All About Xpovio (Selinexor)

what is expovio or celanexor so cell nexter is a very exciting new drug it's a first in class agent which means it's a novel mechanism of action we don't have any other drugs in this category and what's really interesting about this is it's not just myeloma and the reason i think it was published in new england journal is there are other tumors that are also being studied including lymphoma sarcoma endometrial cancer how does the cell and xor work cancer cells have a shuttle protein that moves proteins from the brains of the cell the nucleus into the cytoplasm and oncoproteins and so these are proteins that help the cell grow and these are also blocked from being moving into the from the brain into the cytoplasm and the third protein is the glucocorticoid receptor everybody's favorite drug steroids is actually moved from the brains of the cell into the cytoplasm and by blocking that you all of the these three protein categories that are retained in the nucleus results from the cell death and so i think what's exciting about this is it's amazing that it's working in myeloma but the fact that it applies to other tumors tells that this is a general cancer mechanism right so many cancer cells are utilizing this mechanism to prevent cell death and avoid resist and avoid chemotherapy killing what is the current indication of selenic sore so the current indication for saline extra also known as expovio is basically heavily treated patients so in this study that was done known as the storm the indication is essentially the same as the study eligibility criteria so patients had to be what was considered penta exposed for that study which means the two proteasome inhibitors bortesmid carphylsemip the two images lenolidomide and pomelodamide and the cd38 monoclonal antibody which until recently was just dara but now we have another drug esotexum but basically patients not only had to be exposed to the drugs but more importantly this is really what the label focuses on is triple class refractory so you've not responding to p protozoan inhibitors not responding to imminence not responding to cd38 and so really that's an unmet need and i think that's important because most random most new drugs require large randomized phase three studies this got what was considered an accelerated approval which means it was on a single arm study every patient got the drug there was no comparator arm it was 122 patients who all met these criteria and the fact that they had a response is what led the fda to grant this accelerated approval for this particular indication because this is an unmet medical need in myeloma when patients exhaust those categories of drugs what do we do and so i think it's great that patients have another option what is the dosing of seleniux or like is it used in combination with anything else and is it an oral drug the dosing of salinex is very important we know from initial phase one study that was published in blood by chen in 2018 the phase one studies they escalate the dose of the drug to determine both safety and efficacy and so what we found in that study was that you really don't get the activity of the drug until you get to 80 milligrams twice a week so that's given on day one and three so for example a typical schedule might be monday wednesday monday wednesday monday wednesday monday wednesday and then the dex is added on those same days now it's important to talk about the drug in dosing because of who these patients were so in storm these are patients who typically had had seven prior chemotherapies over 6.6 years that's important because we talk a lot about risk but you know that if you went through seven chemos in 6.6 years these are high risk patients right because if we think about a typical patient getting induction therapy transplant and maintenance if that should be lasting four years and here you have patients that have gone through seven different drugs in 6.6 years it tells you that these patients are high risk and over 50 percent did have high risk features and more importantly or as important when patients sign consent to the day that they got cell and extra which was a median of 12 days there's a 22 increase in the protein these patients had explosive disease so the reason i bring up those points is that i often tell patients this is like you need to accelerate you're trying to get across a ramp on a car if you don't go fast and jump across we're not going to make it over and so when you have such heavily treated disease and when you know this drug requires 80 milligrams twice weekly to dose that is the approved dosing schedule for a single cell and extra with dexamethasone alone so a single agent slash combination with dex regimen and so because of that dosing and schedule we were able to get a response rate um about 26 percent although we can talk more that at mount sinai that response rate was actually 56 we used very aggressive supportive care and so the reason you need that dosing and schedule is that we need to get the disease under control these are patients who many might end up having gone to hospice without disease control once we control the disease then we can pull back because there are side effects that require management but you can't you can't control the disease if your patient's not still on the drug right so i think that's an important part now there are very exciting other combination studies ongoing um and there's a study there's a regimen there's a clinical trial called stomp where basically takes backbone regimens and adds cell and extra so bortezumib uh carfalzemib lenolidomide pommalidomidera and what's important when we do these combination studies is that the dose of cell nectar changes when you do combination studies and it's important to put this into context we've had a lot of drug approvals we makes i think 11 in two decades and let's look at the other drugs that have been improved recently carpals and palm and dara they had single agent approval they had accelerated approval but no one's using those drugs as doublets right because in heavily treated patients you need combination therapy a response rate of 20 to 30 percent is just not enough when you do combination strategies you're getting response rates of 60 to 70 percent and so when you do combination strategies with cell and exer it really depends what the partner drug is so if you're not using an imid the dosing schedule is typically 100 milligrams weekly if you're using an image it can typically lower at 60 milligrams and the reason for that is because the image cause lower blood counts than the other drugs like protozoa inhibitors and cd38 so a hundred for non-image and 60 for imid again both are weekly and the last point i would make on this dosing and schedule is we recently just this week had a press release from cario farm showing that the boston study which was mortezumab decks twice weekly compared to bautism decks with cell and xor and this showed favorable results where the patients had a significantly longer progression free survival with the addition of cell and xr compared to the control arm and what's particularly interesting about this study is that in the control arm bortesmeb was and dexamethasone were given twice weekly whereas in cell and xram it was given once weekly so this is the very the first time this has ever been done because it's risky for a company to use less of the backbone drug means your drug has to work even harder because you're not using as much bortisma than dex so the fact that this regimen was efficacious shows that not only does cell and extra index work by itself in heavily treated patients in less heavily treated patients it can be combined and improve the clinical outcome one of the important features of cell and x-rays it's a oral regimen and or cell next or with dexamethasone obviously oral completely and depending on what your partner drugs if you're doing combination strategies regimens like cell and x or dex and pomolidimide which was presented at ash by christine chen as a completely oral regiment celenex or dex and lenolidomide would also be oral this is great for patients who may be living far away from a cancer center perhaps in a rural area i've been fascinated by how much interest there is xus uh you know patients in china live very very far from infusion centers so there's a big need for oral drugs and i think when you have an active drug uh that's oral it's it's great for patients what are the unique side effects of cell and xor how are they managed and what are the long-term side effects side effects are always an important part of management of any drug and cell and extra definitely has side effects like many all of our other oncologic products and when we first started doing cell and xer treatments our patients also had a hard time but we had the ability to learn from our experience because of the volume of patients so at mount sinai we treated a quarter of the population on storm and we have a manuscript that's now shortly going to be published where we looked at our outcomes compared to the overall population so our response rate was over 50 percent compared to 26 percent our progression free survival was 5.3 months instead of 3.5 months and our overall survival was over 15 months compared to 8.6 months so how did that happen well we learned from our initial experience that this drug does have gi side effects and so i would say the main side effects of cell and x are the categories i would put them are gastrointestinal hematologic fatigue and sodium and so what did we do for each of those categories for gi we realized that a lot of patients had nausea not as much vomiting but more nausea and we think the reason for that is this drug does penetrate the blood-brain barrier and there's a what we call a metagenic center which is the area of the brain that can cause nausea this drug may be activating that so how do we block that we decided to use an aggressive cocktail and we used undancertron or zofran every eight hours especially because the drug has a short half-life you don't have to give it forever because it's a day one and three schedule or once weekly in combination give it for those initial few days that the patient's on so on dan cetron or zofran we also gave a drug called an nk1 receptor antagonist like rolapit or veruby every two weeks there are other nk receptor antagonists the reason we decided on this one is those other drugs like a prepping or a mend can actually activate or potentiate steroids so if you're going to give that drug you actually have to reduce the dexamethasone so if people can get that drug and that's the only one fine just lower the dex and then the third drug that we used is a lanzapine or zyprexa all of these drugs are on label for nausea some people get scared because lanzapine's officially also an antipsychotic drug but it is on label it's studied and it's been approved by the fda for nausea so we start with this aggressive cocktail and then once we've gotten off that ramp and the patient's had a disease response and now we're able to control it there's sometimes other issues that come up that require reduction of the dose anyway then we start pulling back right so i think in oncology the adage is supportive care should start from day one right we shouldn't let patients suffer and then try to address it and catch up it's much better for everyone patient first and foremost to start with the aggressive preventative strategies and then once they're tolerating it while you can eliminate things that are may not be needed the second thing that we for the fatigue it's just to address the other side effects or the other causes of fatigue so this could include anemia it could include thyroid function adrenal insufficiency dehydration which can be treated with fluid so you have to address the underlying cause for those patients where we couldn't find anything else and we'd reduce the drug and that's an important part of side effect management because when we talk about drugs we use a parameter called half-life which is when you take the drug how long does it take to clear the body this has a relatively short half-life of four to six hours and what we know in medicine is that it takes four half-lives to leave the body so pretty much if you take the pill within a day it's going to be gone so you can always reduce the drug when you re-challenge with the next week if the side effect is not manageable so we talked about gi we talked about fatigue for sodium it's often from not having enough food intake or salt intake so we would give typically fluids and or if not responding to that we would sometimes give salt tabs and then the last one is hematology in some ways this is the easiest for our community and academic hematologists oncologists manage because if you're a hematologist oncologist you know how to manage blood counts especially for a bone marrow cancer like myeloma and so it's important to talk about this because saline x or you know whenever we talk about a side effect of the drug it's important to know that the side effect cannot be extricated from patient factors and disease factors so by that i mean the rates of severe thrombocytopenia for example or low platelets are much higher in myeloma than we see in other tumors like lymphoma and liposarcoma because those diseases don't have as much marrow replacement right so myeloma patients typically have been beaten up more by their this time of their disease course their bone marrow may have more myeloma and they're going to have lower blood counts so one of the ways to deal with the blood counts obviously with white count we give growth factors like lupin neupogen or filgrastim is a generic neupogen brand zarzio we can hold the drug again for red cells often we transfuse for platelets we actually used in in this manuscript that is coming out shortly there are drugs that stimulate platelet production like rameplastin or end plate which can be given when the platelets are dropping if you have to hold saline exer you can give these drugs to boost up the platelets and then resume the treatment so i would say that in general our experience showed that side effect management is really important when we looked at the overall number of patients in storm coming off for adverse events versus progression at mount sinai was only two patients which is seven percent compared to 33 and so i think this is proof of the pudding why did our patients have better response rate better pfs better overall survival it's because less patients came off for side effects we were able to keep them on therapy so they could derive benefit and the final point i would make in side effect management a lot of this is counseling when you're telling a patient for the first time about silence or you say look this is a drug that works it's been fda approved as a single agent now also we have evidence in combination completely novel mechanisms of action but there are side effects our plan to do deal with this is really be aggressive about supportive care we're going to start you on a cocktail of medications and if we don't need it we will pull back and if certainly if you need more we will do that but i think if you tell patients that this is not an easy drug for everyone but the side effect managements are effective and it's an effective drug i think that really changes people's willingness to do these things and um also emphasizing that if if there is a side effect we can always hold the drug and the side effects resolve quickly and i think that's shown by the fact that in our patient population even though the pf progression free survival was 5.3 months people live 15 months over 15 months and the reason for that is if and when they start progressing there's no severe side effects that that prevent you from going on to yet another clinical trial right in advanced myeloma this is like a tarzan situation you need to grab onto a vine so that you can then get to your next vine and that's what this little drug allows you to do because of the aggressive side effect management so in terms of long-term side effects we talked about the the gastrointestinal fatigue hematology and sodium notice what we didn't talk about we didn't talk about cardiac renal pulmonary really those are the things that are going to potentially prevent these patients from going on to other treatments or studies and so the fact that we don't have any of those non-heme toxicities the fact that the drug has such a short half-life i think speaks to the ability of this drug to do its thing and if and when you need to move on the patients are ready to go on to their next therapy how can celine xor help relapsing car t patients so we talked about the use and current indication for style and xor but one of the other most unmet medical needs with in myeloma right now is in patients who undergo car t what do we do with those patients if and when they don't continue in remission and that's a very tough population to treat because they can end up with sometimes low blood counts extra medullary disease and perhaps most importantly when we prepare patients for car t they get treatment called flu dairy bean and cyclophosamide and these drugs are very potent immune killing drugs so they can knock out a patient's t cells which is a part of the immune micro immune perhaps the most important part of the immune system and these are the same cells that are responsible for activity in the by specific drugs right so we have these whole new classes of drugs called t cell engagers or by specifics where they have half of the drug binding to the t cell the other half to the myeloma and by bringing the t cells close proximity they kill the myeloma the problem with these carte patients is not only have by definition if they're progressing on cartee that car is not working anymore and they may not have any t cells from the flute arabian and so we recently just published a manuscript in british journal of hematology just this week in march of 2020 that showed activity of cell nectar-based regimens we had seven patients who had cell and extra uh either with dexamethasone bortezumi or carfilzomib that all had responses and what was striking is some of these patients had responses that were were deeper and more durable than during the car so i think that's a really great option because going forward our next unmet medical need in myeloma will probably be post bcma failures right so bcma is that protein that's being targeted in many ways by car t's by bi-specifics by the antibody drug conjugate known as balantamab from gsk and so while these drugs are working what do you do when that stops working so it's another great option for patients and again completely oral so it'll be i think it's another option for patients and i think i'm also very excited about the science being done can we identify who will benefit from solidnext or who might be resistant and amounts on it we're doing some very exciting work potentially finding some biomarkers that might predict for resistance so meaning if somebody has a particularly high expression of a protein such as mage that may predict for lack of response perhaps those are the patients that need combination therapy