New Horizons in EGFR-Mutated NSCLC: Broadening the Impact of Precision Testing

[Music] the following podcast is part of a certified educational activity titled new horizons in egfr mutated nsclc broadening the impact of precision testing in the context of an expanding treatment landscape access the entire activity and complete the post-test at peerview.com forward slash cwe860 downloadable slides and practice aids are also available thank you for listening to peer view podcasts we greatly appreciate your support and would like to hear from you can we ask for a favor participate today in a short one-minute survey at www.peerview.com forward slash podcast survey to share how podcasts play a role in your medical education routine again that's www.peerview.com forward slash podcast survey to participate and now on to today's podcast hello everyone i am dr marie arcella and i am a pathologist from memorial sloan kettering cancer center welcome to this educational activity focused on advances and practicalities of testing and treatment in egfr mutated lung cancer i am joined today by two thoracic oncologists dr sosha petroska from massachusetts general hospital and harvard medical school as well as dr josh obama from university of pennsylvania welcome i'm looking forward to this discussion today thanks for having me great to be here so detection of actionable genetic biomarkers has become a standard of care for therapy selection in clinical management of patients with advanced non-small cell lung cancer numerous genetic alterations have been reported in this setting with egfr and keras as the most common numerous biomarkers however are present at lower frequencies and the vast majority of them are below three percent and are currently targetable alterations with either approved agents um or under clinical trials based on the updated guidelines um that have been issued jointly by uh the college of american pathologist the american society for molecular pathology and the international association for lung cancer in 2013 and updated in 2018 18 the assessment of mutations for egfr and fusions involving alk and ross should be prioritized over other biomarkers even as this as these guidelines were being put together um many other biomarkers of course um were evolving and the nccn in the meantime has been continuing to update their recommendations keeping up with the rapid emergence of the evidence in response to targeted therapies for other biomarkers um even including enteric fusion infusions which are actually very rare um with a long list of guidelines um then this actually supports that one should use next generation sequencing as the most practical practical way of testing rather than performing a series of single gene assays um unfortunately despite all of the guidelines the testing and the the adoption of many of the biomarkers for testing has been actually difficult so in this study presented at asco in 2019 by german at all there was a review of over 1200 patients with non-small cell lung carcinoma in a community setting between 2017 and 2018 and this shows that patients with lung anticarcinoma are markedly under genotype despite the recommendations that i already described for this data for example uh five different community oncology practices uh were queried encompassing 289 oncologists and what you can see is that for each of our testing which has been part of the standard of care for over a decade is still only tested in about 54 of the patients the testing gradually decreases to the point where for all of the biomarkers that actually need to be tested based on the guidelines right now only seven percent of patients get testing for all of the biomarkers um interestingly the pedia1 um immunohistochemistry as a marker is one of the assays that is being adopted and is being performed uh much more at much more higher rate than any of these other biomarkers except for egfr um even more sobering are the numbers of patients that are actually uh treated with their respective agents um among those that are tested and with evidence of targetable alterations in egfr elk and ross and and also bref only about 45 of these patients who have evidence of the mutation actually have received targeted therapy during any line of treatment um in several u.s and global surveys when we actually see is that there are several that that although the markers are being tested um the long turnaround times the lack of molecular testing um in the same institution and sometimes the poor performance status of the patients actually lend to a very long turnaround time which affects how many of these patients i actually are actually receiving therapy so now focusing strictly on egfr which is the topic of our talk today um this is a marker that has become standard of care for well over a decade now and this is an excellent model to explore the evolution of targeted therapy the benefits and the pitfalls and also the barriers that are associated with targeted treatments and personalized medicine mutations have been typically associated with very specific patient phenotype usually female non-smoker and also asian however any patient regardless of their phenotype can have these mutations and can be treated once you give these patients therapy specifically targeted for the marker that they have many of these patients actually develop resistance mutations uh which are commonly associated with um secondary is it with a secondary genetic event that is um that that evolves to bypass um the initial um the initial mutation so after this introduction i would like to uh turn uh to the the type of mutation so the the um the biology of egfr is actually quite complex um and at a basic level i would like to point out that uh there are hundreds of different egf mutations that have been described however most of the the most common mutations are usually conglomerated um in the tarzan kinase domain of the gene uh which is coded by exons 18 to 21. uh sensitizing mutations are those that are sensitive to the current inhibitors um and are and these are primarily located between 18 and 21. um mutations in exon 20 are commonly described that resist as resistance mutations either primary or the novel or secondary to as those that appear after treatment with egfr inhibitors such as t790m and c797s um mutations that are present in exon 20 however are highly variable both in sequence and in their location within x120 itself which also uh dictates that they have variable responses to the inhibitors that are being given but not all of them are actually resistant so um with this background i would like to turn to my clinical colleagues who will outline some of the important aspects of egfr of the egfr timeline that we were talking about before um so i'm going to turn it over to josh right now thanks so much uh you know looking at this timeline you really can see that the field of egfr mutant lung cancer has undergone a metamorphosis right this really began 2004 we identify egfr mutations and really this is the start of understanding of how these work so i pass in 2008 i actually love to think about this trial this trial was designed before we knew that egfr mutations were the mechanism of sensitivity to tki therapy so if you look at the eligibility uh profile of ipas it was basically if you are asian and haven't smoked a lot and that identifies a lot of patients who have egfr mutant disease but in the retrospective in the secondary analysis they can say well wait a minute what happened to those patients who had an egfr mutation and did not and you can clearly then see the remarkable effectiveness of this biomarker such that patients who are egfr negative and looking back probably a lot of them had alk plummets in jafitnib but those who have an egfr mutation respond beautifully to fit nip then uh with work that a lot of it came out of a mass general with doc with uh with zosh's colleagues up there as well as zosa's work herself showing that uh repeated biopsies allow us to understand mechanisms of acquired resistance then we had a brief time of fighting about whether it's our lot nibja fitness or fatinibus the best first line agent um but then we started seeing more about drugs like osimertinib this is a third generation tki and then also had information about dakomitenim another second generation and now most recently at asco this year and now published in new england journal we saw the first evidence of what happens when we give these tkis in the adjuvant space trying to enhance the likelihood of cure to this deadly disease so let's sort of break this down as to what types of drugs are currently approved in the management of metastatic egfr mutant non-small cell lung cancer so first let's start in the top left of this quadrant here the top left quadrant here these are the first generation egfr inhibitors you got your fit nib you've got our lotinib they're both reversible egfr inhibitors um they're approved for the first line management of egfr mutations specifically the exon 19 deletion and l858r that are the vast majority of these mutations shortly thereafter there was an approval for a fat nib um and then also dakomitnib both of those are second generation inhibitors so what do we mean by second generation well they're irreversible egfr inhibitors neither of them have a great amount of cns penetrance and neither of them have efficacy against the t790m mutation that is the most common mechanism of resistance toward lot nibja fitness and because these don't have activity there also a phatnip and dak commit nip a fat nib specifically is not only approved for exon 19 and la-58r but also the rarer alterations of s768i l861q and g719x now if you are listening to this and you are a clinical oncologist and you think that i just said a bunch of alphabet soup do not be overwhelmed because this is really complicated when you get one of your test reports and it shows an egfr mutation it is important to know what type of mutation it is to help guide the best treatment we're going to talk about some of the data and egfr classical mutations and then zosia is going to talk about these exon 20 insertions which is a whole other type of mutation with different types of treatments moving on to the bottom these are the more recent approvals osimertinib was recently approved in the first line management of egfr mutant disease it is also approved in the later line management of egfr mutant disease harboring a t7 90 m mutation and most recently there was a first line approval of erlotinib with the vegf inhibitor ramyusseramab for the treatment of first-line egfr mutant disease so let's take a look at the data that led to the osimertin of approval in the first line this was the flora study flora study randomized patients with a classical egfr mutation to either investigator's choice of verlot nebrasia fitness and remember those are those first generation reversible inhibitors or osimertinip that third generation inhibitor which was already standard of care for t790 positive disease these results are remarkable we saw an improvement in both progression free and overall survival with the use of a newer pilino summer nip there are some more advantages to osimertinib that are not quite captured here first of all it's better tolerated there's less rash with osimertinib than you have with their latin virgin fit nip and also in contrast to our latin and jafitnib osimertinip has excellent cns penetrance so the incidence of brain metastases goes down substantially and there's actually even data about osimertinib working in patients with leptomeningeal carcinomatosis and remember i was talking before about acquired mechanisms of resistance um there is a lot of work that has been done no looking at repeat biopsies the use of liquid biopsies to identify mechanisms of resistance that's how we learned about t790 we're now starting to see the first studies looking at mechanisms of resistance to first first-line osimertinen which is now the standard of care when you look at this pie chart what leaps out to me is that you don't have the same story we had with t790 where there's one mechanism of resistance that is overwhelming in fact that 40 to 50 percent before you get too excited that's unknown okay so all of the other ones represent smaller pieces of the pie um and that be makes it really complicated to guide next line treatments after osimertinib more to come here stay tuned adora this was the trial that was presented at asco and subsequently published in new england journal this was a truly revolutionary study historically we've only used these egfr inhibitors in the setting of metastatic disease but this study took patients with localized egfr mutant non-small cell lung cancer and after surgery after adjuvant chemotherapy at the investigator's discretion randomized them to either the receipt of three years of osimertinib or three years of a placebo now one thing you have to know about the ad or a trial is its primary endpoint was disease-free survival that's a little uncomfortable remember these patients were trying to cure them so we'd like to see an overall survival advantage but the primary endpoint here was disease-free survival nevertheless you can see that you could drive a truck through these survival curves that osimertinib clearly is associated with a marked improvement in the disease-free survival and that this benefit was more greatly highlighted in those patients who had stage 2 to 3a disease which is the primary endpoint and real the group that they wanted to look at but there was also benefit even in the stage 1b there were fewer local regional and distant metastases with osimertinib less incidence of cns metastasis so the cns disease-free survival benefit had a hazard ratio of 0.18 this is remarkable and it will change the way we have to think about egfr mutations on december 18 2020 the food and drug administration approved osimertinib for adjuvant therapy after tumor resection in patients with non-small cell lung cancer whose tumors have egfr exon 19 deletions or exon 21 l858r mutations as detected by an fda approved test the approval was based on findings from the adora trial so what i'd like to do is i'd like to throw this to my colleagues and so how do we incorporate biomarker testing into those with early stage lung cancers osho why don't you tell me how how things work up at harvard that was a great summary josh thanks you know i think it's a really important question i agree with you i think adora is a very exciting trial that kind of changes the paradigm and how we think about testing you know i think we've we've as maria you nicely summarized we've been testing metastatic disease for a long time and frankly even there we don't do a perfect job and and in some places far from it and now we're just going to cast a broader net what i hope is that that broader net will simplify things in a way i think a lot of challenges come about from you know the challenges of identifying which patients should get which testing which genes which types of tests which stages that they have do they qualify for testing and i think as we move to more broad testing that may actually simplify things i'll tell you at our institution we've really worked closely with our pathology colleagues in this setting to try to streamline the testing and actually make reflux testing a part of part of the testing now for surgically resected samples based on this data and this is still a work in progress this is fairly recent data but we hope to move to a time when when we see a patient in the clinic to discuss for example adjuvant chemotherapy and now more broadly adjuvant therapy in general will actually have molecular testing and specifically the egfr testing in hand and and maria you know one of the things that i often experience as a clinical oncologist is that you know i get all excited about a trial data and then i tell my colleagues in pathology and they say well we have to bill for this this is something that actually has to be thought about so maria can you tell us how does the billing work in terms of these earlier stage disease in terms of the testing that we want to do yeah so so this this is one of the issues with uh why testing has not been adopted so widely as much as widely as we would like it to be so um for example in our institution we do have reflex testing and every single lung and carcinoma gets tested regardless of whether it is a a um an advanced carcinoma or a resection so in terms of testing it's extremely difficult to test patients at the time that they have advanced disease because these biopsies are tiny and uh they're very difficult to work with and you always end up with insufficient material to be able to test the idea of being able to actually test a resection with ample material is actually um it it's great in terms of being able to um finally do all of the testing on these patients as broad as you may need with next generation sequencing or with additional uh um smaller panels to be able to get the patient to uh to get to their therapy however at this point this is not something that is paid by insurance companies insurance companies are going to go with what the guidelines are and up to now the guidelines have been based on only patients with advanced carcinoma and those patients with um who who are amenable to every section and who are at lower stages of disease these patients do not actually get uh paid by by insurance or their testing doesn't get paid by insurance so the fact that we would have something like this where it really doesn't matter whether the patient is advanced or not would actually facilitate the testing immensely um and it would help us be able to uh to test broadly up front these mutations again once you have an egfr mutation and you have a recurrence later on is going to be exactly the same mutation so they don't change so so whether you test on the advanced disease or on the on the first sample that was there that was the resection it really doesn't matter for the patient and it really does is a game changer for everybody yeah and you know you you touched on something there which i think that i'd like to ask zosia about here so uh we're gonna be doing testing on earlier stage tumors and you were mentioning maria that broader testing will be easier in that setting social how are you going to handle you know adopting a dora into your practice and if you have a patient who has let's say an alk in the adjuvant setting do you think that these data should be extrapolated to that setting such a great question and a really important one i think one of the challenges with elk and ross and some of these other rare targets is it's going to be incredibly hard to do similar studies in those rare populations um and i think you know what the first thing to say is there are studies ongoing for example for elk there's the alchemist trial and i think it's really important to try to get these patients onto those studies because it's really the only way we're going to get these answers so that's that's the first point for patients who don't have access to trials you know i would be wary at this point i think the adora data is exciting but it's still early as you pointed out right now we're looking at a significant but still a disease-free survival benefit so right now i would be a bit wary to extrapolate these data to other to other targets however i think if we start to see a survival benefit if we really find that these tkis are curing more patients i think that then the impetus will be stronger to perhaps extrapolate to other targets where we may not be able to get direct data from those mutations themselves what are your thoughts on that josh yeah i completely agree i think based on the data we have i would definitely not extrapolate them but i do think that if we had um if we had an overall survival advantage that's remarkable in adora then what i would favor doing would be a trial of let's say a lectin if in that space even a single arm study just show that this is much better than we would expect consistent with what we saw with adora and i think that would be enough for me to extrapolate these findings it's going to be an issue in terms of reimbursement and it's going to be a question that we as a society are going to have to answer because this is it's a big cost there's no denying that but the outcomes for patients with early stage lung cancer are simply unacceptable in my view i think it'll also depend on the toxicity profiles of these various drugs when you talk about different targets i think you know one of the reasons this is so exciting is that osmotinib generally is a well tolerated drug and i was just talking to a patient in clinic last week about this and she said i don't know do i want to take a pill like this for three years what are the side effects going to be and what we know with osimertinib is that that generally is is you know it doesn't have a huge impact on quality of life we at least extrapolating from the metastatic setting but that balance may be a little bit different with other tkis and other targets so there's going to be a lot of i think aspects of this that we'll have to consider as we make these decisions one other question as we before we go on to exon 20 um you know i mentioned briefly the data about ramyusiramab as well as there are a lot of combination studies that are being evaluated in the egfr mutant space so first of all do you think there's currently any role for the first or second generation egfr tkis whether alone or in combination in modern management and also what combination strategies are you excited about moving forward in the first line it's a great question you know right now outside of a clinical trial i think also osimertinib is really my preferred approach i'm convinced by the flora data i think again also martinib's well tolerated it has good cns penetration it clearly showed both a progression-free and overall survival benefit as you nicely summarized but i think we can't rest on our laurels and there's still a long ways to go you know a year and a half is not good enough for first line therapy and i really am hopeful that in the future some of these combinations are going to change our first line strategy you know as you alluded to there's a number of different combination therapy trials ongoing um osimertinib plus chemotherapy the flora two trial also martinib with bevacizumab and other vegf inhibitors osimertinib and jafitnib and other kind of tki tki combinations i personally i'm really excited about the chemo data i think it that data has been really compelling you know when you looked at some of the studies that combined first generation egfr inhibitors plus chemotherapy and then two different studies one out of japan went out of india showed a consistent improvement not only in progression free but also in overall survival i think really highlighting the fact that you know delivering more therapy to these patients who may not always get to second line therapy may be important and so i'm really looking forward to the results of flora too i hope to you know have that study open and put patients on but today outside of a clinical trial i think osimertinib is a great standard of care yeah i completely agree um i'm also very interested we've been involved in the development of an egfr met by specific antibody amy vantamab and uh some of the first line data there i mean there was an objective response rate in a small group of patients but a hundred percent and that is interesting to me because we know that met is a major mechanism of resistance to targeted therapy so i think that that's another area of excitement as we move forward um so i'd like to hand it off to use osha to talk us to talk to us about egfr exxon 20. great thanks so i think this is a very important topic to cover uh you know if we think back to the slide maria that you presented early on that showed just the complexity of egfr mutations i think the first point to make is we think of egfr mutant lung cancer as one kind of group of mutations one type of mutation it's really important to get more granular than that and to recognize that these are very distinct mutations in some cases and i think in particular it's important to recognize the exon 20 insertions as a unique kind of entity and a unique therapeutic challenge if you will so if you look at the figure here you know it really highlights the exon 20 insertions within still within the tyrosine kinase domain spanning a section of exon 20 that covers the c helix and the loop following the c helix and as you can see the exon 20 insertions in and of themselves are a heterogeneous group of mutations there's a number of different ones that have been described and together they seem to make up up to 10 of all egfr mutant lung cancer recognizing that even that number may under represent some of these mutations which haven't been picked up by older pcr based assays and i think we're picking up more and more of them now with next generation sequencing the important thing to know about these exon 20 insertions when you find them is that historically they've been resistant to first and second generation egfr inhibitors with median progression free survival with their lotinib gift nib and a fat nib all less than three months and i think as a result of the limited targeted therapy options for these patients they've generally had a worse prognosis than other types of egfr mutant lung cancer though i do hope that over time this is actually going to change as we have some new and exciting therapies coming forward for these mutations so why are x on 20 insertions so challenging what does this mutation really do and i think it's it's somewhat complex in terms of the structure of these mutations and and it's depicted in this figure here but the bottom line here is that the egfr xn20 insertions seem to push this area called the c helix into an active conformation in a different way than the xn19 and l858r deletions l858r mutations do it and in a way that causes steric hindrance and has made it more difficult to basically to fit some of these tkis into that pocket and cause effective inhibition so when we look at cell line models and we look at different exon 20 insertions as shown on the right hand side here you can see that this is on looking at the the inhibitory concentrations over lotinib required to reduce cell viability you can see that in shown in the blue the gray and the yellow are the exon 20 insertions and they require much higher doses of erlotinib to inhibit cell viability to basically stop these cells from growing that's much higher than what we see in black for the exon 19 deletions and in the clinic what that's translated to is the fact that we can't deliver high enough concentrations of our lot neb to these patients to effectively inhibit these cells from growing and cause clinical responses so that really explains why these older drugs haven't worked and i think it's been very exciting to see some of the newer drugs that have been developed now that exon 20 insertions have been recognized as really their own unique entity and their own unique therapeutic challenge so this table here summarizes some of the recent drugs that have been developed and the the most recent data that we have available for them i'm going to focus here on a few of these mobile certinib and a drug that josh just alluded to amivantamab both of these actually have fda breakthrough therapy designation specifically for egfr exon 20 insertions and we'll talk about some of the data there first i wanted to mention poseotinib if we had had this discussion a year or two ago i think poseyotnev would have been the drug that we spent the majority of our time talking about it was a drug that in preclinical models looked like it was going to work really well for exon 20 insertions and even in an early study it did show some promising signs of activity but what we've seen is with larger follow-up in this study that had 115 patients with egfr 20 insertions the results were frankly disappointing a response rate of 15 pfs of only four months and what we saw was that many of these patients were really struggling with toxicities we saw high rates of diarrhea and about a quarter of patients having grade three or higher diarrhea about a third of patients having grade three or higher skin toxicity or rash and that translated to nearly eighty percent of these patients requiring dose reductions of positive and we think that that's probably you know in large part a function of why this drug has ultimately had somewhat disappointing activity in these larger groups of patients and while studies with positive are still ongoing i think the the toxicity of this drug remains a major challenge moving on to mobile certain if i wanted to spend a couple of slides talking about the data with mobile certain but i think the results here are exciting and certainly something to keep an eye on going forward so these results with mobile certinib which i'll mention used to be called tech 788 you'll still hear us sometimes refer to it as tech 788 are from a study that included 28 patients with egfr exon 20 insertion mutation positive cancers so again a fairly small number but what we saw among these 28 patients was a confirmed response rate of 43 and as you can see on the swimmers plot here on the right a median duration of response of nearly 14 months and a progression for survival of 7.3 months and we saw 90 of patients having diarrhea and a third of them having grade three or higher diarrhea upper gi toxicities nausea vomiting anorexia were also fairly common about half of patients did have have these types of side effects although less of grade three toxicities and about half of patients had rash although here we didn't see any cases of grade three or higher rash and all and all in all about 25 percent of these patients require dose reduction so this drug is not easy you know we know that diarrhea gi toxicities dermatologic toxicities are known and fairly common side effects associated with egfr inhibitors but nevertheless i think a drug that has shown some promising signs of activity and in fact now there's a first line study comparing mobile certain ib2 chemotherapy for newly diagnosed exon 20 insertion positive cancers that i look forward to seeing the results of moving on to amy vantanab also known as jnj372 josh as you alluded to this is a humanized bi-specific antibody that targets egfr and met and is being studied both in the um in the exon 20 space but also in the resistance setting uh for patients with xn19 deletion and l858r and as josh alluded to even some really intriguing and provoking first line data there in combination with the third generation egfr inhibitor lizertanib so in the phase one chrysalis study of amivantamab there was a cohort of patients with egfr exon 20 insertions here 39 patients were included and we saw a response rate of 36 percent progression-free survival here was about 8.3 months so again um you know data that seems to be on par with some of the competitor drugs and certainly you know i think exciting to see a drug with a different mechanism of action also having efficacy for these patients in terms of toxicity you know what we've learned as mevantamab does cause rash here 72 percent of patients had rash although generally these were low grade and then unique to amavantamab is this um infusion related reaction which is detailed a little bit more on the right hand side of this figure what we see is that these are generally mild only a few percent of patients have grade three or higher rash and uniquely it seems to be really only most common on the first on the first infusion this is typically manifest as chill shortness of breath nausea flushing it seems to improve actually with split dosing so if you give the drug split up over the first two days of treatment patients tolerate that much better and as you can see here really doesn't tend to recur so i think this is a manageable toxicity but one you have to warn patients about and be prepared to manage and again both for mobile certain ebonami ventimab the fda has granted these drugs breakthrough therapy designations specifically for exon 20 insertions i think recognizing that in an area where there aren't effective targeted therapies both of these drugs have shown promise i also wanted to highlight the role of osimertinib here we talked about the fact that first generation and second generation tkis don't seem to work very well against these insertions but in pre-clinical models though submertinib as you can see on the left here does have some kind of intermediate activity and i think one of the advantages of osimertinib is that it's a drug with a wide therapeutic window it's quite sparing a wild type egfr and that lends itself well to being able to dose it at higher levels and in the clinic and patients generally tolerate that better than than we've seen with some of the older first and second generation egm egfr inhibitors so based on this data we ran ea 5162 which is a cooperative group study that looked at the osimertinib at 160 milligrams so twice the standard dose of 80 milligrams specifically among patients with egfr exxon 20 insertions this was a small study what we saw here was a confirmed response rate of 4 out of 17 patients or 24 and a medium pfs of 9.6 months generally osimertinib was quite well tolerated the rates of skin toxicities and gi toxicities were quite modest and manageable but again this is a small data set and and i think this data is intriguing enough that we hope to expand the study and learn more about the activity of high-dose osimertinib for these patients and this is another treatment option i think that'll be important to keep an eye on just lastly i wanted to highlight the fact that these are not the only drugs in development for exxon 20 this is a space where there's a lot of activity and a lot of excitement i've summarized a few of them here on the slide so cln-081 is another oral targeted therapy being tested in egfr exon 20 insertion patients we've seen some preliminary results from the ongoing phase one study and seen some responses but of course very early days so something to keep an eye on tarloxetnib is an interesting drug it's a hypoxia activated tki that's been around for a while and pre-clinically was predicted to have some activity against the exon 20 insertions in egfr unfortunately the results that um stephen lew just presented at esmo this year were a little bit disappointing that were unfortunately no responses seen among 11 egfrx on 20 insertion patients however there was some activity in her too and i think that that avenue is being pursued further with tarloxed nib and then lastly um another drug bdtx189 from this is an oral allosteric or b inhibitor which is just now in phase one testing so hopefully we'll see more with of that with that drug in the near future so with that i'll wrap up this whirlwind tour of exon 20 insertions and maybe bring it back to the group um maria maybe just to start off with you i think one of the challenges of clinicians is that as you alluded to this is just getting to be an incredibly complex landscape with an egfr and i will often have colleagues that will come to me and say you know i don't know what to make of this the you know p 774 insertion how do i know whether this is an exon 20 insertion and xn19 deletion you know from a pathology perspective what are some of the efforts that are that are happening to try to make these reports as as easy to access and as easy as interpret for for you know clinicians who recognizing that they often the clinicians interpreting them are often not even lung cancer specialists but often general oncologists that are keeping up with not just lung cancer advances but many other diseases as well yeah i um this is a great question i think that i even have my own colleagues asking me questions on these reports and as as you know reports can be very very difficult to look at because there is no um they are not written in a very homogeneous way one laboratory may may report them in a different way while another laboratory may have notes on where it is located so um there is a significant amount of effort from um from several societies and certainly from amp uh which is the association for molecular pathology to um to bring some sense to the way that these reports um are being written what makes things even more difficult for egfrx 20 is that for a very long time because because of the technology that was being utilized these mutations were usually being reported as insertion mutations rather than duplications which are actually exactly the same mutation so depending on how you report them they could be moved several bases uh forward or or um or before so so it is sometimes difficult to know uh where they are located i think that the most important thing that i can say is that um you have to whenever you have a report you have to be able to get back to your pathologist and say um can you clarify the report and also how do you report this at an institutional level rather than saying you know if they are located between you know 770 or the specific locations it's just better to have a very clear idea how they are reported from the pathologist and when in question you should always ask your pathologist um and and again the other thing would be to make sure that the literature is actually homogeneous and to actually call these mutations um by the specific location and by the type of mutation that that they are rather than uh calling them insertions they should actually be called um duplications when they are in fact a duplication because then that this actually tells you exactly the location where they are um i hope i answered the question i just did let me know if that was sufficient absolutely i mean i think this is such an interesting area and i think it's a it's a great answer and you know what i'll say is that i think this is a confusing area for all of us even those of us that work in the space and i think many of us will often ask our you know our friendly pathologists our colleagues and i you know i think for everyone listening feel free feel empowered to reach out to either the pathologist performing the tests or sometimes to uh myself or another you know oncologist at a larger academic center because this is incredibly tough we all you know sometimes need to phone a friend and i think you know all of these resources are going to be important particularly as it becomes more and more important to identify these and get the right patients on treatment yes i will say in addition to that is that the the um precision medicine is definitely a multidisciplinary effort it is not something that is done by the molecular lab or that it gets interpreted by a species it's actually something that needs to be done at an institutional level with everybody who uses the tests and does the tests in complete agreement so that things can be understood and if the and testing can be done appropriately um so i would emphasize that again this is a multi-disciplinary effort and it has to be done at an institutional level absolutely i think that's a great point um josh i'm curious you know you've been involved in many of these trials you see many of these exon 20 patients and maybe if we just take clinical trials off the table for a moment you know if you see a patient with an egfr exon 20 insertion you read your pathology report you talk to your pathologist you say okay this is an exon 20 insertion what how are you treating these patients outside of a trial what do you think is is you know the preferred approach for these patients are using chemo or using chemo io how do you think about this so it's a really hard problem and i actually am trying to do it sort of like a chess game i'm trying to think of the next thing i want to do and so based upon the data that that you generated for osimertini for high dose osmotic which we can get off label based upon the approval in other settings i have stopped using immunotherapy in the first line management of these patients i use uh platinum double usually carboplatin and pemitrexid and then at the time of progression if i don't have access to a clinical trial i would tend to offer osimertin about 160 milligrams because based on the data that you presented ideally however i think it's important to note these patients really do need access to these clinical trials these drugs are very exciting and i think that it's important for us to develop them so we can get better access around right now i think it's exciting to see you know all of these different options and personally i'll say it's also exciting to see drugs with different mechanisms of action and i think one of the important areas will be how can we use these drugs in sequence you know can we can we help patients to access more than one of these drugs as a way to to you know prolong prolonged progression free and ultimately overall survival but by treating them with different new targets in in sequence so maybe um in the interest of time we can move on to the last section about testing which i think is ultimately you know really the bottom line here if we don't test we will never going to be able to to help patients get on to any of these new and exciting therapies and then we can come back to this discussion after that absolutely so i will take um the next session um which is on well not only how to test but also who to test and when to test so in in terms of who do we test so based on guidelines right now the all patients with advanced stage lung cancer should be tested um for for egfr mutations regardless of their clinical characteristics and as i said before usually patients who have egfr mutations will be women who are asian who are non-smokers but this is actually while the mutations are more common in this type of patient population there are other populations that would have a very very high number of bgfr mutations such as certain substance of latin american populations for example where the mutations could actually be up to 50 percent as in the peruvian population for example um so any and and by the same token patients who are smokers will also get these mutations um so any patient regardless of characteristics as long as they have advanced stage lung cancer should be tested um also any patient at the time of recurrence or progression if they were not tested prior previously and also patients who are at lower stages this by guidelines right now the the testing is encouraged but it's actually not uh it is not required however we already talked about the interim analysis for the adora trial um which gives us a very good reason to make sure that we actually test these patients at an early stage and as i said before it can greatly facilitate the testing um and and reduce the failure rate in lung cancer um also in terms of guidelines um the when do well we talked about when do we test but also um how do you actually test and the guidelines themselves don't actually tell you what is the type of assay that should be done uh current recommendations are that you test by by any method but the ngs of course is the preferred method because you would be able to test for all of the genetic alterations outside of the gfr that are important for a targeted therapy um but if that is not possible then panels or multiplex testing is is the best way to go um the in terms of the tissue right now uh formal infects paraffin embedded tissues cytologic material fresh tissue the tumor tissue itself is the gold standard for testing and we will talk about uh cell free dna in a little bit but at this time the gold standard continues to be the tumor tissue um in terms of um of the sensitivity of the assays that are required so for for specifically for egfr the guidelines say that you should have at least 20 percent tumor um a 20 tumor content which means about 10 variant frequency for a very alien frequency for that specific mutation and this is for the sensitizing mutations however the sensitivity that is required for a patient with acquired resistance for example has to be much lower and the assay should be able to detect mutations when the tumor present is about five percent or a varying allele frequency that is around two percent um and in that in terms of the design and this is where things get actually very difficult for egfr mutations it's because they're the egfr there are so many egf mutations and the answer to choose to be able to test them has to be one that is designed in such a way to be able to pick up any mutation that is found in the general population of lung cancer in a frequency of at least one percent then that means that many many many mutations have to be tested types of mutations and this makes the designing of the assays much more difficult which brings us back to the reason why next generation sequencing is such an attractive technology to be able to assess lung cancers but to go to uh the the ngs testing so many laboratories are broadly adopting this ngs technology again as a very highly attractive technology for assessment of tumor samples but next generation sequencing has there has its pros and it also has its cons so the pros is of course that it allows optimal tissue management and cost containment and a very broad approach that is able to uh test for many mutations and very rare markers so that you can you can treat your patient with either approved agents or alternate targeted therapies under clinical trials however the cons are that the more comprehensive the assay is to be able to detect both fusions and mutations and the broad range of mutations that are present that means that the the turnaround time is much longer there are also some technical drawbacks to next generation sequencing it may alone a single test may not provide all of the answers that are needed for a timely clinical management they also may lack depending on the assay itself the sensitivity that is required to be able to detect the mutations and again a single assay may not detect all of the markers and you may end up having to do two different ngs assays to be able to to test importantly not all ngs assays are the same and you may go from very very comprehensive assays very large hybrid capture panels to even exome sequencing um to more targeted approaches that are cancer specific and even to the very target specific single gene assays uh which is the non-ngs type of the of testing um importantly again um each assay is going to have its own nuances and it is also going to change the turnaround time so you have to really choose the assay and understand some basics of the assays um to be able to decide on one what test to get um the the issue with long and carcinoma specifically is that this is the prototype of the very difficult clinical scenario very advanced stage disease with very limited tumor material a very wide range of clinically relevant genetic biomarkers where you have point mutations insertions and deletions structural changes all these rearrangements and fusions and even now copy number alterations that can be that need to be tested and the samples themselves are not only very small but they can be highly heterogeneous you can have these just very very tiny biopsies with a good amount of tumor but a lot of inflammation which dilutes your your your your varying allele frequency very very fast or you may have a lot of um a lot of other non-neoplastic cells that will dilute the the um the specific um tissue but also the very very small tissue is very difficult to micro dissect so at a testing level these are extremely extremely challenging samples so for us for example we do testing on absolutely everybody as they come in and we have learned a lot of assassins uh a lot of lessons from our own testing so in this slide for example um this is the summary of the first ten thousand samples that we tested by msk impact and lung and carcinoma by far was one of the cancers with that that ended up with incomplete testing um and this is because of the heterogeneity of the sample so despite the optimization that we had at the time when we when we published this report for example um a lot of the samples uh that were the small biopsies and the and and the the cytology samples which are the vast majority of the samples that do you see with lung cancer those were the ones that had um an incomplete testing or the testing was just not it it it led to a failure so about um 75 percent of these samples are have a success uh however you still are left with about 25 percent of the samples that are that that that you won't be able to test or you will not be able to get as much information as you as you needed from them and this is at the time that we had already optimized um a lot of the a lot of the protocols so at that time we started um optimizing our workflows um at an institutional level to be able to get to the point where we could actually have a success rate on regardless of how small the sample was so um in 2015 and 16 recognizing that there were specific issues with psychology samples for example we started the optimization of our uh procedures which was an agreement with the entire institution from the time that the sample was was submitted to the time that it got to surgical pathology how those samples were cut and how those samples actually got to our laboratory and this was a huge amount of effort uh and i will just i won't go over the details but on the slide you have the the uh the two publications that we put together where we showed that by optimizing the workflows alone not even the extraction um we had a success rate that improved from 75 to 92 success rate for next generation sequencing and this was for a very broad assay that was testing for more than 400 genes um but even then as i said you know an assay like msk impact which is our the one that we use it takes about two to three weeks for you to be able to get a diagnosis so we have to institute in between some very uh some single gene assays to be able to allow for um for rapid triaging of these patients that needed a diagnosis so we started um including single gene assays before next generation sequencing so what we actually needed to show was that this including smaller assays two or three tests before you actually do your next generation sequencing would not prevent you from getting the broad analysis on those patients that required very more broad genotyping so on this um we we later published on the fact that we could we could do rapid assays ultra rapid acids for screening of egfr and keras and followed that by ngs and still have the same success on these very small biopsies but again you know you still you we may have a success rate of 92 which is actually very high for these very small samples but they're going to be many patients that are not going to have enough tissue and will end up without a diagnosis and that just brings us to whether you need plasma testing or not or or cell free dna so um while tumor biopsies in terms of the the uh the workflow for testing require multiple steps where you where the oncologist receives uh with the oncologists um would or the um or the radiologists would do a biopsy the eye procedure is performed the pathologist is going to review the um this specific tissue and then that goes to a molecular lab it could take several weeks before you actually get that while with the liquid biopsy is just you get the the the uh the blood sample you isolate the plasma that goes to the molecular lab and you can perform the test and then you can have a diagnosis within just a few days um i wanted to point out that um when you do cell free dna assessment this cell free dna is not only for plasma the cell for dna may be obtained from any body fluid and this is actually a very very um rich source of tissue when you don't actually have a tumor tissue biopsy that is sufficient when should you do a liquid biopsy when the biopsy is insufficient when the biopsy is not feasible when the cell free dna that you obtain from a sample is actually more suitable than but then the biopsy itself um or timing considerations when the patient just really cannot wait for that biopsy to be obtained um or cannot actually have an invasive procedure to be performed um samples of such as cell free dna from from csf for example are very very good samples to be able to test and they are actually better than a biopsy itself um so we are using cell free dna from any body fluid right now to test these patients pleural fluids peritoneal fluids pericardial fluids and these actually give a very very good result but cell free dna from csf is actually superior to the biopsies where you may have about sometimes 25 percent of the cases who get a biopsy uh from the central nervous system would end up with no diagnosis and or a negative cytology and the cell free dna can actually show you mutations that are not only a very very high variant on the frequency compared to the biopsy of the cell pellet from uh from the from the tumor cells that are in the in the csf um but so the number of variants can also be much higher and the mean allele variant frequency will also be much much higher so um there are so many details that we can actually talk about testing but you know obviously we're not going to have the time to do all this um so i'm just you know let's discuss some of the some of the important issues so from the oncology perspective what do you guys think about you know what are the things that we as pathologists should be thinking about uh in terms of testing and how can we overcome some of these barriers that are associated with targeted therapy you know maybe i'll start i think i think this is an area where like you pointed out you know collaborative efforts are really the best way to go and i don't just mean between oncologist pathologists but also you know the proceduralists whether that be the thoracic surgeons the interventional radiologists the interventional pulmonologists whoever is doing the procedure i think this is a place where the close more closely you can work together with all of those stakeholders the better the outcomes and i think you know one of the things that's been great to see over recent years is that i think there's been educational efforts you know aimed not just at pathologists and oncologists but also at those other groups you know to try to increase the recognition of why getting this tissue is important and why working so closely together is important and i think that's even more challenging in the community you know i think it's easy for us to say in academic centers where we work really closely and we have our pathologists and our radiologists on speed dial you know when you're in a community setting where that procedure may be happening at a whole other institution i think it becomes a lot more challenging so i guess the first thing i'll say is that this is just an area that's really rich and and you know ripe for collaboration and and for working closely together to try to get the best outcomes for patients yeah i completely agree and it's it's you know the the communication piece is one aspect of why um having things in the community can be complicated but you know when i think about reflexive testing you know i think that all of our institutions have reflexive testing for molecular for molecular samples that's not as simple as just flicking a switch and saying oh now we have reflexive testing we had to hire a staff of people to look at the biopsies that come in look at what testing has been done in the past to be a steward of that tissue to ensure it gets to the appropriate location and that's a lot of work and it's a lot of time and it helps improve outcomes for patients but sometimes we need to show our cancer centers that that also improves the bottom line but from my perspective the bottom line is helping my patient and there's no doubt in my mind that having reflexive testing improves outcomes uh for getting this test result quickly and then the other step which we spoke about before but i think is so important is ensuring that there is support to understand what the heck this report is saying um to make sure we're all speaking the same language so that the patients can benefit because i see all the time that i have patients come as a second opinion and either the testing was not done to comprehensively evaluate fda approved targets or the testing was done and it's so difficult to interpret the report that the patient didn't get the appropriate treatment that's such an important point and i think you know i have that same experience too of seeing patients you know in consultation where the testing may have been ordered but often you know it's that impetus particularly with the first line therapy that that need to start treatment that can sometimes make it okay that the testing is cooking but we need to start treatment in the meantime and sometimes i think that can lead to decisions that aren't always in the best interest of the patient this rush to start treatment you know we see this frequently in egfr patients where um immunotherapy may be started as part of their first line treatment without waiting you know the molecular testing may or may not have been sent or if it was sent the the you know the doctor and the patient together decided to start treatment before that came back and i think in that situation starting immunotherapy can have significant implications for the safety of giving a tki later on down the road like you alluded to earlier josh you know we know that the rates of pneumonitis with osimertinib and other autoimmune toxicities with those summer nip given after immunotherapy are significantly higher and so i think you know an important point here is not just to order the testing but also to wait for those tests to result to return and to make sure to be acting upon them appropriately and that i think is an important point for the oncologist but also something that really you know you have to involve the patient in that decision because if i were a patient i wouldn't want to wait either i'd want to start treatment as soon as i could but i think here is an example of a time where waiting for that information to make the best decision for the patient is really the the best thing for the patient and i think it's a really critical point when we talk about testing yeah i agree one one last thing that i that i did want to to add i mean from from the molecular pathology perspective is that you know within a laboratory and within pathology itself there it there is such huge complexity on how the tissue moves around in the laboratory so there there are many issues with batching having to batch the test where you have to wait for additional samples for you to be able to perform the assays um and this happens a lot with next generation sequencing when you don't have a very high volume you may have to batch the samples to an entire week so that you can run those assays and there are also delays at many points um within the pathology department in getting the tissue being cut getting the tissue labeled going to the laboratory itself triaging and all of these things that happen so one of the you know this goes back to the communication issue if there is communication to the pathologist to say this is you know these are the samples that are that are really needed to be done um as fast as possible and create a specific triaging mechanisms for for the lung cancer patients this is actually very important and this was one of the things that we we concentrated on and even then there are delays at every step of the way so even sometimes they would the best way that we can get the diagnosis to you guys is to say i'm going to give you a preliminary diagnosis well that is not entirely official and that isn't a data that hasn't been typed but at least it will allow you to get your patient uh to be taken care of while that while that case gets signed out and all of these other things happen in the background um so communication again i think as they is is the most important thing uh within all of the teams that are taking care of the patient you know i often tell my patients i think when we have a new diagnosis you know we're going through the staging workup we're going through the biopsy and i'll actually tell patients that behind the scenes you know they may be seeing myself and my team in the clinic but behind the team behind the scenes there's a whole team of doctors and staff and technicians and other people who are working really hard to get the information as soon as we can and i think sometimes hearing that and also talking to patients about the fact that you know from a medical perspective for the vast majority of patients it really is safe and appropriate to wait for that testing to result to be in close communication now you know one of the things i found actually during the pandemic is with the advent of virtual visits i can tell a patient i'm going to wait i'm going to be in touch with the pathologist as soon as i have those results back we'll set up a virtual visit we don't have to necessarily you know make a plan for you to come on my clinic day and we can we can go over those results as soon as they're available i think that's really helped patients to feel you know more comfortable and in waiting but i think it really requires that that team effort that's so critical here yeah absolutely all right well so i think that we have run out of time we could talk for hours um about this there are so many little things that really need to be done but this ends our educational activity for today highlighting recent progress and best practices in genomic testing and targeted therapy of egfr mutated lung carcinoma i hope that you all found this content uh to your liking and that our discussions were informative and useful to your practice thank you again for joining us and thank you to all the faculty who joined us as well thanks for watching thanks so much thank you for listening download materials and complete the post test for instant credit at peerview.com forward slash cwe860 this activity is supported by independent educational grants from astrazeneca jensen biotech incorporated administered by jansen scientific affairs llc and takeda oncology this activity has been jointly provided by medical learning institute incorporated and pvi peer view institute for medical education

Channel: PeerView Oncology

Views: 1,086

Keywords: Dr. Maria Arcila, Dr. Zofia Piotrowska, Dr. Joshua Bauml, lung cancer, NSCLC, non–small cell lung cancer, EGFR, mutation, EGFR-mutant, EGFR-mutated, osimertinib, poziotinib, mobocertinib, amivantamab, NGS, liquid biopsy, pathology, oncology, thoracic oncology, ADAURA, FLAURA, gefitinib, erlotinib, afatinib, dacomitinib, ramucirumab, L858R, exon 19 deletion, exon 20 insertion, T790M

Id: PGM4l_uMheA

Length: 65min 12sec (3912 seconds)

Published: Fri Feb 05 2021