CAR T-Cell Therapy in Relapsed/Refractory DLBCL: Axicabtagene Ciloleucel

Transcript:
Matthew A. Lunning, DO, FACP: We’re going to shift gears to CAR [chimeric antigen receptor] T-cell therapy in relapsed/refractory large cell lymphoma. Dr Saeed, where is CAR T in your practice outside a clinical trial?

Hayder M. Saeed, MD: With CAR T, we tend to follow the FDA label of indication. To start, we talk about Yescarta or lisocabtagene maraleucel, which are the 2 CAR T cells that have been shown to improve outcome in second-line diffuse large B-cell lymphoma refractory to frontline therapy. Those patients are usually treated with CAR T-cell therapy if they relapse within 1 year. If they also have relatively good performance status, we believe they will tolerate CAR T. Otherwise, most patients will receive CAR T-cell therapy in third line and beyond. When patients get referred to our center, CAR T cells have some issues with limitations to the center that can administer those. If it’s our patients, then we have it readily available. If a patient is referred to us, then depending on where they are in their line of treatment of diffuse large B-cell lymphoma, that’s where we fit them, whether it’s third line or beyond. The good thing is that the activity of CAR T cells has been seen to be consistent in respect of their line of therapy. Even if they’re referred to us in later lines, as long as they have reasonable performance status, then we’re able to fit them into that program.

Matthew A. Lunning, DO, FACP: Excellent. Dr Westin, we heard about axicabtagene-ciloleucel in relapsed/refractory large cell lymphoma. We knew about ZUMA-1, but walk us through ZUMA-7, the trial design, and some of the nuances. Give me 1 thing that our viewers may not know about ZUMA-7.

Jason Westin, MD, MS, FACP: ZUMA-7 was axicabtagene ciloleucel, which we just heard about. Prior to ZUMA-7 being approved in third- or later-line therapy, ZUMA-7 was moving it into second-line therapy and effectively taking patients who were refractory to first line or relapsed within 12 months and randomizing them 1:1 to receive axicabtagene-ciloleucel or platinum chemotherapy. If that works, then high-dose therapy and autologous transplant. There was no crossover on the trial that patients who didn’t respond or have durable benefit to chemotherapy could go off-study and get subsequent cellular immunotherapy in the third line or later. The primary end point of the trial readout was last year, and Fred Locke was the first author in the New England Journal of Medicine. It had a hazard ratio for event-free survival of 0.39, which is a statistically significant improvement…. We just presented the results of the overall survival [OS] primary analysis. It showed a statistically significant improvement in overall survival. This is the first time that’s happened in nearly 30 years in the curative intent setting. The hazard ratio for overall survival was 0.726. There’s a new curative therapy in second-line treatment. Using platinum chemotherapy and saving cell therapy for the third line appears to be an inferior approach.

Matthew A. Lunning, DO, FACP: Let’s dive a little further into ZUMA-7. The control arm was second-line chemotherapy transplant. In your presentation it was 36% if I remember correctly.

Jason Westin, MD, MS, FACP: Your memory serves well.

Matthew A. Lunning, DO, FACP: For those patients who didn’t have a response, the rest had the opportunity to get CAR T cell. About 56% of them went on to get CAR T cell, and the rest got some other form of therapy. Is that correct from your data set?

Jason Westin, MD, MS, FACP: That’s correct. A small percentage of patients, 36%, got the intended definitive therapy, even though 100% of them got the chemotherapy. This speaks to why chemotherapy in the second line in refractory patients is a challenge. Because they’re refractory, they didn’t respond to chemotherapy the first time. But for those patients who didn’t benefit, they didn’t get definitive therapy with transplant or relapse after transplant, and many of them went on to get the subsequent cellular immunotherapy. Despite that high rate of patients getting CAR T-cell therapy in a later line, it was statistically significant. Historically, we’ve tried chemotherapy first and saved CAR T cell for later, but that approach appears to be inferior for overall survival approach.

Matthew A. Lunning, DO, FACP: In your opinion, how does this change the discussion of overall survival advantage? Has your discussion changed?

Jason Westin, MD, MS, FACP: Overall survival is an end point that’s hard to quibble with. You could have a discussion about event-free survival, saying that it may improve outcomes. However, you can still save patients at a later line by giving them a CAR T cell. Overall survival is black and white; you’re either alive or not. This changes the conversation about whether event-free survival the right end point. Different countries view CAR T cell to be second line or saved for third line. This changes the conversation. You have to look at the equipoise between using chemotherapy and transplant vs the statistically significant OS benefit for axicabtagene-ciloleucel in second line.

Transcript edited for clarity.