New Axi-cel Overall Survival Analysis May Disrupt LBCL Treatment Landscape

Jason Westin, MD, FASCP

A new analysis of data from the phase 3 ZUMA-7 clinical trial (NCT03391466), which is evaluating second-line standard of care (SOC) platinum-based chemotherapy against Kite’s chimeric antigen receptor T-cell (CAR-T) therapy axicabtagene ciloleucel (axi-cel; Yescarta), has demonstrated the CAR-T's superiority in terms of overall survival (OS) in the second-line setting for diffuse large B-cell lymphoma (DLBCL). The findings were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois, by Jason Westin, MD, FASCP, the director of the Lymphoma Clinical Research Program at University of Texas MD Anderson Cancer Center.

Following the close of the conference, CGTLive™ spoke with Westin about the new analysis and its implications for the landscape of care in LBCL. He discussed how the findings fit into the rapidly evolving landscape of care for this cancer and touched on plans for further research, which include the phase 3ZUMA-23 clinical trial (NCT05605899) that is assessing axi-cel's potential for use in the high-risk first-line treatment setting.

CGTLive: Can you give some background info about what the current landscape of care looks like for large B-cell lymphoma?

Jason Westin, MD, FASCP: The current landscape of care for patients with DLBCL is evolving rapidly. In the first line setting, for decades, the SOC has beenrituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). There have been many attempts to improve upon it, but none had succeeded, up until just recently with the POLARIX clinical trial showing that in patients with International Prognostic Index (IPI) of 2 to 5 there was a statistically significant improvement in progression-free survival of polatuzumab vedotinwith rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP)—effectively exchanging vincristine for the antibody drug conjugate polatuzumab. In the second line, there's also a change in that the long-standing de facto standard around the world of platinum-based chemotherapy followed in responding patients by high-dose treatment and autologous stem cell transplant (auto transplant) has now been shown to be improved upon both in event-free survival, as well as overall survival, by axi-cel—the ZUMA-7 trial showed that the overall survival was statistically significantly improved with axi-cel. There's also been improvements with lisocabtagene maraleucel(liso-cel; Breyanzi) for event-free survival (EFS). Both of those CAR-T therapies are indicated as standard options in second-line treatment.

Can you give a brief overview of the data you presented at ASCO and the main takeaways for the clinical community?

At the ASCO 2023 meeting we presented the primary overall survival analysis from the ZUMA-7 trial. ZUMA-7 was a global randomized phase 3 study comparing axi-cel, the autologous CD19-targeting CAR T-cell, against platinum-chemo, and in responding patients, platinum-chemo followed by high-dose therapy and auto transplant. We previously showed the EFS end point of the trial, published in The New England Journal of Medicine in 2022, that showed axi-cel significantly improved EFS. What was new at ASCO is we showed that there was a 27% reduction in the risk of death, favoring axi-cel use in second-line—so a significant improvement in the survival of patients if they're treated in second-line with axi-cel. What was also of interest in our trial was that a large proportion of patients on the standard arm went on to receive subsequent cellular immunotherapy. More than half the patients received additional treatment off protocol—effectively the prior standard of ‘chemo [first], and save cell therapy for later’—and despite more than half the patients getting that, there was still a statistically improved overall survival for axi-cel in second line, implying that the old standard is an inferior approach. Based on these results, we argue it's a paradigm shift that axi-cel should be a second-line SOC.

How important do you feel OS is as a measure of success for a therapy like axi-cel compared to other measures of efficacy?

OS, at the end of the day, is the most important outcome that we can measure in a clinical trial because it doesn't get more significant than that: if the patient is alive or is not alive. There are other very important metrics that can be looked at in clinical trials, such as EFS or progression-free survival, and some trials do show significant improvements and don't show OS as an advantage because there's effective therapy that's available in the relapse setting. So I don't think that every trial, in order to be deemed a success, is required to show OS, but in trials that do show it, you're able to draw a strong conclusion that the arm that won for OS is the superior approach.

Were there any challenges or limitations in this study that you'd like to see explored further in future studies?

In the ZUMA-7 clinical trial we explored the use of CAR T-cell therapy in patients that had disease that was refractory to or early relapsed after first-line therapy. The axi-cel paradigm showed that it was better than the old paradigm of chemo and transplant in that patient population. Well, if it won there, wouldn't it be interesting to look at in patients who were not refractory to first-line chemo, but instead patients who were newly diagnosed that had high-risk features? Those patients in the first-line setting that have a high IPI score such as 4 or 5—we know that they have around a 50% chance of achieving a long-term good outcome with R-CHOP, R-EPOCH, or pola-R-CHP-based therapy. There's an unmet need in that first-line setting. At the ASCO 2023 meeting we also presented a trial-in-progress poster for the ZUMA-23 clinical trial. This is a global phase 3 randomized study which is asking the question: “Could axi-cel be a first-line therapy option preferred over R-chemo for those high-risk patients?” The trial is up and running as of this interview. We don't yet have any data, but we're eagerly anticipating those results.

Is there anything else our audience should know?

I think one of the big takeaways from the primary OS analysis is that more patients live longer if they're treated in second-line with axi-cel... The prior paradigm of ‘Let's see if the patient will respond to chemo and then if not, okay, now we'll go for CAR T-cell therapy’—that's been conclusively shown to be an inferior approach and I think it's time to move on as a field and acknowledge that CAR T-cells are superior to chemo and stem cell transplant.

Transcript edited for clarity.

Click here for more coverage of ASCO 2023.

REFERENCE
Westin J, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA‑7 study of axicabtagene ciloleucel versus standard‑of‑care therapy in relapsed/refractory large B-cell lymphoma. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #LBA107