ZUMA-7 Data Underscore Potential of CAR T-cell Therapy as Second-Line Standard in Relapsed/Refractory LBCL

Frederick Locke, MD

Axicabtagene ciloleucel (Yescarta; axi-cel) demonstrated a significant improvement in event-free survival (EFS) compared with standard-of-care (SOC) chemotherapy when used in the second-line treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), and as such, should be considered as a new standard, according to Frederick Locke, MD.

Data from the phase 3 ZUMA-7 trial (NCT03391466), which were presented during the 2021 ASH Annual Meeting and Exposition, showed that at a median follow-up of 24.9 months, treatment with axi-cel resulted in a median EFS of 8.3 months (95% CI, 4.5-15.8) vs 2.0 months (95% CI, 1.6-2.8) with SOC chemotherapy in this population.1 The 24-month EFS rate with the CAR T-cell therapy was 40.5% (95% CI, 33.2%-47.7%) vs 16.3% (95% CI, 11.1%-22.2%) with SOC.

“We are excited about these results. They show that we need to consider referring these patients for CAR T-cell therapy as a second-line treatment,” Locke said. “This is a shift in the treatment paradigm for second-line LBCL. The sooner these patients are referred, the better.”

In an interview with OncLive^®, Locke, vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center, discussed the phase 3 ZUMA-7 trial examining axi-cel in the second-line treatment of patients with relapsed/refractory LBCL, safety and efficacy findings with the therapy, and the significance of the data that have been reported to date.

OncLive^®: What was the design of the phase 3 ZUMA-7 trial?

Locke: ZUMA-7 is the first randomized, multicenter, [global] clinical trial to compare axi-cel with SOC for the second-line treatment of [patients with] LBCL. Patients were randomized 1:1 to receive the CAR T-cell therapy [vs] the current multistep treatment paradigm, which consists of a multiagent chemotherapy regimen. Patients who responded with a partial response or complete response [went] on to receive an autologous hematopoietic stem cell transplant.

The primary end point of the trial was EFS. Events included death due to any cause, patients who progressed, or those who needed to switch to a different anti-lymphoma therapy. We saw that of the patients who were randomized to receive the CAR T-cell therapy, 94% received axi-cel. Conversely, of those who were randomized to the SOC arm, [36%] received the definitive ASCT. As such, there was a remarkable difference in patients who received the definitive therapy.

What were the key findings?

Importantly, the median EFS was over 8 months for axi-cel and only 2 months for the SOC arm. Most importantly, the 24-month EFS rate was approximately 40% for axi-cel vs about 16% for the SOC arm; this means that at 2 years after randomization, over 40% of patients who were on the axi-cel arm did not need additional therapy and remained in remission vs 16% [of those] in the SOC arm.

We are excited about [these results]. The complete response rates were doubled in the axi-cel arm, so there is clearly an efficacy benefit for these patients who [received] axi-cel.

Are there any adverse effects to be aware of? Are there any other challenges that need to be addressed?

CAR T-cell therapy can cause toxicities, and we did see cytokine release syndrome [CRS] and neurologic toxicities occur at rates that were similar to what we had seen in other clinical trials with CAR T-cell therapy.

The SOC arm had similar rates of adverse effects [AEs] and severe AEs. However, the nature of those toxicities was different on the SOC arm. These patients were more likely to have febrile neutropenia and less likely to experience CRS. In general, [the toxicities observed with axi-cel] were manageable, [and are ones] that we are used to [seeing] with CAR T-cell therapy.

Is there anything else that you would like to highlight from this trial?

Another interesting thing [to point out] is that in the SOC arm, if patients progressed, they could receive CAR T-cell therapy or another cellular immunotherapy off study; 56% of patients in the SOC arm went on to receive CAR T-cell therapy as a third or later line of treatment. Despite that, at an interim analysis for overall survival [OS], [the trend favored] axi-cel, suggesting that we are impacting OS for these patients—even if they are able to switch therapy and receive CAR T-cell therapy as a third-line [treatment].

What should your colleagues take away from this research?

CAR T-cell therapy should be a new SOC treatment in the second line for [patients with] LBCL. Importantly, patients need to be referred early. Local oncologists, community oncologists need to know about CAR T-cell therapy. If a patient progresses after frontline chemotherapy, we need to consider getting them to a center that does CAR T-cell therapy very quickly, so that we can give them CAR T-cell therapy as a second-line treatment.

Reference

1. Locke FL, Miklos DB, Jacobson C, et al. Primary analysis of ZUMA‑7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard‑of‑care therapy in patients with relapsed/refractory large B-cell lymphoma. Blood. 2021;138(suppl 1):2. doi:10.1182/blood-2021-148039