Phase III ZUMA-7 study of Yescarta shows improvement in OS for large B-cell lymphoma patients.- Kite/Gilead Sciences

The results showed a statistically significant improvement for Yescarta (axicabtagene ciloleucel) in OS versus historical treatment, which was the standard of care (SOC) in a curative setting for nearly 30 years, for initial treatment of adult patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) within 12 months of completion of first-line therapy. Historical SOC is a multi-step process involving platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy (HDT) and stem cell transplant (ASCT) in those who respond to salvage chemotherapy. These findings will be presented in full later this year at an upcoming scientific meeting.

OS was designated as a clinically important prespecified key secondary endpoint, defined as the length of time from randomization to death from any cause. ZUMA-7 was conducted under a Special Protocol Assessment with the FDA whereby the trial design, clinical endpoints and statistical analysis were agreed upon in advance with the Agency. This pre-specified analysis was also agreed by other health authorities.

ZUMA-7 is considered a landmark trial as the first and largest Phase III study of any CAR T-cell therapy, with the longest follow-up, which has demonstrated event-free survival (EFS), the primary endpoint, that is superior to historical SOC treatment. Data from the ZUMA-7 pivotal trial led to the U.S. approval for initial treatment of R/R LBCL in April 2022 and European Union approval in October 2022, followed by approvals in a number of other countries such as: Great Britain, Israel, Japan, and Switzerland.

About ZUMA-7 Study: ZUMA-7 is a randomized, open-label, global, multicenter, Phase III study evaluating the safety and efficacy of Yescarta versus SOC for initial treatment of adult patients with R/R LBCL within 12 months of first-line therapy. In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or historical SOC second-line treatment. The primary endpoint is EFS as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) and OS. Additional secondary endpoints include patient reported outcomes (PROs) and safety. Per hierarchical testing of primary and key secondary endpoints and group sequential testing of OS, an interim analysis of OS occurred at the time of the primary EFS analysis. The prespecified primary OS analysis was to be conducted after 210 deaths or no later than five years after the first patient was randomized.

Yescarta demonstrated a 2.5-fold increase in patients who were alive at two years and did not experience cancer progression or require the need for additional cancer treatment (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC (hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001). in addition to being the largest and longest study of its kind, zuma-7 study participants on the yescarta arm did not receive additional bridging chemotherapy that could have potentially confounded results.></0.0001).>

Nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (35%) who received on-protocol HDT+ASCT. More patients responded to Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001) and achieved a complete response (cr) with yescarta (cr rate: 65% vs. 32%) than with soc. at the time of the primary efs analysis, more than half of patients in the soc arm subsequently received yescarta off study.></0.0001)>

In the study, Yescarta had a safety profile that was consistent with previous studies. Among the 168 Yescarta-treated patients evaluable for safety, Grade greater than 3 cytokine release syndrome (CRS) and neurologic events were observed in 7% and 25% of patients, respectively. In the SOC arm, 83% of patients had high grade events, mostly cytopenias (low blood counts).