David Maloney:

Hello, I’m Dr David Maloney from the Fred Hutchinson Cancer Research Center in Seattle. And I’m joined by my colleagues here, Dr Karen Jacobson from Dana-Farber Cancer Institute and Dr. Loretta Nastoupil from MD Anderson. And we just had our second day of the hematologic iwCAR-T and had a wonderful discussion on lymphoma jam-packed morning, I guess for me, the big news is we finally have randomized Phase III trial data with actually three clinical trials in large cell lymphoma and pretty exciting results, how do you interpret them?

Karen Jacobson :

We are talking about the three randomized trials, two of which were positive in favor of CAR-T in the second line for high-risk relapsing large B-cell lymphoma patients. And so that’s practice is changing. I think liso-cel and axi-cel are now available to those early relapsing patients in the second line. And I think that’s for the betterment of patients.

Loretta Nastoupil:

I think the other key thing is, all of these were approved on single-arm phase two studies with a lot of discussion about the differences in the patient population and how the trials were conducted. And we have a little bit of a level set where, they were all done in similar patients those that we feel were the highest unmet need in terms of poor outcomes with standard salvage and autotransplant. And so it’s really interesting in my opinion, to see that at least two performed really well and much better than what we had at our disposal otherwise.

David Maloney:

I think it’s important to remember though, that just for the audience that these trials were not CAR-T versus transplant, everybody wants to try to compare that, but it’s really CAR-T versus the intent to transplant. And really the reason these trials win is that the patients that were selected for the trials had to have relapsed within a year of their primary therapy. So they’re either primary refractory or had early relapse. And we know that’s a notorious group where salvage chemotherapy and transplant doesn’t perform very well. And that’s what we saw in the two trials is that less than 50% of the patients actually got transplanted in fact, was between 35 and 40% actually even got to the autotransplant. So it does lead a little bit of controversy about what do you do for a patient if they’ve already gotten salvage chemotherapy and had a good response. Are you going to still transplant them? Or based on this are you going to go straight to CAR-T?

Karen Jacobson :

I’m hoping that happens less and less. I’m hoping that there are earlier referrals from the community because of these trials. But I agree with the statements that were made during the session, which if someone comes to me in a good response to salvage that they’ve started in the community, I probably will continue the salvage chemotherapy and take them to an autotransplant. I think the other question that comes up is, these patients come to you even before they start salvage, but you might need to bridge them with something. And what if they start responding to something after you’ve collected their CAR-Ts, they’re in manufacturing, they’re responding to that salvage as a bridge. It’s very hard for a lot of logistical reasons. I think to switch gears at that point, I think we’re committed at least at our institution committed to CAR-Ts for those patients.

David Maloney:

And I think we would too. What about MD Anderson?

Loretta Nastoupil:

I agree. And I think at least from the TRANSFORM study, we do recognize that there’s a good portion of those patients who had one cycle of salvage chemotherapy and still went on to CAR and they did quite well. And I think the highlights a key aspect here is how do we find optimal candidates for CAR-T and those patients where the disease kinetics allows us really to manufacture product and deliver it safely. And so having good disease control, lower tumor burden in a situation where they’re not progressing, they’re probably going to do better with CAR. So I still think we’ll pursue CAR for many of those patients that may have a reasonable partial response while we’re waiting on CAR to get set up.

David Maloney:

So this study was moving CAR from the third-line to the second-line, but we also heard some intriguing data about trying to move CAR-Ts even sooner, what was your impression of, I guess that was the ZUMA-12 data?

Karen Jacobson :

I think the ZUMA-12 data, it’s a small number of patients, but we’ve seen from small numbers of patients on clinical trials, we’ve seen as it expands to larger patients, the data be really reproducible. So I thought the data looks terrific to see that high of a CR rate to CAR-T therapy and to see that durable response rate is really unheard of. And so I think, my impression of that is that if you can take high risk patients and you catch them in response to a therapy before they’re bound to become refractory CAR-T work even better. And so I think we should be trying to find those patients that we can treat even earlier in their disease course, not necessarily without any chemotherapy, because I think you need to, as Loretta said, need to create the disease kinetic such that you can manufacture CARs and the patients don’t get too sick. And I think we could be really saving people, lots of lines of therapy down the road.

Loretta Nastoupil:

And I think the other important thing too, is that we saw aspects of really healthy T-cells that were not beat up by several lines of prior chemotherapy, but also the toxicity was not worse, so it can be done safely. And so I think this now opens the door to moving it even earlier. So how do you define that high risk patient population where you’re willing to forego anthracycline?

David Maloney:

I think that’s really the key thing is like how do you know?how do you do this study, the followup study for this? So again, this study looked at people with a very high risk disease. They had to have double hit or a high grade B-cell lymphoma and have total four or five interim PET scan after two cycles. And so the real question is how would you just do this on an all comers type basis? Can you find high enough risk that you don’t have to have an interim PET scan to make that decision. And I think that’s what the discussion is to try to use a high risk IPI. But then, I think that’s still complicated to figure out how to do that because the age-adjusted IPI is going to give you a score based on being older than a certain age. And it’s tricky to really find, are you getting the biologic patients that you really found in this trial?

Karen Jacobson :

I think that repeatedly with all of our genomic subclassifications of large cell lymphoma, I think the IPI has been remarkably steadfast in its ability to predict prognosis. I think there’s a lot more reluctance to open a trial of CAR in the frontline for high IPI when you don’t know how CAR is going to perform in that setting. I think having these 40 patients on ZUMA-12 will improve the appetite to take that risk and take that leap. I hope for a randomized trial.

Loretta Nastoupil:

And I think the key part is it’s randomized. So we’ll get an answer, but you want to reduce the barriers and IPI is really easy to derive. And so if we have to wait on a molecular profile to come back, you’re going to select out for good risk patients that are able to allow for that lag time. And so then your control arm’s going to perform well. We all know that their patients that need treatment quickly, but then the question is, are also those patients going to do well with the CAR-T approach. And so I’m really interested to see how this study goes and I’m excited for it.

David Maloney:

I think it’s really going to be exciting to see how, whether we can do that trial. I guess next step was mantle cell lymphoma. We saw continued follow up, that looks very exciting.

Loretta Nastoupil:

With brexu-cel I think the key aspect is that you have to remove those mantle cell lymphoma cells are more likely to have circulating cells. The manufacturing’s a little bit different and it also allows for some exploration of a BTK inhibitor in terms of how that might impact also the phenotype of these T-cells, a little bit different lessons to be learned there, but the outcomes look quite good, particularly in patients who otherwise have poor or dismal outcomes, those that are failing BTK inhibitors. And so I think it’s intriguing. I think, it’s a rare tumor type and they have less options. And so this does provide an effective strategy.

David Maloney:

And you both gave excellent outstanding talks on follicular lymphoma. Karen, you presented the ZUMA-5 data update.

Karen Jacobson :

I think with longer and longer followup now, we’re seeing really, really durable responses, median progression-free survival of almost 40 months with really deep responses, much deeper than we see with any other available therapy. And we’re even seeing in retrospective analysis, a survival benefit over other available therapies. So I think this really does have a place in the treatment landscape for follicular lymphoma, but as we’ve been discussing for all of these other lymphomas is how do you pick those patients who should have it? And can we pick those patients early in their treatment course, so that they can get CAR-Ts earlier and maybe save them lots of lines of therapy. And I think that is the struggle with this disease.

Loretta Nastoupil:

And I think the perception is that these patients are going to live a really long time. And so we don’t want to harm them with our therapy and they have a number of options. So navigating that treatment landscape is no small task, but I do agree with Karen, some of these patients were young, they were progressing through multiple lines of therapies quickly and they derived really favorable outcomes. So now the question is, can we get broader access? Can we deliver it in a way where it could be done outpatient and safer that might reduce the healthcare resource utilization, so that more patients will have access to this? I hope that happens.

David Maloney:

So can we cure follicular lymphoma?

Loretta Nastoupil:

I think we can. The problem is, it’s probably not all patients. And right now we don’t have enough predicted biomarkers to understand how we select them out. But in my practice, young fit patients that are progressing quickly and they look and smell like transformed disease. I just haven’t proven it with a biopsy. Those are the patients I’m going to take to CAR-T all day long.

David Maloney:

So lastly, we had a lot of discussions about multi-antigen targeting, whether it be better to come in with a second CD22 for example, or CD20 on top of CD19, and a lot of discussions about mechanisms of escape and relapse. And so I think we’re starting to learn more biology about T-cell expansion and about these factors that might make these treatments even work better and safer. So I think it was a great morning. And thanks for joining us for highlights from iwCAR-T. Thanks.