Yescarta ZUMA-12 study demonstrates 78% complete response rate as part of first-line treatment in newly diagnosed high-risk large B-cell lymphoma.

This is the first study to evaluate CAR T-cell therapy as part of first-line therapy in high-risk LBCL. The study is based on the desire to utilize potential curative treatment as quickly as possible and the hypothesis that earlier use of CAR T-cell therapy when T cells are healthier may produce better outcomes. The data were presented in an oral session during the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract #739).

After a single infusion of Yescarta, 89% of evaluable patients achieved a response (ORR) (n=37 evaluable for efficacy), including 78% of patients with a complete response (CR) at a median follow-up of 15.9 months. CR rate was consistent among key subgroups. Among evaluable patients, median time to response was one month. At time of data cut-off, 73% of evaluable patients had ongoing responses. Medians for duration of response (DOR), event-free survival (EFS), and progression-free survival (PFS) were not yet reached, with 12-month estimates of 81%, 73%, and 75%, respectively, and an estimated 12-month OS rate of 91%.

Yescarta was successfully manufactured for all 42 enrolled patients with a median turnaround time of 18 days between leukapheresis and delivery to the trial site for treated patients. Levels of CCR7+CD45RA+ T cells (a measure of T-cell fitness) found in pre-infused product were more than double what was measured in the heavily pre-treated third line ZUMA-1 patient population. Levels of CCR7+CD45RA+ T cells in pre-infused product have been associated with a favorable pharmacokinetic (PK) profile. CAR T-cell expansion also appeared greater in ZUMA-12 compared with ZUMA-1.

“Less than half of patients with high-risk LBCL actually achieve long-term remission with standard first-line therapy,” said Sattva S. Neelapu, MD, Professor, Department of Lymphoma-Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “There have been a number of attempts to improve outcomes for high-risk patients, either by intensification of chemotherapy, immunotherapy, or consolidation with autologous stem cell transplantation, but they have not been successful. The impressive response rates in ZUMA-12 support the potential of CAR T-cell therapy earlier in treatment to improve outcomes in these high-risk patients.”

Among all treated patients (n=40), safety observations were consistent with the known safety profile for Yescarta. Grade 3 cytokine release syndrome (CRS) occurred in (8%) of patients and Grade greater than 3 neurologic events occurred in (23%) of patients. No Grade 5 CRS or neurological events occurred. There was one Grade 5 adverse event due to COVID-19. All CRS cases and most neurologic events (28/29) of any grade resolved by the time of data cut-off.

About Zuma -12 : ZUMA-12 is a multicenter, open-label, single-arm Phase II study that enrolled 42 adult patients (greater than 18 years old) with high-risk LBCL. Patients who met the following criteria for high-risk LBCL were considered eligible for the study: double- or triple-hit lymphoma by fluorescent in situ hybridization per investigator or LBCL with IPI score greater than 3; and positive interim PET per Lugano Classification after two cycles of an anti-CD20 monoclonal antibody- and anthracycline-containing regimen. Patients underwent leukapheresis ( greater than two weeks) after prior systemic therapy) and optional non-chemotherapy bridging at investigator discretion, followed by conditioning chemotherapy. The primary endpoint of the trial is complete response rate per the Lugano Classification. Key secondary objectives include objective response rate, duration of response, event-free survival (EFS), progression-free survival, overall survival, frequency of adverse events, and levels of CAR T cells and cytokines in blood and serum. The study is ongoing.

“The high rate of durable response to a one-time infusion of Yescarta in newly diagnosed patients with high-risk LBCL is exceptional,” said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. “Many of these patients typically progress very quickly on current standard-of-care therapies. Further study is needed to understand Yescarta’s potential as first-line therapy, but we are encouraged by these results.”

Yescarta has not been approved by any regulatory agency for the treatment of patients in the first-line setting.