The Evolution of Chimeric Antigen Receptor T Cell Therapy - Episode 1
David Maloney, MD, PhD: We’re now here with 2 recent FDA approvals of CAR T-cell products for patients with relapsed lymphoma, and those are axicabtagene ciloleucel and tisagenlecleucel. What are the FDA-approved indications for these therapies?
Matthew Lunning, DO: So right now, it’s in relapsed/refractory diffuse large B-cell lymphoma, for those patients who have failed or have been refractory to 2 prior lines of therapy. There is the inclusion of patients who have had transformed lymphoma. So, in an indolent lymphoma like follicular lymphoma that then progressed to a diffuse large B-cell lymphoma in this population.
Leo I. Gordon, MD, FACP: I’ll also add to that. We’ve now included those criteria in the NCCN [National Comprehensive Cancer Network] guidelines for B-cell lymphoma. So CARs in these products are now part of the NCCN algorithm for that group of patients.
David Maloney, MD, PhD: So I think both of these agents required 2 prior regimens, right, disease after 2 prior regimens, to go forward?
Leo I. Gordon, MD, FACP: Yes, that’s right.
David Maloney, MD, PhD: So is this an important advance for our patients?
Matthew Lunning, DO: I think it definitely looks like as the data continue to mature that this is an option that patients should be considered for. If you’re a patient with relapsed/refractory large cell lymphoma and you can’t get to transplant, I’m concurrently having this discussion because of the outcomes with second-line therapy. And if I’ve identified a high-risk patient, I’m starting the conversation about CAR T-cell therapy very early in this. If the patient isn’t chemosensitive to the degree that I would want to take them to transplant, we can pivot to the conversation about CAR T cell, and it’s not a foreign topic to them.
Leo I. Gordon, MD, FACP: I think 1 point, David, to your question about the number of prior therapies, is if you look at the transformed group of patients in the clinical trials to date, it was required to have 2 therapies, including an adriamycin-containing regimen for the large cell lymphoma. Whereas there are some patients who have follicular lymphoma, had adriamycin as part of their regimen, and then relapsed or transformed. And there’s still a question and the NCCN guidelines were silent on whether the adriamycin has to be for the aggressive lymphoma or whether there would have to be 2 regimens for the aggressive lymphoma or an aggressive one for follicular lymphoma plus a different one for large cell.
Matthew Lunning, DO: It’s a hard question because it’s really an individualized patient discussion, because some people will come in with 4 or 5 different prior regimens for their follicular lymphoma and then have their transformational event versus somebody who receives R-CHOP [rituximab/cyclophosphamide/doxorubicin hydrochloride/vincristine sulfate/prednisone] frontline and then relapses.
David Maloney, MD, PhD: I think it’s an area of a lot of controversy because we clearly have patients with follicular lymphoma who have even had an anthracycline like R-CHOP and failed the transplant and then transformed. And then what do you do? Your hands are tied, and you can’t really go down the usual pathway.
Matthew Lunning, DO: But I think we understand that it’s a poor-risk population and still, I think, an unmet medical need within lymphoma.
David Maloney, MD, PhD: Right.
Leo I. Gordon, MD, FACP: For the trials, those patients would not have been eligible, but I think in the real world and the way the guidelines are written, they may be.
David Maloney, MD, PhD: We have a third contender that’s in late-stage clinical development. That’s the lisocabtagene maraleucel. Dr Gordon, you’re an investigator on that trial as well.
Leo I. Gordon, MD, FACP: Yes, and the TRANSCEND study, the JCAR017, is now fully accrued with patients for the pivotal trial. We are expecting, at some point, submission to the FDA for approval. So that trial is now fully accrued.
David Maloney, MD, PhD: So let’s review a little bit of the clinical data. Dr Ghosh, can you review the tisagenlecleucel data?
Nilanjan Ghosh, MD, PhD: Yes. So the JULIET trial, which looked at tisagenlecleucel in relapsed or refractory diffuse large cell lymphoma after failure of 2 prior therapies, was just reported in the New England Journal of Medicine. The overall response rate was 52%, with the CR [complete response] rate of 40% in the study. And there were 22% patients who had grade 3/4 CRS [cytokine release syndrome], and there were, I think, about 12% patients who had grade 3/4 neurologic toxicity. At 1 year, 65% of the patients were relapse free.
David Maloney, MD, PhD: And we’re also getting data with lisocabtagene maraleucel that have been reported at several prior meetings, including this 2018 ASH [American Society of Hematology] meeting. Dr Gordon?
Leo I. Gordon, MD, FACP: Right. Well, it looks like the overall response rates are similar, maybe a little bit higher than about 80%. CR rates were at about 55%. The durable CRs are running in the mid-40% range to 50%. Between 45% and 50% of patients have a durable CR, and it appears that those patients who are in complete remission at a year had a very high chance, maybe 90% or more, of remaining in complete remission up to about 2 years.
David Maloney, MD, PhD: And I think that’s what we were seeing with the axicabtagene ciloleucel, as well, because we were now having 2-year data or a little beyond 2-year data, which are really encouraging, showing a very flat progression-free survival curve where patients were staying in remission, and about 39% to 40% of patients appear to stay in remission. Of course, the cure word keeps coming up at that point, and we’re all very excited about trying to decide whether this will result in long-term progression. Clearly, the axicabtagene ciloleucel data are the most mature, and we’re lagging behind in some of the other clinical trials as lisocabtagene is being developed over time. But, I mean, we’re really encouraged by these flat progression-free survival curves and really hoping that this is going to alter the natural history of their disease.
Leo I. Gordon, MD, FACP: Right. I’m impressed. There are 2 ways you can be impressed. You can be impressed by reading the data and looking at the curves, and you can be impressed by actually taking care of these patients. That to me is more meaningful. We’re seeing patients who had multiple treatments, had been refractory, had bulky disease, and at 2 years now—we have data up to 2 years—they remain in remission and are doing well, with a performance status of 0.
Nilanjan Ghosh, MD, PhD: The other thing that you can note across all 3 studies is if someone is in a CR at 3 months, it seems like that could be a surrogate for long-term remission. The drop-off after 3 to 6 months seems to be very small compared with the first assessment and 1 month and 3 months. And that seems to be a trend across most of the studies. We don’t have very long follow-up with the liso-cel study yet, but it appears to be the case.
Transcript Edited for Clarity