Emerging KTE-X19 CAR T-Cell Therapy for MCL

Transcript: Ian Flinn, MD: Tycel, let’s switch gears and talk about cellular therapy. We’re all part of the ZUMA-2 experience and really excited to see that data at ASH [American Society of Hematology Annual Meeting & Exposition], specifically CAR [chimeric antigen receptor] T cells in mantle cell lymphoma. For that patient with multiple relapses, I thought the data were really encouraging. I don’t know what your take on it was.

Tycel Jovelle Phillips, MD: We were allowed to see the abstract. As for the presentation, we’ll hopefully be able to see it this afternoon, and it does look encouraging. I think more important, it’s a very at-need patient population. Again, this is the ibrutinib-refractory patient group. Other than the data that were published from the British looking at R-BAC [rituximab, bendamustine, cytarabine], we’ve all struggled. Nobody has any firm data of any great salvage regimen.

I think [The University of Texas] MD Anderson [Cancer Center] and Weill Cornell [Medicine] compiled several retrospective studies looking at outcomes in this group, and they all looked abysmal. If we can get any treatment that has a very durable response—which will be key in this situation, especially given the cost that’s associated with CAR T-cell therapy—this will be something that will revolutionize how we manage this patient population and allow us to potentially continue extensive I/O [immuno-oncology] in this patient group longer and longer. We may eventually turn into CLL [chronic lymphocytic leukemia] at some point if we get enough effective therapies.

Ian Flinn, MD: Bijal, what are your thoughts on cellular therapy in patients with mantle cell lymphoma? You just outlined very well the need for new therapies in mantle cell lymphoma and especially in patients with multiple relapses. What’s your take?

Bijal Shah, MD: I’m blown away by the data set. In the full-analysis data set of 60 patients, we’re seeing incredible efficacy. If I recall, it was around 80% or so in terms of the response rates, but more important, these are durable. These are durable at a year, and this is not something we normally see. Our expectation in a BTK [Bruton tyrosine kinase]—refractory population is a median survival of somewhere around 2 to 4 months. We’ve more than doubled our expectation. Yes, there are CRS [cytokine release syndrome] and neurotoxicity, and I think those are part of the process of CAR T-cell therapy.

Looking at the data, it looks as if these were essentially reversible and patients aren’t dying from them. In fact, I don’t think there was any grade 5 toxicity attributed to the CAR T-cell treatment seen in the trial. The median age is an older patient population. Again, median age of diagnosis is 68 years in mantle cell lymphoma, so we’re able to take these patients through CAR T-cell treatment and the multiple refractory, BTK-refractory setting and get them better. This is a home run from where I’m sitting. I’m just trying to figure out how soon it’s going to be something that I can use in practice now that it’s outside the trial experience. That’s to give you a sense of how excited I am.

Ian Flinn, MD: Many share your sense of excitement. I’m sitting here thinking, if it works in this very refractory-patient population, what do we need to do to move it earlier? To talk a bit about what Bijal was saying about some of the neurotoxicity, there was a fair amount of neurotoxicity in this trial. That is daunting. What’s your take on the data and also about getting it and moving it forward?

Javier Munoz, MD, FACP: I’m extremely excited about the data. I share your enthusiasm. I have been honored to be part of this wave of cellular therapies with all of you. We have participated together in several trials. I think the numbers speak for themselves. As some background, patients needed to have received and failed a prior BTK inhibitor.

We know from previous publications that this set of patients does particularly poorly. Their overall survival is measured in months—5.8 months, if I recall. The median age of these patients was, if I recall, 65 years, and there were some patients with blastoid features. Twenty-one percent of patients had blastoid mantle cell lymphoma, so we were not cherry-picking when it came to patients. Despite those poor actors, we had an overall response rate of 86% and a complete response rate of 52%. Let’s say the median overall survival was not reached. Going back to the comment that these patients would survive only a few months without these cellular therapies, the data are very impressive.

To answer your second question about clinical trial design, this has been done, let’s say, in diffuse large B-cell lymphoma. You prove yourself in the sickest of the sick, the relapsed/refractory population that has received and failed multiple lines of chemotherapy. Once you prove yourself, you try to move forward, perhaps to second-line therapy and, maybe even 1 day, frontline therapy. For that, we need clinical trials and we need time.

Bijal Shah, MD: Do you think it’s effective enough that we could move it forward without the trial?

Ian Flinn, MD: I don’t know, but I’m wondering whether the better situation is—do you remember that the trial required that patients had to come off the BTK inhibitors? It was a bit of a challenge, right? You probably had many of these patients, as well. You stop it, and they progress so rapidly, and they’re too sick to go on to the trial. Tycel, not today, but tomorrow, should we be continuing patients on ibrutinib? Should we be taking them at the first sign of relapse, or are we looking at bulk of disease before they get so sick? That would be 1 way to move it forward.

Tycel Jovelle Phillips, MD: I think you hit on some key points about utilizing ibrutinib possibly in combination with CAR T-cell treatment, as Penn Medicine Abramson Cancer Center has already shown some CLL patients, or as a bridge to CAR T-cell therapy in some situations to minimize the bulk of disease. Not to be childlike, but it’s like the world is our oyster at this point with some of the information. How do we best manage it to get the best outcomes for our patients? I do agree that moving this up would be the next natural step, especially as more of the data mature and we see the durability of responses. If you’re already getting this far out and it’s such a very heavily pretreated population—which, by far, none of us ever thought we’d see in this patient group based on some of the retrospective data that we have—if you move it to the second-line setting, how long are these patients going to be able to stay in remission? We potentially also use the C-word in patients with mantle cell lymphoma. A lot of us have been very reluctant to ever utter the word cure when we talk about patients.

Ian Flinn, MD: Yes, and if we’re going to get to that, it’s definitely going to be more efficacious to use it earlier rather than to wait until nothing else is working, which is really where we were with this patient population. Bijal, what about making it more tolerable? You and I sit here and say, “Oh, it’s not that bad,” but if you’re a patient going through it…

Bijal Shah, MD: There’s no question. We all talk about the neurotoxicity and the CRS [cytokine release syndrome] being reversible, and that’s true. But when you’re going through it, it doesn’t feel reversible. There have certainly been times where even I have been anxious. We’re going to watch them more closely, we’re going to start the rescue medicines, and we’re going to do what we need to do to get people better.

I’m very encouraged by the fact that people aren’t dying from this therapy. As you point out, some patients have gotten very sick. Dr Michael Wang described a patient with a grade 4 cerebral edema. This is not trivial. This is a big deal. We have to make sure we’re going to be able to carry our patients forward through this therapy, and we have to figure out the best way to do it.

In my opinion, get it in earlier. Get it in with lower tumor burden, and all that stuff goes away. All of a sudden, now we have a much easier-to-deliver product, and we’ve seen this in acute lymphoblastic leukemia. We’ve seen this in diffuse large B-cell lymphoma, in which we’re using these tumor burden assessments to guide not only safety but also effectiveness. That’s my general thought. We’ve got to get it in early—simple induction, CAR T-cell treatment, maybe the C-word.

Transcript Edited for Clarity