Medscape in the Clinic: Sequencing and Rechallenging Oral TKI Therapies in Metastatic CRC

hello everybody my name is Mark Peters and welcome to Medscape in the clinic um I'm currently the CEO of the ANP University Hospital in ANW Belgium and also food professor at the department of oncology my colleague canell regev will uh introduce himself please canwell thank you Mark hi everyone I'm Kamal ragav one of the associate professors in the department of GI medical oncology at the University of Texas MD Anderson Cancer Center really excited to be uh on the show today so today we will discuss to together the different strategies and also the sequence and of course the challenges that we have in the current therapies with metastatic coltic cancer patients we have several options and one of these op s are oral tki therapies but the question is how to sequence in real life setting and that's reason why we're going to discuss at least two cases I welcome um the audience to and also ask them to have some questions because we want to have a debate and to see what is the scope in your uh practice at home to treat these patients and also to have some sequence in the therapies that we have available not only in the US but also in Europe so the first thing that we see is that um we have different lines of treatment like we already discussed um of course the patients that receive more lines of treatments have a better outcome um throughout the world the median overall survival is between 15 but some patients have longer overall survival um if they receive more lines of treatment for example if a patient receives seven lines of treatment um it can be up to uh 37 months in median overall survival this is not only the drugs that they are receiving but also the multidisciplinary approach that currently um is is most of the centers available to to to follow these patients up in their treatment strategies so the question is how can we um try to have a management based on several factors that we have available not only the performance status but also the fact that we are dealing with a very hetrogeneous disease uh we have seen recently some uh ideas on sideness of disease um the the fact that patient have multiple sides of a metastasis might have an impact on the treatment uh selection um but also the performance status of the patient might influence uh the treatment in a given patient so the first case and I hand over to kenwell to introduce the first case of um uh this session is 65y old male patient canell it is your turn to U yeah thank you thank you Mark um so you know we'll start with this case one and this is not an uncommon scenario that we would see in the clinic um a 65y Old Gentleman um initially presented with stage three colon cancer um which was Ras mutated right sided MMR proficient her to negative um but then developed recurence after about six uh after receiving six months of aduan f Fox you know one year later uh you know the Adin F fox went well but of course the patient has some great neuropathy um which is persistent right now uh the recurence is in form of very small liver lesions and then some lung metastases um and the patient was started uh on first line treatment with metastatic for metastatic disease with bmab and ffi so 5 Fu and iroan and received almost 9 months of this treatment with some initial response and then stable disease but the course was complicated by cytopenias requiring multiple dose reduction growth factor support um and one episode of like fbri utr um today you know the ca levels have started to rise again Imaging is now showing some minor disease progression uh with a new liver lesion uh but the patient still maintains their performance status you know so the bigger question that arised is is that this patient is now interested in a break from infused therapies from IV therapies um and the and you know the obvious question is what would be typically the best option at this point and can oral therapy be used to achieve or maintain stable disease as a bridge to systemic chemotherapy um you know especially when the patient has low volume disease and what would you do in case the patient has bulky disease um in this patient obviously uh one of the options that we have is a reintroduction of f Fox as a second line chemo for metastatic disease um you know there there was a one-ear disease free um um interval so it's reasonable however um you know there are two challenges to that kind of uh chemo re challenge number one uh the patient has some toxicity ISS issues that are associate that are complicating the picture particularly neutropenia um and um and then the second issue is the uh the presence of the grade to neuropathy which will get worse uh in case of a re challenge uh with oxal platin um and one of the more important criteria is the patient is also now tired of chemotherapy has been getting chemotherapy for almost 15 months um and wants to stay off the um off IV medications um obviously there are some third line options uh more specifically regb as we have seen from the correct study um Tas 102 as we've seen from resource study Tas 102 plus Bev which is not purely an oral regime but an oral plus IV um which would be the sunlight trial and then we have um you know some insight into the newly FD approved uh fretin from the Fresco 2 study um most of these have of course been in patients uh who have already progressed or are intolerant to 5fu iroan oxal platin based treatments in the metastatic line uh but there are a couple of uh studies that have looked at the role of uh moving these uh therapies up into the second line uh study one of the examples uh is um the Tas uh Plus bav versus folfiri and Bev uh this was a study uh done by kuboki atal it was um um you know it was a randomized trial it was designed as a non-inferiority trial uh but unfortunately failed to meet its primary endpoint uh of median PFS and the median PFS in that uh study uh was about U sorry the median OS in that study was about 14.8 versus 18.1 months so um second line um introduction of failed to do better than b and FF another uh study was a single arm non-randomized trial which was the stream study which was presented at G ASCO um um and it and it's um and basically it compared regor monotherapy um as a sort of Bridge to Second Line treatment uh This was um the primary Endo of this study was progression free survival at 6 months um the median PFS that was seen was about 3.6 months but the study still failed to meet its primary endpoint because the proportion of patients that were progression free at about 6 months were only 30% uh however in that regor ainab study uh from the stream analysis there were patients that were long benefiters from treatment who had median PFS of about 10.2 months these were patients that have either solitary side of disease or lung only metastases where the disease tends to be more indolent uh and despite the short-term PFS that was seen in the Stream there was no compromise of getting subsequent lines of therapy um and nearly 80% of patients went on to get uh get chemotherapy after that so um so you know those are you know couple of Trials but I would love to hear your thought on the role of oral t eyes and this disease stabilization especially when patients are not looking for IV medications or are having problems with bone marrow supression yeah I think it's an excellent question because we are facing every day the same problem that you just covered in the case that you presented um patients are not Progressive stable disease but are tired of or have side effect of their chemotherapy and then the question is what are the options available um the European situation is somewhat different because we have some drugs available but for example in my uh country they are linked to the line of treatment uh that you can give this type of drugs some are not available so we need to be very careful not to introduce some drugs that are not reimbursed in some European countries at the moment but for example this case where you have a patient that receiv reive intravenous chemotherapy in combination with one of the Biologicals and having an impact on the performance stages especially on the neutral Fields I think there is an option to bridge like you already mentioned for a certain period with oral tkis and to see what the disease is going uh to do under that uh treatment with oral tkis when the disease is stable and the side effects are under control I would continue at the moment that you see either progression or the tolerance is becoming um problematic at that moment I would switch again to one of the therapeutic options like f in a given setting or if there is no persistent neuropathy reintroduced like you mentioned for Fox in that setting so we have to be very flexible with the options that we have available and think individually what is the best option for example you mentioned also tus 102 if you have a patient where the tolerance of chemotherapy was um um somewhat difficult I don't think that Tas 102 at that moment even in combination with bism up is the best option right so Mark you brought up a good point about how uh certain therapies are linked to lines of therapy right but it seems like in clinical practice the concept of lines of therapy in color rectal is becoming increasingly blurred with like using triplet cytotoxics in first line treatment yeah um so uh you know for example in this particular patient um you know clearly it seems like cytopenias is an issue so Tas uh with or without Bev is probably not a good option um so obviously you know as sort of like this chemo Bridge um or Bridge bridging to chemo you know either raanb or for kutb which have you know bone marrow suppression of like less than 3% would probably be an optimal choice to try to stabilize the disease and get some more um you know um chemo free U treatment into them yeah I I I think I think the fact that we are not thinking anymore in lines of treatment is the way that Physicians and also the the people that are conducting the clinical trials are thinking for the moment but you have the Physicians and you have the reimbursement authorities and by the end sometimes we have a debate on the cost of drugs and that's the reason why uh people from the reimbursement site are still coming back to lines of treatment because this is an easy way of thinking but it is not clinical reality anymore so we have to be flexible in the options that we have available and like I already said based on the individual uh patient patient situation and characteristic decide what is the best option at a given time point for a given patient and for example um if there is a necessity for a chemotherapy break I think oral tkis um are a good option to bridge to further intensive therapy if necessary so I I think we can switch to the uh second case a 55 year old woman with andras mutated coltic cancer um she received f as the first line and then in a second line setting for fox plus bism up um third line was rip and then the question is if there is progression what are the options um my first question to you um is whether for is your standard in first line this patient uh 55 year old and rust mutated chac cancer would you add some biological or start with f fox in that patient um yeah so um yeah our firstline option for an nras mutated coloral cancer um would of course be um a biological in combination with the chemotherapy uh so in most cases you know I would either give be F fox or b f fi and that would depend on you know the toxicity profile and patient preferences um I mean almost invariably we do not give chemotherapy without a biological and this is a mutated patient so um let's suppose that you start with full fre bisap what would your second line and then after two lines of anti vgf this might be an option would you then go for regor in that setting or would you switch to T 102 in this setting uh either in monotherapy or in combination with bisma so I think after you know after second line treatment um with you know be FY and then be full Fox um you know the options are fairly open um you know it's either aaen Tren or Tas bav um or with Tas with or without bav um it's hard to choose between these three treatments because there is you know very uh there's a lack of data that you know cross Compares all these three treatment regimes uh they of course have shown activity all of them um the only one that we know for sure that we should not use use unless and under contraindicated is Tas without bab because there was a randomized trial the sunlight trial that showed a benefit of adding bism AB um I think the choice between all of these three treatments depends on multiple factors as we have discussed what are the toxicities the patient is having does the patient have you know requirement for like uh or or preference for a non IV treatment um are cytopenia a big issue um has does patient have uncontrolled hypertension uh or cardiovascular risk factors um so I think you know uh it depends from uh case- toase basis yeah but the evidence would show that all of them are are reasonable we have seen um recently some real world data on different strategies especially in later line setting how strong is your feeling on this data will this influence your decision for example there were some data on the the cohort that received Rego um or tus or tus in combination with bisap will this influence your clinical decision or do we absolutely need randomized stal to convince or strategy in a give a patient I think a well done real world evidence um study is actually valuable um you know I think you know for it to Trump a a clean randomized trial that's always um a hard um you know bar to meet uh and that depends on like how strong your real world data collection is um you know I know that uh you know the the osero uh study which was the prospective observational study uh it showed uh that when you give you know regular grab followed by Tas or you know Tas B followed by reg grab or Tas followed by reg there was no like major differences between you know the overall survival uh of these patients baring the ones that got Tas right obviously because of the combination of Tas Bev that works so I think the critical thing there is the lessons that I get from this is I should be able to get patients through multiple lines of treatment and the more lines of treatment they get the better their survival is but you know whether this actually tells me which drug to use or not depends on again the clinical factors that we've discussed before yeah can well we had a question in the chat um there is the cost of the drugs but also the cost of the biomarkers um at what time points in the treatment strategy do you perform your biomarkers and what is your standard set of biomarkers yeah so um we perform um biomarker estimation in all patients with metastatic disease right at the onset so first line metastatic uh there are multiple reasons behind this is that it helps you uh set up the treatment plan for the patient for later on the standard sets of biomarker is you know of course MSI um or or MMR uh testing uh we definitely get I mean we are doing uh expanded NGS panel so it gives us a lot of information but I think that the basic information that comes out and jumps at us is your MSI your Ras status B mutation status herto uh because there are distinct treatment and clinical trials ongoing uh which uh we are very passionate about and we are trying to enroll patients on them but also affects clinical Management in real time um we uh you know beyond that the the only other testing that we often do is uh some biopsies or liquid biopsies particularly um after progression especially on targeted treatments because we want to determine resistance mechanisms that have Arisen and there is also some value in re anti egfr re challenge so I think those is that is the spectrum of biomarkers that we do um but I'm not aware of any biomarkers specifically that help you with third line treatment that so so probably at that moment you decide based on the factors that we just discussed uh the lines of treatment the tolerance of the treatment and the performance of the patients and I think one of the things that we also want to cover is the side effect profile um so um the question is do we see differences so what are the common Adverse Events that we see and do we see uh differences between the tpis that we have available currently C what is the most important things that arterial hypertension and Foods yeah I mean I think that they're all very different drugs uh at least in clinic it appears very different um you know uh the task Bev combination is uh uh is you know essentially uh a third line chemotherapy option I I see it that ways there's a lot of bone marrow suppression that we see sometimes that bone marrow suppression appears to be like higher than uh higher than what you see with like be full FY or be fox in first line setting um I think uh in the Tas Bev versus the feri Bev the neutropenia rate was you know about as high as like 60 70% in the Tas Bev arm compared to like you know maybe 40 50% in like the full Fury Bev arm for cenb I am definitely concerned about the hypertension that is the side effect that we see commonly and this is not the kind of hypertension that you see with rism AB or regorafenib at least in the clinic the these can be like some highgrade hypertension so I'm very cautious about starting something like that in a patient who already has history of uncontrolled hypertension or has lots of hypertension from like prior vef exposure and with regorafenib I think the main side effects is the hand for uh you know skin reaction rash and diarrhea uh so those are the I think the the the key side effects that I think of when I'm treating these patients but uh you know I think the more important thing is we've gotten better at managing it so like how do you how do you really manage these patients how do you counsel these patients in your clinic uh when it comes to these side effects yeah I I think the most important point is um that we have a team of not only Physicians but also nurses that are following these patients very closely also at home some um um devices where we can have home monitoring of the patients and communicate very easily with them a second is um at the moment that you have side effects that are um for example skin toxicity great Tre then we have some dermatologist that is involved to see whether we can have some ideas on treatment and I think what we didn't discuss is the flexibility of the dozing um especially with Rego you know the starting of the correct study was a higher dose a fixed dose and we have seen some problems with the tolerance uh having the flexibility especially um starting low and then increasing the dose and having the same impact on the outcome of the patient I think is it's important to have this type of strategies in our daily um clinic so it's not only the flexibility on which drug but also the flexibility how to manage these um uh drugs and also to manage the side effects so for me the key is um good followup of the patient a multidisciplinary team not only for the efficacy but also for the side effect uh management and I must say with the flexibility of the dozing then most of the patients can continue the treatment without major problems and what is also important in this setting um trying to maintain the quality of life um as long as possible yeah I couldn't agree more I think you know we we have gotten into the habit of actually seeing these patients more frequently than we do actually on systemic chemotherapy um uh and and you know the redos study was a a good example of um a study in in this setting where in you know you have disease stability you have some control over disease but the side effects are significant I mean the great three side effects to be fair are you know upwards of like 50 60% in most of these drugs um so you know trying to like um show or or establish that you could escalate the dose without actually you know it didn't seem like it was you know compromising the efficacy or the outcomes um so I think that that's become sort of our standard practice when it comes to rigor ainb and I'm hoping that there are more guidance about those modifications in tasks and uh Tas B combination as well as Prof do you sometimes have the discussion with your patient openly that there are three options what is the preference of the patient almost invariably um you know barring a clinical trial which of course is our preference not not just in this setting but you know any setting um we do discuss this uh openly because the toxicity like we said the toxicity profiles are so different um and uh you know if I have a patient who has uncontrolled hypertension or cardiovascular risk factors I'm not going to like not tell them about ftin I will with but I will discuss the clinical benefit and the and the risk ratio I think you know that that always helps people not just choose the current line of treatment but also sort of be prepared for like what comes later right because if I tell them okay this is the only option that you have um then they may not understand that you know the aim is not just to get the one option right now this is just a sequencing question and at some point of time they will get the other drugs also yeah um we have been treating these patients for several years on both sides of the the ocean um is it really um important that we have these oral tkis in the treatment amorium of today to treat our patients with metastatic Rec cancer for several reasons not only for efficacy is it a major Improvement yeah I mean I think you know um as we reach that third line of treatment and um you know response is not always the only criteria uh keeping some disease stability maintaining quality of life um is also a particular criteria so I think you know uh as we are developing better drugs through clinical trials uh these are still drugs that have shown you know survival benefits and randomized trials and and therefore patients should get access to these drugs but you're right I mean you know I cannot um you know I think it's still too early to comment on like uh you know the the the cost and the value and the utility of these drugs uh in this setting okay I think we have one minute left um what are your final message to the audience G um open discussions uh regarding treatment options in third or fourth line setting um you know appropriate sequencing based on a variety of patient factors and not just you know one particular factor and then you know first and foremost always try to move patients towards clinical trials yeah that's true and do you have some uh view on the future what is coming out of the clinical trials yeah I think you know these are exciting times Mark uh you know you've been a part of you know all of these developments I think we've uh we are moving into eras of like you know personalization of imuno theapy in the MSS cohort um uh you know we're starting to see some success with uh you know next Generation antibody drug conjugates um uh you know we're starting to like get targeted therapies into more first line option so I'm I'm really excited uh for our patients and and hoping for a better and brighter future okay thank you very much um I think we are ending this session thank you for the audience thank you for the discussion that we had today and you have seen the QR code of a Medscape session that we have previous that is for the moment available at the website of metscape thank you very much thank you Mark

Channel: Medscape

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Id: V-xp3E5ruEM

Length: 30min 24sec (1824 seconds)

Published: Tue May 07 2024