

00:08:37: it makes a more difficult for patients.

00:08:39: Sydney talked about symptoms.

00:08:41: in part of us is uncertainty comes with what that diagnosis who the patient goes to.

00:08:49: We talk about multi-disciplinary care, but at same time are patients necessarily going to the right doctors at the right time?

00:08:56: According to our registry it doesn't seem like a patient would often see many doctors prior starting out as most common diagnostic provider is orthopedic surgeon or sports medicine and that point commonly before diagnosis patients on average six doctors.

00:09:12: so they tend.

00:09:17: that suggests there's this loop.

00:09:19: patients are stuck in.

00:09:20: And it is really the advanced stages, those who have recurrent disease and find TGCT support as well as those continue to look further get off of that merry-go round orthopedic surgery and rheumatology primary care.

00:09:37: then they finally get a sarcoma center where multidisciplinary care but tends be minority group patient.

00:09:46: We talked about diffuse versus localized disease.

00:09:50: There's differences in how those diseases are approached, so Nick talk to us a little bit about surgery for GGCT.

00:09:57: Yeah So I think one of the really interesting pieces again going back to the idea that there really are two disease processes That we think about Surgery really does remain the mainstay For localized TGCT surgery does very well.

00:10:16: So when there's a single nodule that you can go in and remove, we often are able to remove it.

00:10:22: This is a short trip to the operating room —a single recovery—and you move on with your life.

00:10:29: Diffuse disease.

00:10:30: this just was not our experience... It wasn't ours or patients nor communities.

00:10:36: And so where we had diffuse disease We would operate on people get them maybe better for some small period of time before the disease would kind of rear its ugly head.

00:10:49: And so I think surgery itself, for diffuse disease is a work in progress.

00:10:55: it's not that it's part of our armamentarium but certainly as something which we need these other tools to help us.

00:11:05: We did some registry work couple years back and also know there are an urgency to jump into treatment or the operating room.

00:11:15: And I think that's the other kind of key message we as a field have learned and now try to espouse, but you can really do damage to people if you treat before You know what you're doing?

00:11:29: And you've got a good well thought out strategy in.

00:11:32: so i think whereas We used to ten fifteen years ago sort of see this We see somebody with disease in their joint, we gotta go get it before it causes further problems.

00:11:45: So um...we now need to kind of have this tempering uh..of that and make a plan

00:11:53: first."

00:11:54: Dr.

00:11:55: Bernthal when complete macroscopic resection isn't possible for diffuse patients?

00:11:59: And they're symptomatic what would be your next

00:12:01: step?".

00:12:02: So for us, these multidisciplinary approaches in getting with someone like Dr.

00:12:06: Shepard or one of the medical oncologists who we can start having conversations about systemic therapy and weighing pros and cons really trying to make a decision on how we approach systemic therapy versus surgery or together in combination and what order.

00:12:27: But that gets into really patient priorities, patient desires-what their expectations are how symptomatic they are.

00:12:35: but the first step even before that is to make sure they actually have symptoms that require an intervention before we go down that path.

00:12:43: When you talk about symptoms requiring intervention um one of the most common symptoms would drive.

00:12:51: Are you using defined measures or use like standardized measures for symptoms?

00:12:59: Or are you just kind of, you know bothers the patient they need treated.

00:13:03: Yeah So so for us I would say it's a combination of the two.

00:13:06: i mean one thing that orthopedic surgery as a field is pretty good at Is listening to patients for whether they are happy or unhappy in their present state.

00:13:17: That that's a big part of our field is when somebody comes in and says, They have a problem you say how much does it bother ya?

00:13:25: There fortunately are some tools that are bit more scientific an objective.

00:13:29: now we use promise scores which was developed in conjunction with the NIH years ago.

00:13:37: it's nice because its joint agnostic and so whereas we used as a field, We had our knee scores in our hip scores.

00:13:44: And our ankle scores.

00:13:46: It becomes pretty tough to apply that To something like tgct.

00:13:50: That can be in different joints But the promise score sort of gives us sense Of where people are.

00:13:58: I think certainly from a research tracking standpoint, promise is really critical to see how our patients improve with treatments.

00:14:07: To track out outcomes.

00:14:09: I think for an individual patient though honestly a good conversation about how much this impacts them and where it is you get a pretty clear sense from folks right away How debilitating This Is.

00:14:22: and TGCT has A massive range as i'm sure You do Dr.

00:14:26: Shepard.

00:14:27: I've got patients who have massive disease burden on imaging with no symptoms at all, and we've watched them for decades.

00:14:56: maintaining their quality of life and ability to provide for their family.

00:15:02: So the range is wide, we have to listen first.

00:15:05: Yeah definitely a lot getting patient perspective.

00:15:09: that patient reported outcomes work.

00:15:11: they're great for clinical trials but patients don't say.

00:15:17: I got two point improvement on my pain index.

00:15:19: so you know i think it's working.

00:15:21: So I guess when we think about systemic therapies, that's certainly something that we consider.

00:15:28: Like I mentioned before the CSF-I is an important target for treatment of this disease.

00:15:38: maybe if you just take a quick look back at some treatments currently available from a systemic standpoint.

00:15:45: first drug approved would be pexidartinib.

00:15:48: It's a selective inhibitor of the CSF-I receptor that was approved back in twenty nineteen For patients with symptomatic disease, but the approvals is either symptomatic diseases or if surgery would lead to morbidity.

00:16:04: Severe morbidity are functional limitations.

00:16:06: And so this was approved.

00:16:08: based on the phase three and liven study There was a thirty nine percent overall response rate and patients that perceived pexidartinib compared to zero percent for placebo.

00:16:19: twenty-five weeks into the study looking at resist criteria.

00:16:25: We kind of talked before about the disease itself, sometimes this isn't something that's easily characterized by resist measurements.

00:16:34: like a standard way we measure some other tumors.

00:16:38: you know there is a RENS program for this particular drug due to concerns for liver toxicity and it's not approved.

00:16:49: There's a phase three study motion, which led to approval of them salt nib.

00:16:56: It's another tyrosine kinase inhibitor that could be used for patients same criteria symptomatic disease patients who probably shouldn't go to surgery because of morbidity or functional limitations.

00:17:09: again forty percent overall response rate The trial, there was good anti-tumor activity.

00:17:19: The range of motion improved physical function stiffness.

00:17:23: patients felt better.

00:17:24: importantly There was not the hepatic toxicity that we've seen with pexidartinib and it's.

00:17:30: Bensaltinib was approved in February of twenty twenty five In the US And It Was Approved In September Of Twenty Twenty Five In Europe.

00:17:38: Hemicotinib is a drug That We're Going to Spend More Time Talking About.

00:17:43: We're Gonna End Up Reviewing Those Results as we talk about the trial.

00:17:48: more specifically, you know I guess it really takes us to thinking about their considerations when we think of systemic therapies.

00:17:57: Surgery is systemic therapy's win-to start therapies and one of the big keys that we've talked about.

00:18:03: symptoms are huge in terms of when to start more so than size.

00:18:09: Nick has had patients come out with massive disease coming into participate at a clinical trial.

00:18:15: they just didn't qualify Because they didn't have pain.

00:18:18: They did not have stiffness.

00:18:19: that trigger when to start is incredibly important.

00:18:23: Sidney, what do you hear from patients in terms of?

00:18:26: You know That triggered a start and in comfort with using that as a way to start treatments

00:18:31: I will say patients face a lot of anxiety about the decision-making.

00:18:35: There's a sense of urgency to get rid off too proactively.

00:18:38: Do something about a tumor right.

00:18:40: that's very common Especially on the early stages of disease or really stages of the diagnostic process.

00:18:47: And it's really important patients kind of sit with that uncomfortability and decide what's best for their joint because going right into treatment, sometimes side effects don't outweigh the benefit.

00:18:57: if you're doing just fine in same-less surgery—that recovery doesn't seem reasonable when your'e doing just Fine!

00:19:05: That type expectation is guided by having those discussions.

00:19:11: another common factor discussed as family planning?

00:19:15: for those that want to have children or father, or mother-children within the same year.

00:19:20: There's no real understanding of the duration.

00:19:22: you should take these drugs either before surgery or period and what's the best optimal treatment population?

00:19:29: Or the duration so that leads to a lot of uncertainty on when to go off And if there is impact on fertility which still relatively unknown.

00:19:38: besides animal data Which seems promising but Humans aren't the same as a mouse model, right?

00:19:44: So I think that calls into a lot of discussion on family planning.

00:19:48: What are the goals of treatment and how treatments inside effects may impact someone in their everyday life especially if they're young and active?

00:19:56: And so how can you proactively manage those side-effects In the expectations at the same time should all be discussed and or commonly things that patients start reflecting on in their decision making.

00:20:07: And then Nick, you talked about surgery.

00:20:08: and now that we have systemic therapies to shrink tumors for long periods of time.

00:20:16: How does it impact the discussion with patients in terms of timing?

00:20:23: Risk-free currents... Yeah

00:20:25: I mean It has completely revolutionized our field of how we think about surgery, how we apply surgery and how we start thinking about best practices for each individual patient.

00:20:43: And the big thing with TGCT is it is a fluid treating someone with TgCT as partnering And the decision that's made at time zero may not be.

00:20:56: The same decision, made it six months or twelve months and honestly I think thats the joy in this process.

00:21:04: now we have these tools but when you think about surgery to non-surgeons Surgery itself feels very binary.

00:21:14: its go no go.

00:21:15: We either Go To The Operating Room Or We Don't.

00:21:19: And the reality is, that there's a huge amount of gray.

00:21:24: When you have no other tools but surgery for disease... You almost have to go in with mindset.

00:21:32: if I am doing this surgery we are quote-unquote going for broke To get everything out because i don't want put them through something and not have affected outcome.

00:21:45: solving the neoplastic process Now with these tools, I think there's a lot more nuance in that.

00:21:52: My mind always goes to sort of the patients with disease and the hip.

00:21:57: And it's really interesting process for us because you either have go from front or back but you gotta choose one or other.

00:22:06: Historically when folks had TGCT we often times did both which is hugely destabilizing people hips long term.

00:22:16: Now with the systemic therapies, we often will use the drugs to shrink the tumor.

00:22:23: If they're happy... The patient stays on the drug and no surgery.

00:22:26: but if they need this surgery as well oftentimes it lets us sort of downgrade the surgery to say okay let's go get what we can from the front because that's what symptomatic- But We Can Leave The Stabilizers Of The Hip In Back even if it means a single focus of disease, stays in the bat because they're being managed so well.

00:22:46: on systemic therapy.

00:22:47: So I use that as an example.

00:22:49: but i think the concept of surgery is now um A tool and It Is a Tool to sort Of work with The patient To say are They Candidate for Systemic Therapy?

00:23:05: Can We Use Both?

00:23:06: What lowers the morbidity?

00:23:08: in kind of going and tackling this problem?

00:23:11: And frankly, always at the beginning gets a patient back to what they want to do.

00:23:16: And starting with that as the fundamental you know... ...what is their target and how we get them there with this collection of tools We have but rapidly evolving field and Dale partnering With folks like You To Do.

00:23:29: It is the fun of this because we bring the patient right into the center of this multidisciplinary partnership.

00:23:36: How much does surgery even thought out as sort of deep bulking now?

00:23:40: We don't have a conclusion yet, what should and shouldn't be doing.

00:23:44: but I think it's one advantages in our hands that often times get patients on treatment before surgery And so we can see what kind of response they get, and how well they tolerate these systemic agents.

00:24:02: If someone gets on a drug that says I have no side effects—I'm happy it's shrinking but still has pain—then the idea de-bulking becomes really quite reasonable whereas if somebody gets one who says he doesn't like being on drugs or makes me feel you then talk about surgery in completely different light.

00:24:21: let us make an informed decision together.

00:24:24: All right, so as we think about patient journey you think about multidisciplinary teams.

00:24:30: You know what?

00:24:31: We know that there's a lot of people to have be involved in taking care these patients.

00:24:36: kind of a two-part question for both of you Firstly who should be involved and the multi disciplinary care And you know sort of.

00:24:47: secondly.

00:24:48: What does that journey really look like for our patient?

00:24:50: So Sydney maybe will start with you.

00:24:52: Yeah, ideally a patient with localized TGCT that's completely amenable to surgery can have surgery especially if it is under Dr.

00:25:01: Bernthal can correct me, but three or four centimeters.

00:25:03: then it may be completely removable through arthroscopy.

00:25:06: It could potentially stay with an orthopedic surgeon.

00:25:09: But those with diffuse disease large disease that cannot be removed without essentially mincing it up Should be referred to a multidisciplinary team within Orthopedic oncologist at the helm and Then work very closely with them medical oncologists especially for those patients with symptomatic diffuse disease where its unexpected or would not assume that they'd be amenable to complete macroscopic resection with surgery alone.

00:25:34: Yeah, I guess Dr.

00:25:36: Stern hits it as usual.

00:25:40: but the only other thing is we do often really like make sure that radiologists and pathologists are part of these multidisciplinary teams.

00:25:56: because for us, and this goes back to one of the things all three of us have talked about previously which is that delay in diagnosis.

00:26:03: And figuring out what's going on.

00:26:05: but part of this when I've teached CT patients and see so many of them But i still like our multidisciplinary group with MSK radiologists we really sit down.

00:26:21: Is that disease in the front and back, or is it just synovitis?

00:26:27: So getting this idea of exactly what current state because sometimes these are tougher calls to make on imaging and then a pathologist that knows what they're looking at.

00:26:45: And so, you know all of us in the sarcoma world or very used to multidisciplinary teams but we take for granted In this disease How tough?

00:26:56: The management of this can be for the single orthopedic surgeon out in the community who doesn't have these sounding boards to kind lean on to know what they're gonna see when they go in there.

00:27:09: And then maybe the first exposure to surgery is like an orthopedic or rather a sports medicine doc, something.

00:27:15: so not necessarily someone that deals with tumors at regular basis?

00:27:19: I think that's right.

00:27:20: and i tell all of our sports medicine teams and we talk to non-orthopedic oncologist... A happy patient isn't informed patients with TGCT.

00:27:30: it's somebody who has kind of, there are times with this disease where we go into surgery full well knowing that this may not be curative.

00:27:40: And if we know that upfront and we've had the whole team meet with them and they made that decision based on available options This is what want to do.

00:27:49: That's a patient who has partner in process.

00:27:52: I guess from an information standpoint and patient expectations something really hit upon.

00:28:00: This is a serious condition, but not cancer per se.

00:28:03: So they come to see me and they're in a Cancer Center And that causes pause occasionally the whole nature of it cancers.

00:28:10: you.

00:28:11: You need to get rid of all tumor?

00:28:13: We've had these discussions here today about maybe you can leave part if It's not causing symptoms.

00:28:18: then just making sure patients are aware That this is not going to metastasize.

00:28:23: so there some tumor remaining.

00:28:25: thats okay.

00:28:27: we Need to Get Patients To The Right People quickly specialized centers, people experiencing seeing this disease coming up with good treatment plans talking about surgery and talking about systemic therapies in order to optimize outcomes.

00:28:42: Okay so now we're gonna talk about the maneuver.

00:28:45: phase three trials randomized double blind placebo control trial.

00:28:50: that was done at twenty-three sites um In China it was done in Europe ten sites North America.

00:28:55: So it's truly an international study.

00:28:59: Patients were eighteen years of age or older.

00:29:02: They had histologically confirmed TGCT met.

00:29:05: they had unresectable measurable disease by resist criteria and one Of the tumors had to be at least two centimeter.

00:29:11: And um, they had have symptoms To Be eligible to enroll as a double-blind trial For the primary analysis there are ninety four patients enrolled in a two-to-one fashion to get Pemocotinib Or placebo And there was a twenty-four week open label period.

00:29:32: So that treatment period, it was the initial twenty four weeks for the primary endpoint.

00:29:37: It's an opal-label extension allowed afterward to wish all patients could get PemaCot in it.

00:29:45: Dr.

00:29:46: Shepard thanks for describing study design of Maneuver.

00:29:50: Can you walk us through the primary efficacy data presented at ASCO?

00:29:57: Let's start off baseline characteristics on this study.

00:30:00: They're well balanced between the pemicotinib arm and the placebo arm.

00:30:04: Both patients had tumors that were located in the knee, the ankle ,and hip.

00:30:09: About sixty percent of patients have prior surgery.

00:30:12: if we look at the primary efficacy endpoint It was based on independent review any resist criteria And so The primary end point that resists criteria.

00:30:24: overall response was fifty-four percent in patients who were seen per mccontinib compared to three percent of patients on placebo and an early onset response is observed at thirteen weeks into the study.

00:30:40: Key secondary endpoints are overall responses by blinded independent review based on tumor volume score, the mean change from baseline clinical outcome assessments.

00:30:53: If we look at some of those other outcomes, they include range of motion.

00:30:57: Worst pain on numeric rating scale, worst stiffness score and promise.

00:31:05: Looking to the data itself, pemicotinibsia market statistically significant efficacy based on tumor volume score.

00:31:13: Sixty-one percent of patients compared this three per cent with placebo.

00:31:17: so good response both by traditional resist and by tumor volume score.

00:31:23: Tumor volume score is something we look at oftentimes with this disease, it kind of captures the disease burden a little bit differently not something that typically used clinically but its important measure for clinical trials.

00:31:37: there was statistically significant clinically meaningful improvement in outcome measures range emotion pain stiffness and promise overall good responses.

00:31:51: measures of tumor burden itself and in the clinical measures, um... In terms if you know how patients felt in their function.

00:31:58: Yeah Um thanks Dr.

00:31:59: Shefford.

00:32:00: And I think highlighting those key outcomes from maneuver that were presented at ASCO You Know i think we all can sort of land on a summary Of it That um..in The Maneuver Trial uh.. Pim Medi-Ten point by resist, by imaging.

00:32:19: By TV asset met that primary endpoint.

00:32:22: but I think to the thing we all care about more as treating physicians and patients.

00:32:30: is it improved at all of secondary endpoints which are patient reported outcomes?

00:32:37: So maybe we can pivot because I know, uh... We presented some updated data at ESMO.

00:32:45: Do you mind walking us through that data?

00:32:47: Yeah so the ESMO data was a twenty-four week open label extension from the primary analysis stuff and in that particular analysis sixty three patients were eligible to enter.

00:32:58: that patient who continued to get the pemicontinib through Extension had an overall response rate, again by blinded review of seventy-six percent.

00:33:14: So that was a median follow up over four hundred days so very long followup.

00:33:22: great response rates complete and partial response rates six percent complete partial response rate.

00:33:34: So, you know stable disease was currently certainly present as well.

00:33:42: but good efficacy data in that open level expansion.

00:33:48: the duration of response had not been reached in that Open Label extension.

00:33:54: again despite If you look at tumor volume scores, overall response rates again seventy-four percent in patients with pemicotinib and consistent with the overall response rate by resist.

00:34:12: So both tumor volume score and resist criteria gave similar favorable response rates.

00:34:22: Again from a very practical standpoint we're you know normally in the clinic we're not doing the tumor volume scores but it's good to see that, certainly that captures for these tumors maybe a little bit better how much tumors currently present.

00:34:38: There are durable improvements that continue to end clinical outcomes beyond a year.

00:34:43: there is improvements and range of motion worse pain worst stiffness promise scores overall on the twenty four week open label follow-up from the phase three maneuver trial, they overall response rates by independent review per resist and tumor volume score were similarly improved.

00:34:59: There's clinically meaningful improvements continued clinical responses in things like range of motion stiffness and pain.

00:35:08: so having thought about efficacy data we've talked.

00:35:14: sometimes Patients are worried about surgery versus systemic treatments because of adverse events.

00:35:20: So Nick maybe could you tell us a little bit about the?

00:35:24: Adverse events that we're seeing in the trials.

00:35:26: yeah, thanks.

00:35:28: And and you know as we always anchor these discussions in a non malignant disease safety is Essential and so it's well.

00:35:38: It's always really exciting to hear and has Pima cotton him showed its very effective.

00:35:43: You Know We all look very granularly at this safety data to say in a benign, mesenchymal tumor.

00:35:51: How's it tolerated?

00:35:52: And so... In the sixty-three patients who received pemicotinib throughout and the twenty four week primary analysis and extension treatment was generally well tolerated.

00:36:07: adverse events were the vast majority.

00:36:09: grade one two um, a hundred percent of the patients on treatment had some grade one to AEs.

00:36:16: but also the uh, ninety-four percent of The Patients Who Were On Placebo Have Grade One Or Two.

00:36:24: Uh, AEs As Well.

00:36:25: Um.

00:36:26: and there were grade three four treatment emergent AEs in thirty-four Percent Of The Pimicotinib Group.

00:36:35: so What are those, and what's the driver?

00:36:40: And how symptomatic.

00:36:41: Are they?

00:36:41: well as with a lot of CSF-I inhibition there is facial edema There some itching Some periorbital edema They're some reports of fatigue and nausea and headache.

00:36:54: That all kind of.

00:36:55: Those are common side effects we saw in these trials.

00:37:00: The most common lab abnormalities responded with dose interruptions and dose reductions, which are the things we're used to seeing with CSF-I inhibitors.

00:37:12: These CPK elevations and lactate dehydrogenase.

00:37:18: And so these all were quite manageable.

00:37:23: The most common grade three, four treatment emergent adverse events where increase in CPK reported an eight patients by the end of the analysis and ten patients By the end Of the twenty-four week open label.

00:37:38: the other great three for events Were the rash in six percent?

00:37:43: Paritis in three percent and lipase in three point two percent.

00:37:47: importantly when we look at the open label follow-up.

00:37:51: There were no additional new safety signals.

00:37:54: That's always.

00:37:54: one of the things we really worry about with these trials is, Is the drug tolerated?

00:37:59: Do do we develop problems over time?

00:38:02: and it seemed that we did not.

00:38:04: And critically there was no evidence of colostatic hepatotoxicity or drug-induced liver injury which It is really kind of front and center in all of our minds around CSF I inhibition.

00:38:16: so That that's quite encouraging.

00:38:21: five patients total in the primary analysis, so that's eight percent required a dose reduction at some point and one patient ended up discontinuing treatment.

00:38:32: So it is uh, dose reductions are common though and-and twenty five percent of the patients at some point had a dose reduction when we followed them up in the extension.

00:38:51: And a total of discontinuation of drug for adverse events was six per cent when you look at the duration.

00:38:57: so um overall ah...the safety data I think um..you know Dale your used to managing these more than anyone on-in the medical oncology side.

00:39:07: So maybe you can summarize that uh....that litany as result.

00:39:12: Yeah, I mean so you know.

00:39:13: in summary we see that in the twenty-four week open label follow up and then analysis was well tolerated.

00:39:22: These are things.

00:39:23: what these drugs on a regular basis it is low incidence of treatment discontinuations.

00:39:29: there weren't many dose reductions.

00:39:33: importantly for this category of drugs wasn't the colostatic hepatic toxicity which initially for this class of drug.

00:39:42: And then the other one that fathers patients from a symptom standpoint is there was not hair or skin hypopigmentation, so in general it's very well tolerated.

00:39:56: Dr.

00:39:56: Shepard could I ask you

00:39:57: a quick question?

00:39:59: We see CPK elevations and they can be quite stark for community doctors that aren't used to it.

00:40:03: That with asymptomatic correct And those did not require any treatment interruptions, which we didn't talk about because I know a significant portion may need dose and eruptions.

00:40:14: That's what we expect in the TGCT field.

00:40:16: but could you potentially speak to how the CPK would be managed for this hopeful drug or an additional CSF-I inhibitors?

00:40:27: Yeah!

00:40:27: In general it is something that again at least getting someone seen that treats us even if we're not the ones to continue with a follow-up, at least setting things in motion.

00:40:41: It's important to have people measuring the right thing and monitoring correctly, measuring liver function CPKs.

00:40:49: Occasionally there is need to hold the dose reduce because of it.

00:40:55: but I think for patients who are going be treating the community is denote.

00:41:01: look I mean, i think that's the primary thing.

00:41:05: Yeah it is such a great discussion and we always love hearing you Dale in just sort of medical oncology field how your parsing through as each option comes from our side.

00:41:21: there are couple things to look at.

00:41:26: We are out of the period in which we worry about very dangerous side effects that come from trialing a drug.

00:41:42: And, you know early on it was a very low rate of one drug.

00:41:46: but there was this feeling of what if the floor drops out from under us?

00:41:51: If we give that drug and now we're in a place where this becomes much easier to talk Trial a drug, see how it goes.

00:42:03: See what you feel on the drug.

00:42:06: are you better?

00:42:07: Are your worse?

00:42:07: almost all of them?

00:42:08: we know these drugs work Almost all of him.

00:42:11: The joint feels better.

00:42:13: How did the side effects impact?

00:42:15: you do have any or none and I think one of the really encouraging things about the landscape as our armamentarium grows is that We have found that as patients switch from one CSF, one inhibitor to another for whatever reason they actually have somewhat different side effects and different magnitude but still have really good efficacy.

00:42:40: And so I think that's really encouraging.

00:42:42: So For me You know, while the nuance of which is gonna be your first drug for which patient is going to always fall in Dale's camp and The Medical Oncology Camp.

00:42:53: To decide I like looking at it as what?

00:42:57: What Is our overall environment right now?

00:43:00: And what does that threshold?

00:43:02: are we burning any bridges by trying one seeing what the patient thinks if they do Like It or don't trying a different one if they're unhappy, and surgery just being one of those options to put in play.

00:43:15: But as I mentioned before...I mean i-i just think it's a longitudinal disease that we have these regular checkpoints to say how are you doing?

00:43:25: And this is not decision for life!

00:43:28: That the joy come off trial and become drugs.

00:43:34: People can take drug holidays and we can see how that goes.

00:43:37: We can switch from one CSF-I inhibitor to another, put surgery somewhere in the middle... ...we now have those options to really tailor it for specific patients' needs.

00:43:46: Just add a patient advocacy perspective.

00:43:49: It's important to understand goals That dose interruption or dose modification isn't considered failure.

00:43:57: I think that becomes a really big understanding of what are

00:44:13: the goals.

00:44:27: sharing insights as well, any parting thoughts?

00:44:30: It's always a treat to kind of look into this disease is such a rapidly changing landscape and work with both you guys in here perspectives.

00:44:40: Um... it's an exciting time as maneuvering new data comes out another tool for us to push back to the disease.

00:44:50: that can be really debilitating and frustrating if we don't have tools.

00:44:54: so were just in better place.

00:44:56: Yeah, looking forward to more options for my

00:45:26: community.