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Selinexor Dose, Efficacy, and Adverse Effects

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Monday, Jan 21, 2019



Transcript:

Ajai Chari, MD:
Selinexor is a nuclear transport inhibitor that targets XP01, which is upregulated in myeloma cells. And the schedule in STORM was 80 mg of Selinexor twice weekly, along with dexamethasone twice weekly at 40 mg, and the primary endpoint was response in PFS [progression-free survival]. And so the response rate was about 25%; PFS, about 3 1/2 months.

And although those may seem modest, it’s important to remember there was a very interesting publication that in relapsed/refractory myeloma, for a novel agent to have a real, any real chance of getting regulatory approval and widespread clinical use, you need to have a response rate of about 15% to 20%. And that gets harder and harder the more heavily treated patients become. So the fact that we saw this response rate in PFS, I think, is really encouraging, and it’s why the drug has gotten fast-track designation.

In terms of the survival outcomes seen in STORM, part IIB, the phase II study, the overall survival for all patients was 6.3 months. However, in those who had at least a minimal response or higher, those patients actually did not even attain a median overall survival. So I think that’s really encouraging, and we know that back when we only had PIs [protease inhibitors] and IMiDs immunomodulatory drugs, when a patient was double refractory, the PFS was 5 months and the OS [overall survival] was 9 months. And now we’re even dealing with a more heavily treated population. So these results are very encouraging and clearly will require a randomized phase III study for regulatory purposes, but it’ll be interesting to see what the FDA decides in terms of an accelerated path to having this combination approved.

The adverse effects of selinexor and dexamethasone seen in the STORM study can primarily be lumped into 3 categories, the first being hematologic. So there were high rates of neutropenia—upwards of 50%—thrombocytopenia. But, again, I would caution that these are patients who were heavily treated. They were allowed to enter the study with quite low blood counts. And fortunately, they were not associated with a lot of infectious complications or bleeding complications. So if patients had those clinical complications, we would be a lot more concerned. But the reality is that in this kind of patient population, the alternative regimens that we would often be choosing for them would be something like 96-hour chemo regimens like VDT PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide], which are guaranteed to give nearly 90-plus percent of rates of neutropenia and thrombocytopenia. That said, it does require monitoring and transfusion support, and the doses can be modified to lower doses of selinexor.

The next category of adverse effect is GI [gastrointestinal]. So, in the patients that we’ve treated, it’s not necessarily nausea per se; perhaps decreased appetite and weight loss. And I think, again, that requires a lot of interventions. Fortunately, there are a lot of drugs that are used for antiemetic purposes, and coming up with the right combination for each patient is important. We also incorporated hydration, too, especially in the cycle when you’re trying to find the right dose. I think those are helpful strategies.

And then the third and final adverse effect profile—I would just say it’s constitutional, kind of asthenia fatigue. And I think the way we deal with this is when I consent patients for selinexor or I tell them, “Look, you’ve had heavily treated disease. This is a really exciting and active therapy, and the regimen and the dose that we start you on may not be the right final dose. We’re going to start it at the approved dosing and we’ll see how you do. And if needed, we will adjust the doses and add additional medication to get you through this.”
And I think setting that patient expectation is helpful when you’re dealing with the adverse effects. But I think we’ve seen some really impressive results in patients who have failed almost every other therapy. It’s important to remember that this study is the largest study of heavily treated patients. They had a median of 7 lines of prior therapy, and they were required to be penta exposed. So that population has not really been studied before, and I think it is really going to be very exciting for patients to have yet another option if the FDA votes favorably.

Transcript edited for clarity.
 
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Transcript:

Ajai Chari, MD:
Selinexor is a nuclear transport inhibitor that targets XP01, which is upregulated in myeloma cells. And the schedule in STORM was 80 mg of Selinexor twice weekly, along with dexamethasone twice weekly at 40 mg, and the primary endpoint was response in PFS [progression-free survival]. And so the response rate was about 25%; PFS, about 3 1/2 months.

And although those may seem modest, it’s important to remember there was a very interesting publication that in relapsed/refractory myeloma, for a novel agent to have a real, any real chance of getting regulatory approval and widespread clinical use, you need to have a response rate of about 15% to 20%. And that gets harder and harder the more heavily treated patients become. So the fact that we saw this response rate in PFS, I think, is really encouraging, and it’s why the drug has gotten fast-track designation.

In terms of the survival outcomes seen in STORM, part IIB, the phase II study, the overall survival for all patients was 6.3 months. However, in those who had at least a minimal response or higher, those patients actually did not even attain a median overall survival. So I think that’s really encouraging, and we know that back when we only had PIs [protease inhibitors] and IMiDs immunomodulatory drugs, when a patient was double refractory, the PFS was 5 months and the OS [overall survival] was 9 months. And now we’re even dealing with a more heavily treated population. So these results are very encouraging and clearly will require a randomized phase III study for regulatory purposes, but it’ll be interesting to see what the FDA decides in terms of an accelerated path to having this combination approved.

The adverse effects of selinexor and dexamethasone seen in the STORM study can primarily be lumped into 3 categories, the first being hematologic. So there were high rates of neutropenia—upwards of 50%—thrombocytopenia. But, again, I would caution that these are patients who were heavily treated. They were allowed to enter the study with quite low blood counts. And fortunately, they were not associated with a lot of infectious complications or bleeding complications. So if patients had those clinical complications, we would be a lot more concerned. But the reality is that in this kind of patient population, the alternative regimens that we would often be choosing for them would be something like 96-hour chemo regimens like VDT PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide], which are guaranteed to give nearly 90-plus percent of rates of neutropenia and thrombocytopenia. That said, it does require monitoring and transfusion support, and the doses can be modified to lower doses of selinexor.

The next category of adverse effect is GI [gastrointestinal]. So, in the patients that we’ve treated, it’s not necessarily nausea per se; perhaps decreased appetite and weight loss. And I think, again, that requires a lot of interventions. Fortunately, there are a lot of drugs that are used for antiemetic purposes, and coming up with the right combination for each patient is important. We also incorporated hydration, too, especially in the cycle when you’re trying to find the right dose. I think those are helpful strategies.

And then the third and final adverse effect profile—I would just say it’s constitutional, kind of asthenia fatigue. And I think the way we deal with this is when I consent patients for selinexor or I tell them, “Look, you’ve had heavily treated disease. This is a really exciting and active therapy, and the regimen and the dose that we start you on may not be the right final dose. We’re going to start it at the approved dosing and we’ll see how you do. And if needed, we will adjust the doses and add additional medication to get you through this.”
And I think setting that patient expectation is helpful when you’re dealing with the adverse effects. But I think we’ve seen some really impressive results in patients who have failed almost every other therapy. It’s important to remember that this study is the largest study of heavily treated patients. They had a median of 7 lines of prior therapy, and they were required to be penta exposed. So that population has not really been studied before, and I think it is really going to be very exciting for patients to have yet another option if the FDA votes favorably.

Transcript edited for clarity.
 
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