The Role of PI3K Inhibitors in Relapsed/Refractory FL and MZL - Episode 6
Experts in hematology/oncology review data from the UNITY-NHL trial and share insights on the sequencing of therapies in R/R FL and MZL.
Ian W. Flinn, MD, PhD: As you mentioned, this drug was tested in the UNITY trial—the UNITY-NHL trial. It was a large, multiarm phase 2 study that tested different drugs in different groups of patients, but there was very similar efficacy to what we see with the other PI3 kinase inhibitors. There was a better adverse-event profile.
Jason M. Melear, MD: The UNITY-NHL trial had participants with follicular lymphoma, who had a better duration of response—11 months—and a response rate of a little less than 50%. It also had marginal zone. The other trials have had marginal zone too, but this led to an approval for treating marginal zone lymphoma in relapsed disease, so as a second line or later, essentially. That’s unique also, correct? Other agents are not approved for a marginal zone?
Ian W. Flinn, MD, PhD: That’s exactly right. It is not a huge patient population, but it’s not surprising to me because of the early phase studies that had a variety of patients with different low-grade lymphomas; it works. You should not get an argument anymore from the insurance companies because you have a drug that’s specifically approved for that, so it’s an important addition.
Jason M. Melear, MD: These agents do get a little more effective in the marginal zone. It looked like the duration of response had not been reached in the trial. The response rate was a little better—around 50—so I would say there’s a little more of an effect there.
Ian W. Flinn, MD, PhD: It’s approved for earlier lines of therapy for patients with marginal zone lymphoma. It’s just for the second line of treatment for marginal zone lymphoma, which is nice.
Jason M. Melear, MD: Where do you put the PI3Ks for follicular lymphoma? They are approved for the general population after—they are essentially a third-line therapy, correct? The umbralisib, interestingly, was essentially approved for a fourth-line therapy, or a line later than the others. Where do you normally put in your agents? Do you put them as third-line treatments or even later or earlier?
Ian W. Flinn, MD, PhD: I usually use them as third-line agents in the treatment of patients with follicular lymphoma. I generally start with chemotherapy-immunotherapy, with bendamustine and rituximab. The data, compared with R² [rituximab, lenalidomide], are very impressive. I use it as a second line therapy. That’s generally where I use a PI3 kinase inhibitor. There may be regimens that are slightly different, but that’s the basic paradigm that I’ve come to over the years. Sometimes you could reverse that: You get someone who was treated with to R² [rituximab, lenalidomide] first and then BR [bendamustine, rituximab], but that’s a rare patient. That happens because we’re getting such good, durable remissions with chemotherapy up front. Now that we have so many choices in the treatment of follicular lymphoma for these patients, often they have a very long duration of survival. We’re trying to have these options, to manage them over time, and in particular use things that are not going to cause long-term adverse events or toxicities, like damage to their bone marrow. Getting away from chemotherapy-immunotherapy in second and subsequent lines of therapy is important for the long-term care of these patients. Do you do things differently? Is that similar to what you’ve been doing?
Jason M. Melear, MD: I do almost exactly the same. I tend to use BR [bendamustine, rituximab] first and then I’ll use R² [rituximab, lenalidomide] because that’s a tolerable regimen. I have thought about using, or have tried to use, R² [rituximab, lenalidomide] more in the first-line setting. It’s not approved in that way, but do you ever find any issues with insurance, or are they pretty lenient about using R² [rituximab, lenalidomide] in the first-line setting?
Ian W. Flinn, MD, PhD: Most of the R² [rituximab, lenalidomide] regimens that I have given to patients as treatment in the front line have been on clinical trial, so we haven’t had that issue. There is the RELEVANCE trial, which showed that these therapies are equivalent as a frontline treatment, published in the New England Journal of Medicine. I think it’s fine. Some patients may want that. It’s rare. It’s not that they don’t have adverse effects. R² [rituximab, lenalidomide] has its own set of adverse events. It’s not necessarily a benign therapy. Some people think it’s not cytotoxic chemotherapy. Maybe that concept is attractive to patients. But for the vast majority of patients, I start on BR [bendamustine, rituximab] or, when treating someone I’m particularly worried about transforming, I use R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. Then I go to R² [rituximab, lenalidomide] as a second line.
Jason M. Melear, MD: I do the same thing, and I’ve found, over the years, that I do not use single agents like Rituxan anymore because of R² [rituximab, lenalidomide]. Another agent that I am thinking about putting into our treatment plan is tazemetostat, which has just been recently approved. It’s another oral agent, so it’s yet another option. I typically use the chemotherapy once, then hopefully I never have to use chemotherapy again. That’s the goal, so it’s great to have all these new oral agents— the toxicity is getting better with time. I think very similarly to you. Have you incorporated tazemetostat into your paradigm at all?
Ian W. Flinn, MD, PhD: I have. I’m not 100% sure where to incorporate it. Certainly, for patients who have an EZH2 mutation, I might use it as third line. You could make an argument that, even when treating patients who do not have any mutations—maybe you don’t know—it’s certainly a reasonable drug to use as third line as well. I’ve been playing with that and trying to see how that comes out. We will have other trials coming up that look at whether those data are reproducible and how well patients who have diseases that are nonmutant do with tazemetostat. I don’t think I’ve settled on something I do for every patient. I go along with the circumstances: the adverse-event profile, how old the patients are, whether they’re able to tolerate different things. That’s what I’m looking at.
Jason M. Melear, MD: With the recent approval of umbralisib, do you feel it fits in for you? We talked about its adverse effects seeming to be a little better. Do you think you’ll use that as your preferred treatment, or do you use all of them in some level?
Ian W. Flinn, MD, PhD: I’ll probably switch over to using umbralisib. I have a lot of experience with it. I have a lot of experience with all these drugs because I was part of the development of all 3 oral inhibitors, and it comes with all of them. As I said earlier, to me the differentiating factor among all 3 of these—as well as copanlisib, the IV [intravenous] formulation of a PI3 kinase inhibitor—is the adverse-event profile. We can see that in the data from the trials, but based on personal experience, it has been much better with umbralisib. I don’t see a reason to try 1 or the other drugs anymore. Maybe there isn’t a specific reason. Duvelisib has broader activity in terms of other malignancies. It’s being investigated as treatment for patients with T-cell lymphomas, so it might have a role there, but for treating straight-up follicular lymphoma or marginal zone lymphoma, I will go with umbralisib for most of my patients.
Jason M. Melear, MD: That’s right. I agree with you. That has been my experience. From what I’ve used, there’s no unique advantage, unless for some reason, someone felt that IV was preferable for them. You have patients who do have certain preferences like that, but otherwise, from the oral standpoint, that’s what I lean toward using.
This transcript has been edited for clarity.