BACKGROUND: Second-line standard therapy for patients with relapsed or refractory large B-cell lymphoma is high-dose chemotherapy and autologous stem-cell transplantation (ASCT), but the prognosis after first-line therapy is poor for many patients, who are unable to receive definitive therapy. Using a second-line therapy with a different mechanism of action may therefore benefit these patients. Axicabtagene ciloleucel, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is indicated for the treatment of patients with relapsed or refractory large B-cell lymphoma after ≥2 systemic therapies. The ZUMA-1 study showed good responses with axicabtagene ciloleucel in patients with refractory large B-cell lymphoma, resulting in a 5-year overall survival (OS) of 43%.1 These results were the basis for the ZUMA-7 study.
METHODS: ZUMA-7 was an international, randomized, phase 3 clinical trial that compared axicabtagene ciloleucel with standard of care in the second-line setting for patients with early relapsed or refractory large B-cell lymphoma. Patients were randomized (1:1) to axicabtagene ciloleucel (N = 180) or to standard of care (N = 179). The CAR T-cell arm received a single infusion of 2 × 106 CAR T-cells/kg after conditioning with cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2 on days 5, 4, and 3 before infusion. The standard-of-care arm received 2 or 3 cycles of protocol-based investigator-selected, platinum-based chemoimmunotherapy, followed by high-dose chemotherapy and ASCT in patients who responded to chemoimmunotherapy. The primary end point was event-free survival (EFS). The secondary end points included response to therapy, OS, and safety.
RESULTS: The study included 359 patients with early relapsed or refractory large B-cell lymphoma who had received first-line chemotherapy. EFS was longer in patients who received axicabtagene ciloleucel than in those who received standard of care. At a median follow-up of 24.9 months, the median EFS was 8.3 months in the CAR T-cell arm compared with 2 months in the standard-of-care arm, and the 24-month EFS was 41% and 16%, respectively (hazard ratio for adverse events [AEs] or death, 0.40; 95% confidence interval, 0.31-0.51; P <.001). The response rate was 83%, including 65% complete responses, in the axicabtagene ciloleucel arm versus 50%, including 32% complete responses, in the standard-of-care group. An interim analysis at 2 years showed an estimated OS of 61% in the CAR T-cell arm versus 52% in the standard-of-care arm. The rate of AEs, including grade ≥3 AEs, was high in both groups—91% versus 83%, respectively. In all, 6% of patients in the axicabtagene ciloleucel arm had grade ≥3 cytokine-release syndrome (CRS) and 21% of patients had neurologic AEs. No deaths related to CRS or neurologic AEs occurred in that arm. Based on these results, the researchers concluded that axicabtagene ciloleucel may be a viable alternative to the use of chemoimmunotherapy, high-dose chemotherapy, and ASCT as a second-line treatment for patients with relapsed or refractory large B-cell lymphoma.
- Jacobson CA, Locke FL, Ghobadi A, et al. Long-term (4- and 5-year) overall survival in ZUMA-1, the pivotal study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma. Poster presented at the American Society of Hematology annual meeting; December 11-14, 2021; Atlanta, GA.
Source: Locke FL, Miklos DB, Jacobson CA, et al; for all ZUMA-7 investigators and contributing Kite members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654.
Commentary by Robert J. Ignoffo
There is an unmet need for therapies that produce durable responses in patients with relapsed or refractory large B-cell lymphoma. The current National Comprehensive Cancer Network (NCCN) guidelines list several second-line therapies, all of which are platinum-based regimens. In addition, the NCCN guidelines place axicabtagene ciloleucel as a third-line agent in the treatment of early relapsed or refractory large B-cell lymphoma. This phase 3 international study has raised the status of this CAR T-cell therapy to being an effective second-line agent for this poorly responsive cancer. The study compared axicabtagene ciloleucel and standard platinum-based second-line therapy. At 2 years, the duration of EFS more than quadrupled the EFS duration with standard therapy (from 2 months to 8.3 months), along with a high overall response rate. It is important to note that CAR T-cell therapy is recommended for early, namely, <12-month relapse or refractory disease. For disease relapse at >12 months, the use of salvage chemotherapy, alone or followed by ASCT, is recommended.
CRS and neurologic AEs are considered life-threatening reactions and occurred in 13% and 60% of patients, respectively, but no deaths from these events occurred during the study. Tocilizumab, the antidote to CRS, was used in 65% of the safety population. The median time to CRS onset was 3 days after infusion, with a median duration of 7 days. Grade 3 adverse effects with axicabtagene ciloleucel included neutropenia (69%) and neurotoxicity (21%). No late serious AEs were attributed to axicabtagene ciloleucel.
In summary, axicabtagene ciloleucel is an effective treatment and compares favorably to platinum-based chemoimmunotherapy, high-dose chemotherapy, and ASCT for the second-line treatment of relapsed or refractory large B-cell lymphoma.