Dosing Strategies and Adverse Events in Patients Treated with Selinexor
Discourse centered around dosing strategies for selinexor-based therapies.
Dr. Peter Forsberg: Just to get a little bit more granular with the data, I do think for a lot of folks mechanism of action is appealing, oral therapy is appealing, and having something that can partner based on this group of data that's emerging. But I think for a lot of folks, when they think about selinexor, they worry about some of the side effects, about toxicity profiles. I think that what is important is to know about some of the differences maybe a little bit between twice-weekly, and once-weekly dosing, and then to get a little bit more granular about what may be a more manageable than sometimes people conceptualize it to be toxicity profile. So, these are the hematologic adverse events from the BOSTON trial, and the STOMP study, what we can clearly see is that in patients who receive selinexor-based combinations that there is a higher rate of all types of myelosuppression but particularly, thrombocytopenia, and then it does appear that when you put it with certain partners, as you mentioned, hematologic toxicity or myelosuppressive overlap being a dose limiter that when we do put it together with pomalidomide, we do see higher rates of neutropenia and anemia. But a relatively similar rate of thrombocytopenia, which tends to be the more pronounced with bortezomib at least. This is the non-hematologic toxicities, or adverse events, again with BOSTON and specifically with the SPD arm from the STOMP trial. I think that the notable adverse events that are clearly more common when in the selinexor-based cohorts, include nausea, fatigue, reduced appetite, and potential for things like weight loss. So I think those are notable adverse events and ones that I think you do have to be thoughtful and proactive around as you consider how best to consider initiating with dosing and supporting patients. So you mentioned that you were just starting a patient on a combination, you said 60 milligrams in that combination. What's your typical starting dose for selinexor in practice? Is it geared around STOMP doses? Is it a little bit different? Is it more similar to BOSTON? Or is it just a – really depends on the scenario?
Dr.Joshua Richter: So the short easy answer is, it depends on the scenario and I can just get out of answering that specifically. But I think the starting doses that they quote here as the MTDs are generally what I do. All else being equal 100 milligrams weekly with Velcade, I give 80 weekly with Kyprolis, and 60 weekly with pom or rev and – usually with pom. But that being said, I think there's coming emerging data that between 60 and a 100 milligrams, there may not be huge leaps in efficacy, and you may save a little on toxicity by going 60 or 80. So for patients that are a little bit older, frail, or worse kidneys, or worse marrow reserve, I back down to 60 or 80 just to hedge my bets, because it's still extremely active at 60 milligrams.
Dr. Peter Forsberg: I'd say that I think for me there is a little bit of diversity in terms of my initial dosing. I certainly have become more and more comfortable with starting at a lower dosing level and if a patient tolerates well, could always consider escalating the dose if – once you get through. Because we do know that some of those issues that we run into, some of the GI issues like nausea, are more pronounced first cycle. So if you can support patients through that initial cycle beyond getting a sense for their marrow function, you may gain yourself some additional wiggle room if you do really want to buff up that efficacy. But I do agree that I think that the data does seem to be pointing towards the fact that there may not be huge efficacy differences between some of the dosing levels. So I would certainly say that if I start with those, STOMP as a guide based on partners, or STOMP and BOSTON as a guide, I certainly don't hesitate to modify dosing based on toxicity. If a patient develops substantial GI issues or notable marrow suppression, taking a pause and resuming with a slightly lower dose. A 20-milligram reduction based on dose and cohort is something I certainly don't hesitate to do, knowing that I don't suspect that I'm losing too much in efficacy with those adjustments. In terms of planning around supportive care, do you have a one-size-fits-most approach to some of the supportive care, or is it a little more diverse as well?
Dr. Joshua Richter: So my general approach, all else being equal, is to try to be more proactive than reactive. And I think you brought that up and I think that's a really important thing is to get ahead of this, especially for any GI or nausea, you want to avoid any risk of anticipatory nausea. So I tend to be more aggressive early on, exactly like you said that you have to worry about it in the first cycle or so. So giving steroids, I give Zofran and I'm a huge fan of Varubi, rolapitant in this case. And some people may not be as familiar with rolapitant. It's like Emend which is aprepitant, except there are fewer drug-drug interactions with rolapitant, it's 180 milligrams every two weeks. It can sometimes be a little bit complicated to get insurance to pay for it because they have to go to the last page in their book to say, what the hell is this drug I've never heard of before? So for those patients that I can't get it quick enough, I'll give olanzapine as the third drug to offset their risk of GI tox.
