Syk Inhibition in Adult ITP: The FIT1 and FIT2 Trials

Transcript: Segment Description: A comprehensive review of the FIT1 and FIT2 trials, which tested fostamatinib as therapy for patients with adult immune thrombocytopenic purpura.

Ivy Altomare, MD: Ralph, you were 1 of the key investigators on the FIT study, can you summarize the data from randomized phase III leading to fostamatinib, or Tavalisse, approval.

Ralph V. Boccia, MD: There are 2 FIT trials—FIT1 and FIT2—done 1 mostly in Europe, 1 done mostly in this country, and we participated obviously in the FIT trial here. As Amit was saying, randomized placebo-controlled phase III trials. And then a third trial considered in this was the extension trial after the initial 24 weeks for the FIT trials.

It was a median of 8-1/2 years since the initial diagnosis, median of 6 prior lines of therapy. This is in an era where patients were already pretreated with TPO [thrombopoietin] mimetic agents. Pretreated often, about a third of them got rituximab before. So a very late population studied in this trial.

The primary end point was what was called a stable response. Each of the trials that we’ve done with the different drugs that we’ve participated in have had a different name for what their primary end point is. But it’s usually in the latter part of the study, patients are coming in every 2 weeks, and it’s like 6 out of the last 8 weeks to maintain a platelet count; the goal is the safe level of 50,000. We’ve had this pretty much universally through all the drug development in the ITP [immune thrombocytopenic purpura] drug trials. And about 20% of patients have what’s called a stable response. If you look at overall response, it’s closer to 40% of patients.

Now again, these were very heavily pretreated patients, and I’ll bring up the poster that we presented just a couple of nights ago where we did a post hoc analysis, a data cut of the patients who got it in second line. And the overall response rate is over 80%. And if you look at the responders, about 85% of them continue to maintain that response. So the responses are durable as well.

And you can then see for those patients who got it in the first year, so it’s second-line therapy during the first year, it’s a 90% complete response rate. And then it drops down from there to about 70% or so in the second and the third year. Just again emphasizing the earlier treatment.

Ivy Altomare, MD: Yes, interesting. And what I understand from the long-term extension study, similar to what you said, if patients achieve a response, I think in the long-term extension study, the median duration of response is something like 52 weeks, extremely long.

Ralph V. Boccia, MD: At 3 years over 50% of the patients were still responding.

Ivy Altomare, MD: This is 1 of the things that interested me, that some of the patients who didn’t respond early, which is what we expected to see, when kept on the drug, very late they started to increase their platelet counts, which was very interesting.

Ralph V. Boccia, MD: To your point, this was an interesting trial design because patients were allowed to go on to the extension trial if they had not responded to the initial FIT trial. And to your point, Terry, a portion of those actually had a late response.

Amit Mehta, MD: Yes, that’s a great point also because we have to understand clinically the kinetics of these responses—different drugs and different response kinetics. It’s important to know that with this kind of strategy with Syk [spleen tyrosine kinase] inhibition, there may be a gradual response over time. Also quite fascinating under the FIT phase III trials was that some patients were kept on the drug, even while not responding, at the discretion of the clinician, because they felt that there was so-called clinical benefit. Meaning in practical terms, patient platelet count was less than 50,000, the definition, but acceptable results. The patient’s platelet count was maybe up to 30,000, 35,000 and not bleeding, so the hematologist felt that, “My patient’s benefiting, let me continue the medication, they’re clinically stable.” And in those patients, as Terry and Ralph both have mentioned, there’s perhaps gradual increase over time.

If you see the response curves in the publication, it’s a gradual uptake over many months, which is in contrast to some other options we have where there may be more of a spike response, such as with romiplostim, for example. And so it’s important for clinicians to understand that these are the kinetics of the response. You may not see a dramatic increase immediately, and that doesn’t mean that the drug is not necessarily effective, as long as clinically the situation is still acceptable in terms of their count and their bleeding symptomatology.

Ralph V. Boccia, MD: And I think 1 other point to make, and we’ve seen this in all the trials with all the drugs we’ve done, is you may achieve that clinical benefit without necessarily achieving that, whatever it is, 20% in this study, and maybe 60% or 70% in romiplostim and eltrombopag, which were much earlier of course in the development with fewer prior lines of therapy in other drugs. But there are patients who will get a platelet count rise of 20,000 that is clinically meaningful. Their bleeding stops, their bruising stops. They’re in much better shape, they feel better.

Ivy Altomare, MD: Yes. So what kind of patients now, outside of the clinical trial setting, are benefitting from Tavalisse?

Ralph V. Boccia, MD: Well, certainly based on its label we can use it any time after frontline therapy fails. So a line of therapy. So we sit with our patients and we talk about what is that next line of therapy going to look like? Is it something we’re going to take a pill for? What kind of other medications do they take? What kind of perhaps feeding lifestyle do they have, and foods that they eat, and what not. How often do they want to come into the clinic? And that’s what helps us.

Is it somebody for instance with inflammatory bowel disease and has a problem with diarrhea? Well, that’s not going to be someone you want to give a drug to that might cause diarrhea. On the other hand, you might have somebody with normal blood pressure and normal bowel function, and that’s a good candidate for it.

Amit Mehta, MD: Also one thing I could add is from what Ralph presented in his poster, is that’s why it’s very good that we now have that data presented from the ASH [American Society of Hematology] annual meeting in 2019, that if you do use it, even though we felt clinically like perhaps this was happening, that earlier line therapy resulted in better responses, but it’s always good to see that we have data to support that. And you mentioned 80% of patients in second line were achieving a 50,000 platelet count threshold, and if I remember correctly from your poster, Ralph, 91% achieved a platelet count greater than 30,000.

Those are I think clinically meaningful numbers for physicians to say, “OK, that’s a threshold and response rate that’s high enough that justifies us to say, yes, if we consider fostamatinib as our drug for the second-line type of scenario, there’s a realistic reason to believe that they’ll have a good chance of benefit.”

Ivy Altomare, MD: Yes. We talked a little bit earlier about the thrombosis risk inherently in patients with ITP, and we know that there’s an association between the TPO receptor agonist in thrombosis. There is an abstract at this meeting discussing the rates of thrombosis in the FIT experience. And it’s actually interesting that in over 150 years of patient treatment on fostamatinib, there’s been only 1 observed transient blood clot.

Ralph V. Boccia, MD: Yes, this is the first drug that we’ve helped in participating in the development of where we haven’t seen the risk of thrombosis increase.

Ivy Altomare, MD: Yes. If that’s a concern for a particular patient, I think that this drug fits in very nicely. Rich, any experiences with this drug? And what are your thoughts?

Richard F. McDonough, MD: Sure. I think when you talked before about the clinical benefit, we haven’t really talked too much about what is our target, what are we trying to get to for our patient? And I think that clinical benefit is important. If you have a patient whose platelet count is in the single digits and bleeding, bruising, and you’ve gotten them to the 30,000s or 40,000s, and they’re otherwise doing well, I think that’s an important category. I’ve had patients who have had stronger responses, but I’ve had patients who wouldn’t have fit the original clinical definition by the trial to be the stable response. But they’re getting a benefit, they’re in the 40,000s. They have to be on an antiplatelet therapy for concomitant cardiac condition, and so, and they’re doing well with it.

Ivy Altomare, MD: And the risk of thrombosis there.

Richard F. McDonough, MD: Exactly.

Ivy Altomare, MD: Well, that just shows how the trial patient isn’t always applicable to real-life patients, in every disease.

Transcript Edited for Clarity