Frederick L. Locke 1, David B. Miklos 2, Caron Jacobson 3, Miguel-Angel Perales 4, Marie José Kersten 5, Olalekan O. Oluwole 6, Armin Ghobad 7, Aaron P. Rapoport 8, Joseph P. McGuirk 9, John M. Pagel 10, Javier Muñoz 11, Umar Farooq 12, Tom Van Meerten 13, Patrick M. Reagan 14, Anna Sureda 15, Ian W. Flinn 16, Peter Vandenberghe 17, Kevin Song 18, Michael Dickinson 19, Monique C. Minnema 20, Peter A. Riedell 21, Lori A. Leslie 22, Sridhar Chaganti 23, Yin Yang 24, Simone Filosto 24, Marco Schupp 24, Christina To 24, Paul Cheng 24, Leo I. Gordon 25 and Jason R. Westin 26

1 Moffitt Cancer Center, Tampa, FL, United States

2 Stanford University School of Medicine, Stanford University, Stanford, CA, United States

3 Dana-Farber Cancer Institute, Boston, MA, United States

4 Memorial Sloan-Kettering Cancer Center, New York, NY, United States

5 Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

6 Vanderbilt-Ingram Cancer Center, Nashville, TN, United States

7 Washington University School of Medicine, Washington University, Saint Louis, MO, United States

8 The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, University of Maryland, Baltimore, MD, United States

9 University of Kansas Cancer Center, University of Kansas, Kansas City, KS, United States

10 Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, United States

11 Banner MD Anderson Cancer Center, Gilbert, AZ, United States

12 Department of Internal Medicine, University of Iowa, Iowa City, IA, United States

13 University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

14 University of Rochester School of Medicine, University of Rochester, Rochester, NY, United States

15 Hematology Department, Institut Català d’Oncologia-Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain

16 Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, United States

17 University Hospitals Leuven, Leuven, Belgium

18 Division of Hematology, University of British Columbia and Leukemia/BMT Program of BC, Vancouver General Hospital, Vancouver, BC, Canada

19 Peter MacCallum Cancer Centre, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia

20 University Medical Centers, University of Utrecht, Utrecht, The Netherlands

21 The University of Chicago Medical Center, University of Chicago, Chicago, IL, United States

22 John Theurer Cancer Center, Hackensack, NJ, United States

23 Centre for Clinical Haematology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom

24 Kite, a Gilead Company, Santa Monica, CA, United States

25 Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL, United States

26 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Background: The standard of care (SOC) treatment (Tx) in the curative setting for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after 1st-line (1L) chemoimmunotherapy (CIT) is high-dose therapy with autologous stem cell rescue (HDT-ASCT) if responsive to 2nd-line (2L) CIT; however, as many pts do not respond to or cannot tolerate 2L CIT, outcomes remain poor. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for R/R LBCL after ≥2 prior systemic therapies.

Purpose: To report the results of the primary analysis of ZUMA-7, a global, randomized, Phase 3 trial of axi-cel vs. SOC in patients with 2L R/R LBCL.

Methods: Eligible pts ≥ 18 y with LBCL, refractory to or relapsed ≤12 mo of 1L CIT were randomized 1:1 to axi-cel or SOC (2–3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen followed by HDC-ASCT if CIT-responsive). Although there was no planned trial crossover between arms, pts not responding to SOC could receive CAR T-cell therapy off protocol. The primary endpoint was event-free survival (EFS: time to earliest date of disease progression, death from any cause, or new lymphoma Tx) by blinded central review. Key secondary endpoints, tested hierarchically, were objective response rate (ORR) and overall survival (OS; interim analysis); safety was also a secondary endpoint.

Results: As of 18 March 2021, 359 pts were randomized to axi-cel (N = 180) or SOC (N = 179). Overall, the median age was 59 y (range, 21–81; 30% ≥ 65 y), 74% of pts had primary refractory disease and 46% had high 2L age-adjusted IPI (2–3). While 170 (94%) axi-cel pts were infused, only 64 (36%) of SOC pts reached HDT-ASCT after 2L CIT. The primary endpoint of EFS was met (HR: 0.398; p < 0.0001). At 24.9 mo median follow-up, median EFS was significantly longer with axi-cel vs. SOC (8.3 mo vs. 2 mo, respectively), and Kaplan–Meier estimates of the 24-mo EFS rates were 41% vs. 16%. ORR and CR rates were higher with axi-cel vs. SOC (ORR: 83% vs. 50%; p < 0.0001; CR: 65% vs. 32%). Median OS, evaluated as a preplanned interim analysis, was not reached for axi-cel vs. 25.7 mo for SOC (HR: 0.708; p = 0.0159). In the SOC arm, 100 pts (56%) received commercially available or investigational CAR T-cell therapy off protocol as subsequent Tx. Grade ≥ 3 treatment-emergent adverse events occurred in 155 (91%) and 140 (83%) pts, and Tx-related deaths occurred in 1 and 2 pts in the axi-cel and SOC arms, respectively. In pts treated with axi-cel, grade ≥ 3 cytokine release syndrome (CRS) occurred in 11 (6%) and grade ≥ 3 neurologic events (NEs) occurred in 36 (21%). No grade 5 CRS or NEs occurred.

Conclusions: Axi-cel showed statistically significant improvement over SOC, with >4-fold greater median EFS, 2.5-fold greater EFS at 2 y, double the CR rate, and more than double the percentage of pts receiving definitive Tx. Safety of axi-cel was manageable and consistent with 3rd-line (3L) axi-cel therapy.