Comparing CAR T-Cell Therapies in Lymphoma

The Big Three in CAR T-Cell Therapies

Ann S. LaCasce, MD, MMSc: Hello. I am Ann LaCasce, an associate professor of medicine at Dana-Farber Cancer Institute in Boston and a lymphoma specialist. I would like to welcome you to Medscape Oncology Insights, coming to you from the 2017 American Society of Hematology (ASH) annual meeting. Today we will be discussing some of the highlights of the lymphoma and chimeric antigen receptor (CAR) T-cell sessions at the meeting.

Joining me is Caron Jacobson, a friend and colleague. She is also a lymphoma specialist at Dana-Farber and a leader in the field of CAR T-cell studies. Welcome, Caron.

Caron A. Jacobson, MD: Hi, Ann. Thanks.

Dr LaCasce: Let's start with CAR T cells. What did you think of the different presentations and how the different products compare in terms of efficacy?

Dr Jacobson: We are really talking about the anti–CD19-directed CAR T cells and the three products that are furthest along in development: tisagenlecleucel (Novartis), axicabtagene ciloleucel (Kite), and JCAR017 (Juno).^[1,2,3]

What is pretty remarkable is that across all three products, even though they differ in terms of the costimulatory domain and the kinetics of the CAR T-cell expansion, we are seeing similar efficacy.

These are in a tremendous number of patients, and it is really hard and dangerous to compare from one study to another. I do think the numbers are similar enough that we can be excited about all three studies.

Dr LaCasce: In terms of the toxicity, is there really any significant difference among the different studies?

Dr Jacobson: Again, I think it is difficult to compare one study with another. They are not randomized and not necessarily within the same patient populations. However, I do think it's very interesting that we're seeing low rates of grade 3 and 4 cytokine-release syndrome—actually the low rates in general—with JCAR017and also lower rates of grade 3 and 4 neurotoxicity. Those numbers are closer to what we were seeing in the other studies.

What's the Underlying Mechanism?

Dr LaCasce: Do you have any sense as to why that might be the fact? Is it that the costimulatory molecule is different?

Dr Jacobson: There are two things that may be different. One is that the Juno study of JCAR017^[3] allows for bridging therapy from between the time of phoresis and the time of CAR T-cell infusion. We know that tumor cell burden does correlate with toxicity. If patients get some effective bridging therapy, which we do not think will have a long-term impact in such a way that it skews their efficacy data, it may actually debulk them temporarily before they get their CAR T cells back.

That is one aspect. The other is that we do know the kinetics of the 4-1BB costimulatory domain differ from the kinetics of the CD28 domain. We do not yet know what effect that has on efficacy, but that certainly may have an effect on toxicity.

Dr LaCasce: With regard to neurologic toxicity, which is really the thing we worry about the most, are there any new insights as to why that happens? How can we predict for it and manage it?

Dr Jacobson: The Juno group did present some of the pretreatment patient characteristics and biomarker analyses. It looks like patients with higher pretreatment tumor burden, lactate dehydrogenase (LDH) levels, and inflammatory cytokines are at increased risk for neurotoxicity. Similar things have been seen across the studies.

Something not presented at this meeting was the data that recently came out from the Fred Hutchinson Cancer Research Center.^[4] Researchers looked at what is going in the blood vessels that permeate the brain, and there does seem to be some element of endothelial injury that probably increases the blood/brain barrier permeability. There are cells and inflammatory cytokines that traffic in that setting. We have a lot to learn about neurotoxicity, and there is a lot of room for improvement. I think it is all worthwhile, because this is such a remarkable therapy.

Dr LaCasce: How do you see this rolling out now that we have the first commercially available product? How is that going to change how we are managing patients?

It creates a standard of care for patients where there was not one before.

Dr Jacobson: It creates a standard of care for patients where there was not one before. These are patients who either relapse after autotransplant or were not eligible for autotransplant because they had chemoinsensitive disease. These were patients that you put on targeted agents with a 20%-30% chance of having a response. Or you put them on clinical trials. Now we do have a standard of care option. I think that that is practice-changing.

The next wave of studies is going to be the randomized studies that take patients who are at high risk for not responding to salvage chemotherapy or doing well with an autotransplant and randomizing them at the point of relapse after their first-line chemotherapy to either CAR or salvage and autotransplant. That may move this therapy earlier.

Dr LaCasce: And that may be associated with less toxicity, which is really incredibly exciting.

ECHELON-1

Dr LaCasce: Switching gears, there was the ECHELON-1 study^[5] presented at the plenary session, where patients with advanced-stage Hodgkin lymphoma received upfront either brentuximab + AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m², vinblastine 6 mg/m², dacarbazine 375 mg/m²; A + AVD) or ABVD (doxorubicin 25 mg/m², bleomycin 10 units/m², vinblastine 6 mg/m², dacarbazine).

I think the big question everyone wants to know is whether this going to change practice in the United States, globally. What do you think of this study?

Dr Jacobson: I was eagerly awaiting these results because the early phase, single-arm study actually looked so promising, with such a high 3-year progression-free survival (PFS) rate for a group of patients that, if you looked at historical controls, did much worse. I think there is a PFS benefit but no overall survival benefit, and increased toxicity with this regimen. I think it's going to be variably practice-changing across the globe.

Dr LaCasce: It is a positive study with regard to how it was designed, but whether or not that is going to translate will be interesting to see.

What do you think about the toxicity? Do you worry about this being more broadly applied and people getting into trouble with neutropenia, or other infections or toxicities associated with it?

Dr Jacobson: I think we all know how to deal with the neutropenia we see after ABVD chemotherapy, and this is going to be a different ball of wax. Also, the neuropathy is actually much less reversible than what we see with alkaloids. I have patients whom I treated on this study who have debilitating neuropathy years after finishing therapies.

Dr LaCasce: We are going to need much longer-term follow-up, I think.

Acalabrutinib's Approval

Dr LaCasce: The third abstract I would love to hear your thoughts on, which has already led to a drug approval, is the acalabrutinib data.^[6] What did you think about that?

Dr Jacobson: Again, it is hard to compare that with the historical control seen with ibrutinib, but it does look like maybe the complete response rate is potentially a little bit higher. The most intriguing thing is that it potentially has a more favorable side-effect profile. It does not look like it is a completely clean drug, because as we treat more patients and treat them for longer, we are seeing some atrial fibrillation and the other off-target effects that we saw with ibrutinib, but certainly to a much lower extent. It may be a safer drug to give to patients with a cardiac history or with a history of atrial fibrillation. I do think you are going to see it widely adopted in clinical practice.

Dr LaCasce: What do you think is the next step with that drug?

Dr Jacobson: We need to potentially look at combining it with therapies and maybe even moving it up earlier into the disease treatment. The other thing we need is just longer-term follow-up, so we can confirm the safety profile.

Dr LaCasce: Caron, thank you so much. This has been a great and fascinating discussion, like we have all the time when we are back at home.

Dr Jacobson: Thanks for asking thoughtful questions.

Dr LaCasce: Thank you for joining us. This is Ann LaCasce, from ASH 2017 in Atlanta.

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