In part 2 of this video series, Bijal Shah, MD, Assistant Member, Moffitt Cancer Center, Tampa Florida, discusses the next steps of the phase 2 ZUMA-3 study of KTE-X19, a novel anti-CD19 chimeric antigen recept (CAR) T-cell therapy in relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), the data of which were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

The first thing is KITE (KTE-X19) has already gone to the FDA. We're hopeful that the FDA will agree that these results are meaningful and appropriately safe for an adult population with relapsed ALL. We'll have an FDA-approved product.

Then what happens in terms of the line in which it's approved for and how it ultimately gets used in the clinic will be the subject of lots of future abstracts and papers. I'm amazed at what we saw come out of ASH in 2020. I'm going to refer the folks watching this to two particular abstracts.

One, Nirali Shah presented data as part of an NCI consortium, looking at outcomes with CAR-T cell immunotherapy. There was a concern that prior blinatumomab may impact the success and the durable remission rate associated with CAR-T cell immunotherapy.

It's early data, and I will say we did not see the same thing in our study. Prior blina did not seem to have an impact, nor did prior inotuzumab for that matter. It is an evolving space, and it'll be very interesting to understand who were those prior blina-treated patients. Were they more like to have also had an allo? If so, how does that inform therapy after the CAR-T cell immunotherapy?

If you pay close attention to the data that she presented, for patients who had prior blina and then got CAR-T cell therapy, there's a very sharp drop-off. Then the curve almost plateaus. You see very little drop-off between 6 and 12 months, both as it relates to EFS and RFS. There may be some plateau as we get out further, but the bottom line is there's more of a drop in EFS and RFS in the non-blina treated patients.

It makes you think, "OK, maybe this is the impact of therapies delivered after CAR T-cell immune therapy, like transplant, that are driving this endpoint to some degree." These are things that we need to better understand.

The other abstract that's worth taking a deeper dive into is the PRWCC. This is the Pediatric Real-World CAR-T Consortium. This was presented by Liora Schultz from Stanford. This was around 200 patients. Here, they had a little bit more clinical data for the patients that we're going to be looking at.

In this particular study, prior CD-19-directed therapy, which included CAR-T in some cases, had no impact  on the response, had no impact on survival. It seemed as though it didn't matter. What mattered tremendously was tumor bulk.

This was, to me, where I see CAR-T cell therapy evolving.

The patients who derived the most benefit had fewer than 5 percent blasts without extramedullary disease outside the CNS. These were patients with exceptionally low-burden disease who benefited the most from CAR-T cell immunotherapy.

In fact, there was a group of almost 50 patients out of the 200 or so that had no detectable disease by flow cytometry, by MRD flow, that went into CAR-T cell therapy. They still developed B-cell aplasia, implying that there was still CAR-T cell expansion and CAR-T cell activity.

You follow those EFS curves, it's incredible. The data were outstanding in the patients. Where I hope we land with all of these novel clinical trial designs with CAR-T cell therapy, with the assumption that we have the FDA approval. I have to make that very clear. I don't like to speak for the FDA or anybody in a regulatory position. With that assumption, my hope is that we'll begin to integrate CAR-T cell therapy in adults into earlier lines of therapy and begin to more critically ask, "What is the role of allogeneic stem cell transplant consolidation after CAR-T cell immunotherapy?"

My hope is we'll be able to finally move away from that as a standard approach for our patients.

We and many others have presented concepts to KITE. My best guess is, if we're going to change front-line therapy for adults, this is going to have to be conducted through the cooperative group mechanism.

ALL is still a rare disease, and we have to understand how to generate data that's going to be generalizable across the board. I suspect that KITE will have to work with the cooperative groups to develop this therapy if we're going to go into the front-line setting in that manner.

In the meantime, because those studies take a long time to design and ultimately initiate, my hope is that there'll be several pilots both in the US and Europe. What I imagine we'll see is some combination of both retrospective and prospective data using CAR-T in novel situations that may fall outside of the eligibility that we saw here with the ZUMA-3 trial.

This is exactly what we've seen in mantle cell lymphoma. This is exactly what we've seen with diffuse large B-cell lymphoma.

That's why I think we're going to probably take a similar approach with these real-world consortium data in helping to guide what will be a larger study to ultimately take us to that point where we can say, "We improved on that 38 percent benchmark. We are in a better place. There are more patients being cured."

We also presented data on allogeneic CAR-T cell therapy. I think that this is an important area that is evolving. You heard me allude to the fact that, with bridging therapy, some patients got sick and never made it to the CAR-T cell infusion.

As we get better and better with allogeneic CAR-T cell therapy, my hope is we'll be able to integrate and potentially one day even replace autologous CAR-T  cell therapy. We're not talking anymore about having to collect, manufacture, and then infuse, but have a product off the shelf, in the freezer, ready to deliver when a patient needs it most.

It's not a pipe dream. If you look at some of the NK CAR-T cell data, if you look at some of the data from Allogene, and you look at the data now from Precision BioSciences, showing not only can it work, it does. We see expansion. We see disease activity. We see a lot of very, very encouraging evidence of activity. I'm really excited by the allo CAR-T space. I think there's going to be a lot that we see as we go forward.

The other area that I'll hit on briefly is we're still having some difficulty in managing those who don't fall cleanly in the B-cell/ALL space. We can talk about MLL gene rearrangements and how that is complicated by high rates of relapse when we target CD-19, whether that be myeloid lineage shifts or just an easier path toward CD-19 down-regulation. We see similar things in B myeloid leukemias. We haven't even touched on T-cell ALLs and what to do for that cohort of patients.

We presented data at EHA looking at Vyxeos in this population. There are other novel therapies, too. You asked me about my research, and that's why I'm sharing what we had done and what we shared. I don't want to imply that's all there is.

I think the menin inhibitors are very, very exciting. There's lots of other new tools coming to this space. Coming back to Vyxeos very briefly, it's liposomal therapy. Now, we're in a liposomal world with Moderna and Pfizer, and all these things. People are starting to understand there's something unique about how these liposomes can deliver therapy to leukemias.

What do we see? We see a concentration of chemotherapy in the bone marrow compartment, particularly in the blast compartment, where we most want it. These agents are effective, meaning if the cancer is sensitive to cytarabine and to an anthracycline, as we deliver with Vyxeos, then we can anticipate disease activity.

That's what we saw. We were very pleased by seeing the disease activity from the patients that we treated. Interestingly, it wasn't a spectrum of toxicity that was more pronounced. This was also a finding from the Vyxeos trials in older adults, those with secondary AML and so on, that were presented previously.

It works, and you would anticipate more toxicity because you're concentrating the drug in the marrow compartment. The reality is that means you're not going to get as much enteritis. You're not going to get as much inflammation of the gut, so you're not going to get the leaky gut and the bacterial infections that are more commonly seen with traditional cytarabine and daunorubicin.

There are other similar things that you might expect with chemotherapy, be that anthracycline-associated cardiotoxicity and so on. You're going to see less of that when it's delivered liposomally. That's what we observed here, too. It generally was safe, and we treated older patients, we treated younger patients, we treated the whole nine yards.

What was great about this study is we enrolled people with B-myeloid leukemias and BTP-type leukemias. I think it's going to be important to think beyond just CD-19. That's where some of these tools are taking us and things I'm excited about to go forward.