Highlights
- Axicabtagene Ciloleucel (Axi-cel) has transitioned from a third-line ‘hail mary’ therapy to a definitive second-line standard of care for high-risk Large B-cell Lymphoma (LBCL).
- The ZUMA-7 trial demonstrated a significant improvement in event-free survival (EFS) compared to the long-standing standard of platinum-based salvage and autologous stem cell transplant (ASCT).
- Long-term follow-up from the ZUMA-1 trial confirms the potential for functional cure, with a five-year overall survival rate exceeding 40% in previously refractory patients.
- Expanding indications now include relapsed/refractory Mantle Cell Lymphoma (ZUMA-2) and Indolent Follicular Lymphoma (ZUMA-5).
Background
Axicabtagene ciloleucel (Axi-cel) is an autologous, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy utilizing a CD28 costimulatory domain. Since its initial FDA approval in 2017, Axi-cel has reshaped the treatment landscape for aggressive B-cell lymphomas. For decades, patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) faced a dismal prognosis, particularly those who were primary refractory or relapsed within 12 months of frontline chemoimmunotherapy. The unmet need for therapies capable of inducing durable remissions led to the rapid clinical development of the ZUMA trial program, which has now expanded across various disease subtypes and treatment lines.
Key Content
The Foundation: ZUMA-1 and Long-Term Durability
The pivotal ZUMA-1 (NCT02348216) Phase 1/2 trial served as the bedrock for Axi-cel’s regulatory approval. The study enrolled patients with refractory LBCL, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL).
In the primary analysis, Axi-cel achieved an objective response rate (ORR) of 82% and a complete response (CR) rate of 54%. Recent five-year follow-up data presented in 2022 revealed a median overall survival (OS) of 25.8 months, with a 5-year OS rate of 42.6%. Crucially, 92% of patients who achieved a CR at 12 or 24 months remained alive and disease-free at 5 years, suggesting that for a significant subset of patients, Axi-cel offers a functional cure.
Redefining the Second-Line Standard: ZUMA-7
One of the most consequential developments in hematologic oncology was the ZUMA-7 (NCT03391466) trial. This Phase 3 randomized controlled trial compared Axi-cel directly against the standard of care (SoC)—second-line chemoimmunotherapy followed by high-dose therapy and ASCT in responders—for patients with LBCL who relapsed within 12 months of frontline therapy.
Results showed a median EFS of 8.3 months for Axi-cel versus 2.0 months for SoC. At 24 months, the EFS rate was 41% for Axi-cel compared to 16% for SoC (HR 0.40; P < 0.001). Furthermore, the OS analysis presented at ASCO 2023 demonstrated a statistically significant improvement in OS for the Axi-cel arm despite a high rate of crossover, cementing Axi-cel as the preferred second-line treatment for early-relapse or primary refractory LBCL.
Expansion to Mantle Cell and Indolent Lymphomas
Axi-cel has also shown remarkable efficacy in other B-cell malignancies:
- Mantle Cell Lymphoma (ZUMA-2): In the ZUMA-2 (NCT02601313) trial, patients with R/R MCL who had previously failed BTK inhibitors received Axi-cel. The ORR was 93%, with a 67% CR rate. These results provided a lifeline for a patient population with an expected survival of less than 6 months.
- Indolent Lymphomas (ZUMA-5): The ZUMA-5 trial investigated Axi-cel in R/R Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL). For FL, the ORR was 94% with a 79% CR rate. Median progression-free survival (PFS) was not reached at the time of primary analysis, demonstrating that high-potency CAR-T can provide durable responses in indolent diseases.
Moving to First-Line High-Risk Therapy: ZUMA-12
The ZUMA-12 (NCT03761836) trial represents the current frontier, investigating Axi-cel as part of first-line therapy for patients with high-risk LBCL (defined by double/triple-hit status or high IPI scores). Preliminary results showed an ORR of 89% and a CR rate of 78%. If these responses prove durable, it may lead to a paradigm shift where CAR-T is utilized before traditional chemotherapy-induced resistance develops.
Expert Commentary
The success of Axi-cel is intrinsically linked to its CD28 costimulatory domain, which facilitates rapid T-cell expansion and potent effector function. However, this is balanced by a distinct toxicity profile, including higher rates of high-grade Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) compared to 4-1BB-based CAR-Ts like Lisocabtagene maraleucel.
Expert consensus now emphasizes earlier intervention. The ZUMA-7 data essentially invalidated the long-held belief that ASCT is the best second-line option for high-risk patients. However, logistical challenges remain, including the 3-4 week manufacturing ‘vein-to-vein’ time, which can be prohibitive for patients with rapidly progressive disease. Future research must address antigen escape (CD19 loss) and the immunosuppressive tumor microenvironment that leads to late relapses.
Conclusion
Axicabtagene ciloleucel has evolved from a last-resort clinical trial intervention to a cornerstone of modern lymphoma management. Its proven OS benefit in the second-line setting and durable 5-year data in the third-line setting have set a high bar for upcoming cellular and bispecific therapies. Ongoing investigations into frontline application and toxicity mitigation will likely further refine its clinical utility in the coming years.
References
- Neelapu SS, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-2544. PMID: 29226797
- Locke FL, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022;386(7):640-654. PMID: 34891533
- Wang M, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020;382(14):1331-1342. PMID: 32101561
- Jacobson CA, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. PMID: 34895487
