麻豆传媒

Durable responses were seen when axicabtagene ciloleucel (axi-cel; Yescarta) was administered as a first-line therapy for patients with high-risk large B-cell lymphoma (LBCL), according to findings from the . Administration of axi-cel also improved overall survival (OS) and progression-free survival (PFS) versus standard of care treatment in patients with relapsed/refractory LBCL who are at least 65 years of age, according to data from a subgroup analysis of the . Both studies were presented at the recent American Society of Hematology (ASH) annual meeting.

In this third of four exclusive episodes, 麻豆传媒 brought together three expert leaders in the field, all from Ohio State University Wexner Medical Center in Columbus -- moderator , is joined by , and -- for a virtual roundtable discussion on the two axicabtagene ciloleucel studies.

Following is a transcript of their remarks:

Maddocks: Let's move on. Now we're going to pair a couple abstracts together, talk about many people's favorite topic in diffuse large B-cell lymphoma [DLBCL] -- CAR T-cell therapy.

As we've discussed a little bit, CAR T-cell therapy approval third line or later, but now we have second-line approvals, but there's interest in moving that even further upfront into the first-line therapy. So we've seen a little bit of data on ZUMA-12, which was a trial looking at response-adapted CAR T-cell therapy in the frontline setting after patients received a few cycles of chemoimmunotherapy. So this year at ASH they did the 3-year analysis of ZUMA-12, a phase II study of the axi-cel as first-line therapy in patients with high-risk large B-cell lymphoma Thoughts on this trial?

Bond: So it was exciting to see an update in ZUMA-12. It was a small study, so it was only 37 patients and it was really looking at patients that had high-risk features and had a positive PET scan after initial treatment with chemoimmunotherapy for two cycles. So patients that still had some disease at least by PET scan and really at 3 years the response rate still... the response rate was very high, but the responses seem to be maintained in the majority of patients with a complete response. And so there's really, to me, impressive durability of the responses for this. Maybe you could say first one-and-a-half lines placement or somewhere between first- and second-line treatment. So after initial chemotherapy.

We see that we have approval for axi-cel in second-line treatment. And often the question, there's a question of timing and I think this is somewhat reassuring if you have a patient that's not responded initially and you're not able to complete chemotherapy because of the lack of response, that early treatment with axi-cel in that setting seems to be feasible in the study population at least.

And so I think that's one direct application, but just with how durable the responses were and high the response rates are, we may see more, looking at least [at] this setting, where you have at least positive patients or even potentially for the highest risk patients just as a frontline option for treatment.

Sawalha: Yeah, I agree. Very, very interesting study. Very exciting results, but still very small number of patients. So we have to keep that in mind. I'm really looking forward to the results of the , the phase III randomized clinical trial that will randomize patients with a higher risk large B-cell lymphoma to axi-cel versus standard of care after receiving one cycle of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisone].

So I'll be definitely eagerly awaiting the results to see how axi-cel can potentially move to even earlier lines of treatment large B-cell lymphoma and how are we going to deal with access issues if that happens. But that would be a good problem to deal with at that time.

Maddocks: Just briefly, thoughts on if that should just be high-risk population or if we're headed towards this in all diffuse large B-cell lymphoma?

Sawalha: I think honestly with access and cost and still potential toxicities, I would be cautious and hesitant to say this is for all patients with DLBC, large B-cell lymphoma. R-CHOP or pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone] still cures most of the patients with these lymphomas.

Ideally we would know which patient is not going to respond to these treatments. We can potentially use CAR T-cells. Maybe ctDNA [circulating tumor DNA] or MRD [minimal residual disease] will help us with that one day. But I think given the cost and access and toxicity, I don't think we're there yet.

Bond: Yeah, I agree with that and I think that we're going to talk about all from ZUMA-7 where there was an overall survival benefit shown second line with CAR-T, and even there in second line where we see an overall survival benefit, we have seen that there's just not as much uptake as you would expect of CAR-T second line. I think there's a lot of room to improve access second line. I think first line there's a lot of barriers that are there, including just that you have other effective options.

And so I think you would need to somehow be selecting really very high-risk patients to use it there. But I think we have a long way to go, even just to get use in second line where we see a real benefit to more patients, even here in the United States.

Maddocks: And I think of course we'll have to see how it plays out with the bispecifics being studied in frontline with chemoimmunotherapy as well.

OK. Dr. Bond, you alluded very well to our next abstract. So improved overall survival with axi-cel versus standard of care in second-line large B-cell lymphoma among the elderly. A subgroup analysis of ZUMA-7. So this past summer we saw results presented with longer follow-up. ZUMA-7, there was an overall survival benefit in to the CAR product in the second-line setting over standard of care. This was subgroup looking at patients who were 65 and older or 70 [and] older. Comments on this abstract?

Sawalha: I think to me it says that we shouldn't really exclude patients from CAR T-cell just based on age. I think it's something that we always have to consider, but if the patient is fit and eligible, we should do that as the preferred second-line treatment for these high-risk patients -- primary refractory, early relapse -- especially that 50% of the patients on the standard arm, the transplant arm, ended up receiving CAR T-cell later. But still despite that, we saw a survival benefit with earlier use of CAR T-cells.

Bond: Yeah, and this was a fairly large old group of patients. There were 109 patients that were 65 or older on ZUMA-7 that they put in the analysis and you see a similar magnitude of benefit for the older patients as you do for all patients. And even when they looked at the patients over 70, actually the hazard ratio was numerically lower. So there even a benefit there in the patients over 70.

So I think the big take-home message is just to not exclude patients that are over 65, over 70 from CAR-T and that we know we can deliver this. And I think even from the time the study's been conducted, there's more experience at centers that give CAR-T. And I think there's probably more comfort actually with treating older patients. So definitely continue to refer patients that you have that are older to CAR-T centers. And really exciting to see this translate even for older patients to a real benefit.

Maddocks: And I think the other point to make is there's also another product approved in this setting as well. It can be a good option for older patients.

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