ZUMA-7: Axi-Cel in Patients with Relapsed/Refractory DLBCL

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Experts overview the ZUMA-7 trial of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory DLBCL, and discuss how tumor volume correlates with clinical outcomes.

Transcript:

Andre H. Goy, MD: Back to the CAR [chimeric antigen receptor] T cells. We talked a little bit about this, but where does CAR T-cell therapy currently fit in your paradigm, given the fact that we have the second line and third line? If you can just give a quick overview.

Andrew Ip, MD: If the patient relapsed or are considered refractory, which was defined in the trials differently, but basically if they relapsed within 12 months, those patients after first-line treatment should be considered a candidate for CAR T-cell therapy. In the 12- to 18-month window, in which you will still see relapses after 12 months and under 18 months, that’s more of a discussion. Are they eligible for autologous stem cell transplant? If they’re ineligible, then you could still go to, potentially, standard-of-care CAR T-cell therapy and state clearly that they’re ineligible for a bone marrow transplant for X, Y, or Z reasons.

For me, for any patient who’s relapsed basically 18 months or less post-R-CHOP [rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone], or post-EPOCH [etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)] or hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone], those patients, for standard of care, should all be considered for cellular therapy. If it’s after 18 months, then those patients could still be very chemosensitive, given they had a relatively long event-free survival, and they could potentially get some sort of salvage treatment and consider consolidation [autologous transplant] in that setting.

Andre H. Goy, MD: I agree, this is the shift of the paradigm. And I would say that, for our audience, that if you look at the axi-cel in the third line, second line, and first line consolidation from the ZUMA-7 trial [NCT03391466], the CR [complete response] rate went from 58% to 75% to 83%. So I think if we refer patients earlier, we’d probably have a better T-cell fitness and these primary refractory patients should get CAR T-cell therapy as early as possible. This change is thanks to, obviously, CAR T approval, but also the second-line trial. We have 3 trials, the ZUMA-7 and the TRANSFORM trial [NCT03575351] in particular changed the standard of care, which was established over 40 years ago.

Andrew Ip, MD: Yes. The ZUMA-7 trial obviously was the axi-cel product, the TRANSFORM trial was the liso-cel [lisocabtagene maraleucel] product, and both are approved for second-line treatments as I just mentioned before. Those are obviously big game changers that you just mentioned, in changing the landscape. I think we’ve talked about it already here, but I do want to point out that there was an abstract. Because I think it always comes up from even our cellular therapy BMT [blood and marrow transplant] colleagues who deliver the CAR T-cell therapy who ask, “Andrew, why would you want to give CAR T-cell therapy to someone who has a very bulky tumor? Don’t you think you need to give them some more chemotherapy or give them something else to try to debulk them and then send them to CAR T-cell therapy?”

In the ZUMA-7 trial, they looked specifically at the metabolic tumor volume. And what they showed, these curves were very striking, is if you had high tumor volume, bulky disease, axi-cel beat everything in terms of standard of care. Even when comparing it with low metabolic tumor volume, you can see there are still differences in outcomes, but in general, axi-cel did much better than the standard care for the bulky disease. So why delay someone’s treatments to benefit just because we’re a little concerned?

Now, there certainly was some increased risk of ICANS [immune effector cell associated neurotoxicity] and CRS [cytokine release syndrome] when they have higher metabolic tumor volume. But I think experienced CAR T cell centers, at this point, can handle cytokine release syndrome, grade 2 or maybe grade 3, or even some neurotoxicity. Of course, we don’t want it to be grade 4 or grade 5, but I think we can all now understand that we can handle some neurotoxicity and CRS. But we don’t want to delay these patients from getting to CAR T-cell therapy.

So I at least want the audience to understand that yes, of course, they can be bulky and very symptomatic, and you want to maybe debulk them because we’re maybe in the mindset that’s what you should do prior to the autologous stem cell transplant. Usually, you want to get them into as good of a response as possible. But I think for CAR T-cell therapy, it’s different. These are different drugs; these are immunotherapy drugs, and they don’t necessarily need to have a patient be completely debulked.

Andre H. Goy, MD: I agree. This is a difficult population. The early relapsed/refractory patient, which was a part of this population in these trials. The EFS [event-free survival], PFS [progression-free survival], and outcome were dramatically different, and the CR rate was way more than double and up to triple in comparison with the standard of care. It really changed again the standard of care that was established for a decade.

Andrew Ip, MD: I’ll try to hammer the point more for the audience. Because at least in the ZUMA-7 trial, it was about 41% 2-year EFS vs 16% standard of care 2 years ago. That’s an absolute 25% difference, or about a 3-time improvement, as you mentioned. But with a 25% absolute difference, a number needed to save a life probably is 4. If you think about how many patients with DLBCL [diffuse large B-cell lymphoma] we see in our clinic, it could be 100 a year, and you could potentially save an additional 25 lives a year, at least at a busy lymphoma place. But even in the community, if you see 3 or 4 lymphoma patients a year and then maybe a few relapses a year, you could save 1 additional patient just by referring them to CAR T-cell therapy. That’s very powerful and certainly needs to be the message we give in general.

Andre H. Goy, MD: Absolutely. And then you talked about the elderly patients who aren’t eligible for transplant. You and I have seen patients who are not able to get high-dose therapy and transplant because it’s myeloablative and infection and toxicity. And we can give CAR T-cell therapy to patients who are 75 or 80 years old with no problem, and this is quite satisfying.

Transcript edited for clarity.

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