FDA Approval Summary: Axicabtagene Ciloleucel for Second-Line Treatment of Large B-cell Lymphoma.

In April 2022, the U.S. FDA approved axicabtagene ciloleucel for adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Approval was based on ZUMA-7, a randomized (1:1), open-label trial in 359 patients with primary refractory LBCL (74%) or early relapse who were transplant candidates. The study compared a single course of axicabtagene ciloleucel to standard therapy, consisting of chemoimmunotherapy followed by high-dose therapy and autologous hematopoietic stem cell transplantation (HSCT) in responding patients. Overall, 94% of the experimental arm received chimeric antigen receptor (CAR) T-cell product, and 35% of the control arm received on-protocol HSCT. The primary endpoint was event-free survival, which was significantly longer in the axicabtagene ciloleucel arm with a hazard ratio of 0.40 (95% CI: 0.31, 0.51; p-value <0.0001) and estimated median of 8.3 months, versus 2.0 months with standard therapy. Among 168 recipients of axicabtagene ciloleucel, cytokine release syndrome occurred in 92% (Grade ≥3, 7%), neurologic toxicity in 74% (Grade ≥3, 25%), prolonged cytopenias in 33%, and fatal adverse reactions in 1.8%. This is the first FDA approval of a CAR T-cell therapy for LBCL in the second-line setting and reflects a potential paradigm shift.