How to Treat Cutaneous Melanoma – Deep Dive with Dr. Sapna Patel

hello everyone I am Rahul gosain and I’m Rohit gosain and we are oncology Brothers today we have the pleasure of having a renowned educator and a clinician Dr Sapna Patel from the MD Anderson Cancer Center with Dr Patel we hope to focus on the current standard of care treatment options for cutaneous melanoma Sapna thank you so much for joining us today thank you Rahul RI thank you for having me welcome sner to start off we’ll start with management of stage 0 and 1A where tumor is less than 8 mm without ulceration these patients undergo surgery they are rarely seen by medical oncologist but when you do see them how often do you follow up with them yeah great question as a reminder melanoma is the only solid tumor measured in millimeters all other tumors are measured in centimeters and of course as we get through these staging we’ll see that it becomes um aggressive with metastatic potential in just a millimeter worth of tumor these are treated with wide local excision um there’s a trend in the US and maybe elsewhere to consider a Mo procedure which is a stage surgical procedure for these historically MO is for squa cell and basil cells and really should not be used for melanoma so why local excision is still really the standard with what we call a bread loafing path histopathological assessment and if they do end up in medical ology the nccn guidelines would suggest it’s really a physical examination that needs to ensue these are um it would be considered Overkill to be to do regular radiographic surveillance for these maybe Baseline Imaging is okay um but then really you should let the clinical symptoms guide you absolutely thank you for going over you brought up that how a small change even few millimeters can upstage these patients so moving right along with Stage 1B to 2A in this patient population subna who is getting sentinel lymph node evaluation essentially the msl2 trial told us that really these are the ones that need to get a sentinel lymph node so why loc excision and Sentinel lymph node for stage 1B and up melanomas is still considered the standard of care there are some novel assays in development to try to predict Sentinel lymph node positivity but now we don’t think it replaces the TR traditional lymphoscintigraphy injection of a radionuclide and then uh retrieval of the Sentinel lymph node and truly it it’s it Bears a saying that these wi local excisions are the second um kind of histopathological assessment on a melanoma the first being the biopsy specimen but with the stage 1B to 2A after that when they end up in medical oncology pretty much annual surveillance would say suffice for these thanks for going over that especially when we are talking about optional Sentinel ly node biopsy evaluation now moving along into Stage 2B or more where Sentinel lymo biopsy is rather mandatory and Stage 2B involves t3b which is tumor size 2 to 4 MIM with ulceration or t4a more than 4 million without ulceration Choice here is observation radiation or immunotherapy now we have seen some promising results with immunotherapy now where do you see this fits in and how much benefit are we really buying with Adin immunotherapy yeah so the stage 2B to 2C is on the basis of the keynote 716 study 3A is a small group of patients that was in the keynote 054 study and the keynote 053 or the swag s144 study that were P pism AB either versus placebo and the 054 or investigators Choice control in the s144 so for 2b2 C the use of pism ab after clear Sentinel lymph Noe evaluation so this was an omission of Sentinel lymph Noe and at least a stage two it was clearly a stage two because of Sentinel lymph node evaluation fism AB is carrying um a benefit in in over Placebo of about 0.65 Hazard ratio so about a 30 30 5% Improvement in what we call recurrence free survival and distant metastasis free survival we do not yet have overall survival data in the stage 3A population the small subsets from the keynote 054 and swag s144 or keynote 053 study the it’s similar we have these um Hazard ratios that essentially cross one on the confidence interval they were a small set of the main study it’s hard to know if you’re actually deriving benefit three a is a population with nonulcerated primary and a microscopic lymph node so even back in our interferon days this is not clearly the patient population we would have necessarily dispositioned for adant therapy you know you brought up that we’re waiting on OS uh I feel like melanoma has been a poster child in leading immunotherapy trials as a generalist we’re all looking forward to these OS data because a lot of our lung cancer breast cancer studies are where we are today in melanoma saying let’s wait on the OS and we have the PFS right now right so subna coming back to the same patient population and talking about surveillance scans in stage two nccn gives us a little more leeway saying you should consider scans every 3 to 12 months for first two years how often do you uh get scans in your clinic okay so this is where becomes a little tricky stage 2B has the equivalent recurrence rate of a stage 3B melanoma so that’s confusing it’s not involving the lymph nodes but it has the similar recurrence rate as that involving the lymph n so for a stage 2B I think it’s very reasonable to do maybe three times a year maybe you know twice a year if the patient is comfortable for stage three 3A the recurrence rate is quite low we will often quote something along the lines of 12% 5year melanoma specific uh recurrence so if you have a 12year recurrence or 12E um uh inverted melanoma specific survival so none survival from melanoma at 5 years 12% we think that that’s a group even if we reduce their risk of recurrence by 65 you know Hazard ratio 35% something like that it’s still really just a small chance of recurrence meanwhile the risk of toxicity we know far exceeds that so for a stage three patient because their risk of recurrence is inherently low this is the population I think it’s very reasonable to do twice a year people’s Instinct will be that’s a stage three let’s do it three and four times a year but remember that their recurrence rate is less than stage 2B now stage 2C is very tricky stage 2C is ominous and they have a worse um survival than stage 2B 3A and 3B then how can that be it’s because 2 C is basically a thick ulcerated melanoma and ulceration carries its own significant prognostic value poor prognostic value so a stage 2C patient I think it’s very reasonable to surveil them quarterly now I know we’ve covered early and localized disease rather fast but let us dive into locally Advanced where medical oncology plays a pivotal role based on swag 1801 results involving pism app in preoperative setting versus atuan setting can you please share how you approach stage 3B where n1b is how stage 3B is defined clinically detecting one node or n1c which is in transit micro satellite or satellite met metastasis so I think if you have a patient presenting with an operable but clinically detectable you can see it on the scan you can see it in the office or you can palpate it melanoma I think that’s the time to engage with the surgeon and say Hey listen based on the results of this randomized Phase 2 Tri s801 shall we consider a little bit of preoperative pd1 therapy and that’s where you can give anywhere from 1 to three doses the study was designed for three doses with the option if you thought you were having clinical deterioration or progression you could give less than that and go straight to surgery retain that operability get that tumor out while you’re hopefully priming the immune system to give you a more Amplified and more diverse immune response if you leave the tumor in place for a short period so sub this is the same patient population that gets Perry up you go through surgery and now you have an option of adant immunal therapy but if the same patient is B positive your another option is a b mechan abits how do you choose who gets adant immunotherapy versus bin mechab biters if there is no contraindication for immunotherapy yeah perfect question this is where we really need to think about it what I will stress very heavily if a patient takes Neo adant immunotherapy and for whatever reason you want to assess what to do next on the basis of their pathology that’s a big caution sign right now we have no evidence that you should make a determination what to do based on the pathology that comes out the patient hasn’t failed anything they were still operable the treatment hasn’t failed just because it didn’t generate a strong response remember immunotherapy is not about shrinking the tumor directly it’s not tumor toxic directly it’s indirect it takes time Neo adate preoperative therapy is a finite short course if the tumor didn’t shrink no problem you still probably Amplified an intact immune system so right now I would say there is no evidence to switch after the use of neoag and immunotherapy to targeted therapy the patient has not recurred you have you don’t have any evidence at that immunotherapy has not done what it was intended to do Prime and immune system so the switch I would not do in a patient who did not take Neo adant immunotherapy they have no contraindications to adant targeted or imuno and they’re sitting in front of you this is the situation where I would consider some real world data we have clinical trial data that says active Interventional therapy whether it’s single agent pd1 or targeted therapy reduces your risk of melanom recurrence compared to Placebo compared to doing nothing by 50% or more great so we know we can do something to reduce the risk of occurrence but which something so if you look at real world data there was a real world series on about 800 melanoma patients globally done Australia Europe us and it was adant pd1 patients in the real world and it was describing patterns of recurrence so if you look at that patient population 34 of the patients who recurred now this was a short follow-up period so only a portion of patients had recurred maybe like 177% of these 800 but of those 177% three quarters had recurred while taking their adant therapy and only one quarter had recurred after cessation of therapy at a median of about 5 and a half months after cessation if you look at adant targeted therapy real world global series it’s the inverse 3/4 of patients are recurring after completion of their entire year of adant therapy only one quarter recurring while taking it now the patterns of recurrence are very similar more than 50% or distant metastasis this is all fine but impacts the response to that next line Frontline metastatic treatment so adant pd1 the only thing that’s really generating a response after that is iil liab or iil liab in combination more pd1 alone or with some experimental interesting this or that is not doing too much however the response to targeted therapy is very strong on the other hand if you give adant targeted therapy and now you’re faced with the recurrence you have every immunotherapy generating a very strong Frontline response more targeted therapy likely doesn’t do anything for you but as we’ll talk about Frontline targeted therapy in the metastatic setting is not our Preferred Choice anyway so this might be the scenario adant setting without preoperative immunotherapy where targeted therapy plays a role standard of care the recurrence rate are quite recurrence rates are quite low while taking it and perhaps you might actually um only overall survival will tell us right but perhaps this is the group of patients that actually will end up with an overall survival benefit if they were actually able to eliminate microscopic clones whereas the immunotherapy is not eliminating the Clones necessarily it’s trying to get your immune system activated to see those microscopic clones thanks for reiterating some of the aggressive disease burden that we do see here it is important to just stress that we have the option of preoperative immunotherapy and if one has not received that post surgery if there is targeted mutation present to rely on the targeted therapy or immunotherapy if there is no targeted therapy present now moving right along uh for metastatic disease if we have upfront BFF mutation now regardless of this mutation would you rely on Neo ippy okay so this is a great question Frontline metastatic you have the BFF mutation right now what we think is you park that information and you still use combination immunotherapy on the basis of the dream seek trial and the combat trial now if you look at dream seek there was a portion of patients maybe 18% or so that patient population who had very rapid progression on immunotherapy first such rapid disease progression they never made it to be ra targeted therapy we think that is really heartbreaking when somebody with an actionable cancer mutation never actually sees their targeted therapy even if a bridge to get them you know some benefit um so when looking at that patient population there were a few things that study was too stringent on the crossover it made you weit it made you confirm progression you had to wash out so we wouldn’t do that in the real world in the real world if you think you have somebody rapidly progressing you switch them quickly you don’t do not have to wait till week 12 if at week six you don’t like it you switch them on the other hand what you might use is that Baseline LDH some subset analysis from the Su combit study which was targeted therapy first switching to IO at disease progression iino switching to targeted therapy at disease progression or targeted therapy with a planned duration of 8 weeks and a forced switch tobo and then a switch at disease progression back to the targeted therapy that sandwich arm that so-called sandwich arm looked to do fairly well almost equivalent to the immunotherapy first arm and it may it looks to be doing even better in progression free survival and overall survival in the elevated LDH Baseline group so if you have if you’re checking LDH routinely on your patient Frontline medicine static they have a BFF mutation and you do not like the look of that LDH because it’s over upper limit you can consider a short course of B Mac with a forc switch now with a couple of caveats the combat said eight weeks and then switch for a lot of biological reasons that might be too long BFF therapy and so in the real world based on some data that came out of Harvard a decade ago it may be more like one to two weeks get that b in there to block that enene and then switch them to the I Neo as long as you have no tolerance issues take that bf Mech away keep them on Ito until disease progression and then do the switch over to targeted therapy perfect and for our listeners we’ve covered this post esmo when this was all hot after press with Dr Sapna Patel so go back to that discussion so to reiterate if LDH is elevated and you have BFF mutation this is the right patient to consider B mechan for a short period before we switch them to epino so now coming back to epino the dose of iepi is one Meg per keg the way to go or higher dose what we’ve seen in older melanoma studies yeah original checkm 067 is 3 milligrams per kilogram you take it for four induction doses so you get a total dose of 12 milligrams per kilogram if you use the low dose 1 milligram per kilogram of ippy for four doses you’re getting four milligrams of ippy that’s 25% of the dose there are certain scenarios where we think that might not be good enough brain metastasis mucosal melanoma Uval melanoma the other thing to remember is the Checkmate 511 compared the higher the standard dose of iy 3 milligrams per kilogram with this inverted dose in combination with noolab and it found the inverted dose to be lower in toxicity it would be you know a kind of a medical school error to say they were equivalent in efficacy because it was not powered to do that in a 200 some patient study and we could be making a type 1 error small sample size telling us oh these two regimens are the same but if we enrolled 5,000 patients we might see there are some small but meaningful differences so the standard is it beim m 3 milligrams per kilogram for a lot of reasons if your toxicity management is if you don’t have a deep roster of sub specialty if it’s all on you to manage these toxicities and it is perfectly okay to use that inverted regimen the lower dose of iy in the front line setting while you’re focusing on B mutated patients can you share some of the tricks that you use to manage skin toxicity or pyrexia with b and make Inhibitors oh yeah there’s a a study um comi A+ is the pyrexia management algorithm the pyrexia management study for um deanb tetb so if you end up encountering some toxicity with fever with photosensitivity it’s it’s there’s a nice algorithm there that might be wor worth looking at and you can also get it from the drug manufacturer the algorithm but essentially it it it’s drug holds drug holidays right now my issue with drug holidays is that you’re taking away drug when you should be keeping it at steady state in the body the other issue is taking it away and reintroducing it just reintroduces typically the side effect it’s not that you’ve really done anything to to um sensitize the body so the other thing you can do is fairly uh aggressive use of anti pyrexia agents for the first two weeks you can also start start the dose lower and build it up over the course of one to two weeks so it’s just not a watershed of pills in the body for skin toxicity low dose of prazone should be a last resort maybe five milligrams or less but it can be used to mitigate the skin toxicity without we hope impacting an immune response and you can also um can also use topical uh topical you know um volaran gel topical com compounding formulations if you get things like athema no doome which can be these painful B nodules and while we’re covering this the other question that we tend to run into in the community who should we use anti-ac tree combinations for over ctla4 or single agent IO or bft mechan bitter so who’s the right patient that I should be thinking about that yeah so obviously neoa opdag is approved in the Frontline metastatic setting with an improvement in EFS but um did not meet hierarchical uh Improvement in OS so we really shouldn’t even talk about objective respons rate then in that study but this is also it goes back to this idea of if you feel like somebody needs combination therapy um maybe based on Rising LDH or burden of disease but you really don’t feel like they can tolerate the toxicity of the ippy liab component do you feel that they do need doublet then this would be a situation to consider Nella um you know I think what we’re trying to figure out is could you start with a dose or two of single agent pd1 and if you clinically assess that LDH is climbing or you don’t feel you know at at the six week or eight week Mark the scan is showing you what you were hoping to see which was an early hint of efficacy maybe then you could add the Neo there instead of sort of saying they must have progression before I switch treatment or I’ll start them right off the bat and then uhoh I’ve got myocarditis and adrenal insufficient to handle because it’s still a combination therapy with toxicity technically there’s a Frontline triple approved but nobody and actually when you look at nccn you can’t even find it listed there and so really it has fallen out of favor nccn obviously has the bias of all these academics saying no no but we don’t use it but it’s approved it’s not like Community couldn’t use it yeah so one of the things I think we need to stay tuned for is that’s this idea of PFS 2 or total PFS Su combat sort of described this because if all the triplet studies get you 15 to 16 months PFS great so that’s your first PFS so what do you do next if that next treatment gets you six months or nine months now you’re up to 22 or 25 months is that what total PFS one and two is getting you with theit I don’t know if it’s not may but then of course we’ve got the toxicity issue so then we’re going to have to be really comfortable with toxicity management when we start doing triplets and we have to clarify what we mean by triplet it’s BF Mech pd1 a going to be interesting in what one is going to use second line in that case yeah yeah see if you did BME pd1 or the VM KOB aism PDL one arguably you still have I Neo to touch arguably you still have OPD lag you know so it’s not exact I think people feel like oh you’ve used everything but now we’re getting to the point where we haven’t exactly yeah no this this is getting complicated but thankfully that’s a good thing for our patients thanks for covering so many PRS today with us sub now thank you so much for taking the time to join us today and going over the current treatment landscape for melanoma for our listeners stay with us for a recap for a recap with Dr Patel in this discussion we have covered the current standard of care treatment for melanoma starting from early stage and then all the way to metastatic settings where the treatment is with pallative intent with Dr Patel we’ve discussed Ro of surgery and then adant immunal therapy for early stages for stage three or four seable disease we’ve also covered the role of neoadjuvant or preoperative pemis map followed by surgery and then continuing with pemis map thereafter in metastatic settings checking and then targeting B mutation is important even if you have BFF mutation this disease can be responsive to immunotherapy getting comfortable with managing toxicities for BFF and Mech Inhibitors and immun mediated toxicities is extremely important tune in again to stay up toate with current standard of care treatment options and practice changing data with us the oncology Brothers

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Dr. Rahul

Dr. Rahul is a Chief of Medical Oncology, making up one-half of the ‘Oncology Brothers.’ He is a valued member of the Guthrie Corning Cancer Center, contributing his extensive knowledge of technology