Second-Line Axicabtagene Ciloleucel Therapy Improves Outcomes in Patients with Large B-Cell Lymphoma: ZUMA-7

JHOP - April 2022 Vol 12, No 2 - From the Literature, Lymphoma, CAR T-Cell Therapy
COMMENTARY by Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA
Clinical Professor Emeritus, University of California, San Francisco; Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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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.

  1. 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.

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