EZH2 Inhibition in R/R FL: Safety & Efficacy Data

Ian Flinn, MD, PhD: Krish, Andy went into this a little, but maybe it bears further discussion: the clinical trial that led to the FDA approval of tazemetostat, which was recently published in Lancet Oncology. Can you walk us through that data in more detail?

Krish Patel, MD: Sure. This was an open-label, phase 2 trial that was published late last year. This was a single-arm study of tazemetostat given at 800 mg twice daily as continuous oral therapy. Patients who were enrolled in the trial had to have at least 2 prior lines of therapy. This trial uniquely took all comers. It included patients with stage IIIB disease. There was a small number of patients with what we would call high-grade follicular lymphoma. In essence, as others have pointed out, the study took patients whether they had mutations or not. All comers came, and then they analyzed the responses and the outcomes by presence of the EZH2 mutation or not.

I’ll review some of the efficacy data that colleagues have already shared. There was a higher response seen in patients who had a mutation—approaching 70% or so. It’s about half that in wild-type patients. In terms of duration of response, it was fairly similar between the 2 groups—around 10 to 11 months. The other thing I’ll note is that if we look at the PFS [progression-free survival] in the wild-type group, it looks pretty similar to the mutant group. So perhaps response isn’t necessarily the best surrogate to look at in this setting? Because even if we look at all comers for the wild-type group, the PFS is pretty similar to what we saw in the mutant group.

This is really an intriguing data set. As Loretta might share with us in a moment, the toxicity profile of this drug is what should probably excite most of us. In the single-agent study, the drug was extremely well tolerated and certainly efficacious. It is potentially a really good platform to combine with other therapies.

Ian Flinn, MD, PhD: That is a good segue into Loretta’s discussion on the drug’s adverse-event profile. Efficacy is 1 part of the equation in picking a therapy. But as we just had a discussion about when talking about PI3 kinase inhibitors, it’s really important to weigh that with what the adverse effects are. If it’s like giving water, then we give it to everybody. But it’s not, so we have to pick and choose. What are your thoughts on tazemetostat and its adverse-event profile?

Loretta J. Nastoupil, MD: That’s where it really is intriguing. We see very few rates of grade 3 or higher toxicity and very low rates of dose modifications and treatment discontinuations as a result of toxicity. That’s particularly important in this patient population. We’re expecting them to receive multiple lines of treatment. The goal of care is to extend life but also make sure that it comes with good quality of life. That’s something you can achieve with this therapy. More important, as we start to look at this mechanism of action and how you might target that with combination strategies, the safety profile suggests that you should be able to combine this and not have significant additive toxicity. So as a single agent, it’s particularly attractive. It’s potentially more attractive when you start to combine it with other things.

Transcript Edited for Clarity