New therapies and treatment selection in patients with relapsed/refractory FL

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Bijal D. Shah, MD, MS: Caron, we have some really cool drugs coming in the more advanced relapsed/refractory setting, a whole bunch of PI3K inhibitors, I think new CD20 antibodies, even CAR T [chimeric antigen receptor T-cell therapy]. How do you decide who to treat and with what?

Caron A. Jacobson, MD, MPH: Yes, it is a very difficult discussion to have with patients. I think what has been remarkable is that the PI3 kinases seem very consistent in response rate and complete response [CR] rate and sustainable remission rate. But the duration of remission tends to be around 1 year for these. Right now, of course, we have duvelisib, idelalisib, copanlisib and umbralisib, but there are many more in clinical development.

We have also seen approval of tazemetostat, the EZH2 inhibitor, in this disease for both EZH2 wild type and EZH2– mutated disease. Admittedly, response rates are higher in EZH2-mutated disease, but progression-free survival appears to be very similar in the two groups. And that really tells us that it works by a multitude of mechanisms.

Then the last thing that was recently approved in this line of treatment is axicabtagene ciloleucel based on the ZUMA-5 study, which clearly showed the highest complete response rate, over about 80% for lymphoma follicular. And for patients who get a complete response, we saw the data presented at ASH [American Society of Hematology annual meeting] This year [2021], with a follow-up now of almost 24 months, more than 70% of these patients are still in response. Again, just as with mantle cell lymphoma, we don’t know if this will be a cure for follicular lymphoma patients or a subset of follicular lymphoma patients, but c This is clearly the longest duration of remission we get. in this line of advanced therapy. It comes with toxicities and requires intensive monitoring. It’s a complicated and expensive therapy, and so how to adapt it to our patients who may die with, but not from, their follicular lymphoma is really difficult.

Of course it’s going to have to compete with something that isn’t FDA. [Food and Drug Administration] still approved but coming in, which are CD20 bispecific antibodies, and these drugs seem to be very active. They have very high CR rates in follicular lymphoma. It seems that these are not definitive therapies. We don’t see a plateau in the duration of the response and progression-free survival curves, but they provide quite a long clinical benefit for these patients, and they’re easier. They can be administered in the clinic. They can be donated in the community. Their adverse effect profile is more favorable. I think right now it’s a discussion with our patients. Do patients prefer some sort of one-time approach or coming in every 3 weeks for their infusion? I think right now it’s very personalized with your patients.

Bijal D. Shah, MD, MS: You recently performed a comparison of expectations, focusing on ZUMA-5, follicular lymphoma patients who were treated with axicabtagen versus other agents they might otherwise get in the same setting. I believe it was called the SCHOLAR-5 study. Can you tell us a bit more?

Caron A. Jacobson, MD, MPH: Yes. I think it’s a really important study, although it’s not perfect because it’s not really a randomized trial. SCHOLAR-5 was a combination of retrospective reviews of modern third-line approaches to follicular lymphoma at a number of international sites in Europe and the United States. Then it also included data from Gilead [Sciences] DELTA trial of idelalisib in this line of treatment. And they did a propensity score weighting match for the patients on ZUMA-5. So they were very close in terms of the risk characteristics that we know to look for, but of course there may be others that we don’t know to look for. ZUMA-5 was superior to other available therapies that have been used in this setting since SCHOLAR-5 in terms of response rate, complete response rate, time to next treatment, and time to treatment. treatment failure.

But more importantly, it was statistically significantly superior in terms of overall survival at 3 years, which was a shock, I think, that no one thought you could see an overall survival benefit in follicular lymphoma. There is an asterisk because this is not a randomized trial, but this is probably the best data we have on this type of support using CAR T-cell therapy for patients on this line of therapy advanced.

Bijal D. Shah, MD, MS: It is most encouraging.

Transcript edited for clarity.

Martin E. Berry