ZUMA-7: Axi-Cel in Second Line Is the “New Standard” in R/R LBCL, Locke Says

Coming into the 63rd Annual American Society of Hematology Meeting and Exposition, Gilead Sciences had already announced that axicabtagene ciloleucel (axi-cel), sold as Yescarta, offered an event-free survival (EFS) rate of more than 60% over the current standard of care for patients whose initial treatment for large B-cell lymphoma (LBCL) failed or whose cancer returned within a year.

For Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa, the lead study author of the phase 3 ZUMA-7 trial that studied the use of axi-cel in these patients, the question was: what now?

The answer is clear, he said. Axi-cel, with years of data behind it, will quickly become the new standard for these patients.

“ZUMA-7 met its primary EFS end point, demonstrating statistically significant and clinically meaningful improvement in efficacy with axi-cel vs second-line SOC in relapsed/refractory large B-cell lymphoma,” Locke said the ASH plenary session Sunday afternoon. “Results from the ZUMA-7 trial herald a paradigm shift: axi-cel should be a new standard for patients with second-line relapsed/refractory large B-cell lymphoma.”

Locke presented the data for ZUMA-7 to a large crowd, many of whom had heard the main data points but had other questions: if patients treated with axi-cel in the second-line setting fail, what happens next? Could an autologous stem cell transplant (ASCT), which has been the standard of care for the second-line patients, now follow axi-cel?

“We don't know what the appropriate therapy would be for a patient in the third line if they receive CAR T-cell therapy in the second line,” Locke said during a press briefing held prior to the plenary session. “We don't understand what the resistance mechanisms, if they overlap…I think that will be an area of intense study in the years to come.”

He said in ZUMA-7, patients could go on to transplant if they progressed after receiving axi-cel; 19 patients did so, and 9 are still alive. “We don't fully understand the answer to that question.”

And in response to a question, Locke acknowledged that minority patients had been underrepresented in ZUMA-7; across the conference there were discussions of how to make these expensive therapies available to all patients, regardless of socioeconomic status.

Differences with TRANSFORM. Axi-cel was approved in the fall of 2017, within months of the first CAR T-cell therapy, and is now approved in for several types of R/R LBCL. Clinicians have become much better at managing the most significant adverse events (AEs) arising from cytokine release syndrome (CRS), which occurs as the customized therapy attacks the cancer within the patient’s body.

Unlike TRANSFORM, which studied lisocabtagene maraleucel (liso-cel), the ZUMA-7 study did not allow chemotherapy as a bridging therapy—a point of demarcation between the 2 studies that Locke emphasized at a press briefing the day prior. But will bridging therapy be given in a real-world setting?

Advantages of axi-cel. As City of Hope’s Alex F. Herrera, MD, noted in his plenary introduction, the question of using CAR T-cell therapy generally and axi-cel specifically arose quickly after clinicians saw its success in the third-line setting.

Locke noted that ZUMA-7 produced an advantage right away that was seen with TRANSFORM the day prior: when the standard of care for second-line relapsed or refractory (R/R) LBCL salvage chemotherapy followed by a high-dose therapy and ASCT, the challenge is getting patients to the point of receiving the transplant in the first place. In ZUMA-7, 94% of those randomized to receive axi-cel were infused with treatment, while only 36% in the standard of care (SOC) group received a transplant.

Results from ZUMA-7 showed the following:

• After a median follow-up of 24.9 months, results showed that the median EFS was 8.3 months (95% CI, 4.5-15.8) for patients treated with axi-cel compared with 2.0 months (95% CI, 1.6-2.8) for those on SOC (HR, 0.398; 95% CI, 0.308-0.514; P < .0001).
• The objective response rate was 83% for axi-cel vs 50% in SOC (odds ratio, 5.31; 95% CI, 3.1-8.9; P < .0001).
• Median overall survival, evaluated as a preplanned interim analysis, favored axi-cel over SOC, but did not yet meet statistical significance (not reached vs 35.1 months, HR, 0.730; P=.027). Although the study did not include a crossover design, patients who failed on SOC and later received axi-cel could be confounding these results, Locke said.
• Grade 3 or higher neurologic events occurred in 21% of the axi-cel group and 1% of the SOC group; common symptoms included tremor (26% vs 1%), confusional state (24% vs 2%,), and aphasia (21% vs 0%). All were treated with corticosteroids. Median time to onset was 7 days with axi-cel and 23 days with SOC; median duration as 9 days vs 23 days.
• Grade 3 or higher CRS was seen in 6% of axi-cel patients; CRS was managed with tocilizumab (65%) corticosteroids (24%) and vasopressors (6%).
• Other grade 3 or higher AEs occurred in 91% of the axi-cel group vs 83% of the SOC group. Most common were neutropenia (69% vs 41%), anemia (30% vs 39%), and leukopenia (29% vs 22%).
• The axi-cel arm had 1 treatment-related death; the SOC group had 2.
• Axi-cel was superior to SOC across key subgroups, including those young and older than 65 years of age; patients whose first-line therapy failed and those whose relapsed within the first year after their first therapy succeeded.

ZUMA-7 is distinguished by the fact that patients were given corticosteroids only, not chemotherapy, prior to axi-cel treatment. “By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy patients are exposed to and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem cell transplant,” Locke said.

Reference

Locke F, Miklos DB, Jacobson CA, 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. Presented at: 2021 ASH Annual Meeting and Exposition; December 12, 2021; Atlanta, GA. Abstract 2.