Use of PI3K Inhibitors in B-cell Malignancies - Episode 4
Ian Flinn, MD, PhD: In follicular lymphoma, the PI3-kinase inhibitors are approved for patients with 2 prior therapies. As we think about our treatment paradigms, this is actually probably important in their proper place for them. Until relatively recently, our treatment strategies for follicular lymphoma hadn’t changed in a long time. There is a lot of heterogeneity from 1 institution to another, and from 1 doctor to the next, about how patients were approached and how they were treated with that. Some of that is becoming clear, and while there’s still room for customization based on a patient’s characteristics, it seems that for many patients, frontline therapy is a combination of bendamustine or rituximab—or at least bendamustine and a CD20 antibody, most commonly rituximab.
We know from studies that the combination of lenalidomide and rituximab, the so-called R2 regimen, has efficacy both in the frontline setting—what’s basically equivalent to chemotherapy—and also in the relapsed population. I think a lot of doctors are now using that regimen, the R2 [lenalidomide, rituximab] regimen, as a second-line therapy for patients with follicular lymphoma. We’re starting out with chemoimmunotherapy, most commonly bendamustine and rituximab followed by first relapse, the combination of lenalidomide and rituximab—the R2 regimen—which then opens up and makes clear what we’re doing in the third-line setting.
That is where I think the PI3-kinase inhibitors really come in.
There are now 3 different PI3-kinase inhibitors that are approved for relapsed follicular lymphoma. Two of them are oral, duvelisib and idelalisib, and the third is an IV [intravenous] drug, copanlisib. Duvelisib was approved based on the patients accrued in the DYNAMO study. The DYNAMO trial was a multinational, single-arm, phase II trial for patients who have double refractory follicular lymphoma and low-grade lymphoma. By double refractory we mean refractory to both rituximab as well as to chemotherapy. That study met its primary endpoint, which was response rate, and it had substantial efficacy in terms of progression-free survival and duration of response.
The design of the trial that led to the approval of idelalisib was very similar. It was for a single-arm, multinational trial for patients with low-grade lymphoma who were also double refractory—again, refractory to both chemotherapy as well as to rituximab. There are also impressive results in this patient population with response rates in excess of 50%, and durable progression-free survival as well as duration of response.
The trial design for copanlisib was a little different. In this study, patients had to have 2 prior therapies. They didn’t have to be double refractory. But the results were frankly very similar, and they’re very similar across all 3 trials in terms of efficacy. Again, the response rates were in excess of 50% with durable progression-free survival and duration of response.
Transcript Edited for Clarity