Treatment with axicabtagene ciloleucel in the second-line setting led to significant improvement in overall survival compared with high-dose therapy plus transplant in patients with early relapsed or refractory large B-cell lymphoma.
Primary overall survival results from the phase 3 ZUMA-7 trial (NCT03391466) show that the use of second-line axicabtagene ciloleucel (axi-cel; Yescarta) significantly improved overall survival (OS) compared with high-dose therapy plus autologous stem cell transplant (HDT/ASCT) in patients with early relapsed or refractory large B-cell lymphoma (LBCL). Treatment with the agent led to a 27.4% reduction in the risk of death, according to data presented during the 2023 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.1,2
Moreover, although the trial was not powered for subgroup analysis, the overall survival (OS) benefit was consistent across all key patient subgroups, even though 57% of patients in the SOC arm received subsequent cellular immunotherapy, off-protocol, following disease progression with platinum-based chemoimmunotherapy.1
At a median follow-up of 47.2 months, the median OS with axi-cel was not reached vs 31 months with SOC (HR, 0.726; 95% CI, 0.540-0.977; one-sided P = .0168), yielding a 27.4% reduction in the risk of death. The 4-year OS rates were 54.6% vs 46.0%, respectively.
Of note, patients in the SOC arm achieved increased survival rates compared with historical studies—yet axi-cel was still associated with superior OS.
According to investigators, the findings from this trial will effectively shift the treatment paradigm. In a presentation of the findings, Jason Westin, MD, stated, “Is my patient eligible for ASCT” should no longer be the first question that the treating hematologist/oncologist asks, but rather, “How long ago was my patient’s first-line therapy?” If less than a year has transpired since a patient received their first line of therapy (approximately 75% of patients), then CAR T-cell therapy should be the preferred second-line treatment over salvage/ASCT, he added.
“ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B-cell lymphoma based on superior survival,” Westin, who is the director of the Lymphoma Clinical Research Program and section chief of the Aggressive Lymphoma research team in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said, adding that this is the first randomized controlled trial in nearly 30 years to improve OS in the second-line setting for patients with LBCL.
As Westin explained, chemotherapy followed by HDT/ASCT has been the standard second-line curative treatment for patients with LBCL for approximately 30 years. However, most patients cannot receive HDT/ASCT and therefore face poor prognoses.
Axi-cel is an anti-CD19 CAR T-cell therapy given as a one-time dose and was previously approved for these patients as a third-line or later treatment. Earlier analyses of the phase 3 ZUMA-7 trial demonstrated an event-free survival (EFS) improvement with axi-cel as second-line treatment in this patient population. These data served as the basis for the approval of axi-cel for adults with relapsed or refractory LBCL following frontline therapy, in addition to after second-line therapy.
Patients who were eligible for enrollment were those who were at least 18 years of age and had relapsed or refractory LBCL. These were patients whose disease had progressed within 12 months of their first-line therapy and who were planned to undergo HDT/ASCT. Patients who were randomly assigned to receive CAR T-cell therapy underwent conditioning chemotherapy beforehand. Patients randomly assigned to SOC were scheduled to undergo at least 2 cycles of investigator-selected platinum-based chemoimmunotherapy. In the SOC arm, patients who responded to chemoimmunotherapy proceeded to HDT/ASCT. Those who did not respond proceeded to additional treatments off protocol.
The primary end point was EFS by blinded central review. Key secondary end points included overall response rate and OS. Progression-free survival (PFS), safety, and patient-reported outcomes were additional secondary end points.
Baseline characteristics were balanced between the 2 treatment arms. Of note, the percentage of patients who were 65 years or older was 28% (n = 51) vs 32% (n = 58), and the rates of patients who were primary refractory were 74% (n = 133) vs 73% (n = 131), respectively.
The trial enrolled patients between January 25, 2018, and October 4, 2019. The EFS primary analysis data cutoff was March 18, 2021. In the primary analysis, the median EFS was 8.13 months with axi-cel (n = 180; 95% CI, 4.5-15.8) and 2.0 months with SOC (n = 179; 95% CI, 1.6-2.8). The 24-month EFS rates were 40.5% (95% CI, 33.2%-47.7%) vs 16.3% (95% CI, 11.1%-22.2%), respectively (HR, 0.398; 95% CI, 0.308-0.514; P < .0001).
Ultimately, 359 patients were randomly assigned to 1 of the 2 treatment arms. Nearly 3 times more patients in the axi-cel arm received intended curative treatment. In the axi-cel arm (n = 180), 178 underwent leukapheresis, 172 received lymphodepleting chemotherapy, and 170 (94%) received CAR T-cell infusion. In the SOC arm (n = 179), 168 received at least 1 dose of salvage chemotherapy, 80 responded to salvage chemotherapy, and 69 responded to salvage chemotherapy and subsequently underwent leukapheresis (n = 69). Sixty-four (36%) received HDT/HSCT.
This OS analysis revealed that axi-cel also significantly improved PFS. The 4-year PFS rates in the axi-cel vs SOC arm, respectively, were 41.8% vs 24.4%, and the median PFS was 14.7 months with axi-cel vs 3.7 months with SOC (HR, 0.506; 95% CI, 0.383-0.669; one-sided P < .0001).
Of note, there were no changes in the rate of cumulative treatment-related serious or fatal adverse effects (AEs) since the primary EFS analysis.
Because 57% of patients received subsequent cellular immunotherapy, AE comparisons between cohorts are difficult, Westin noted. Regardless, cytokine release syndrome (CRS) occurred at any grade in 92% of patients in the axi-cel arm. Also, in the axi-cel arm (n = 170), the rate of grade 3 CRS was 6%.
Between the axi-cel arm and the SOC arm (n = 168), the rates of any grade neurological events were 61% vs 20%, respectively. The rates of grade 3 or worse events were 21% vs 1%, respectively. The rates of any grade hypogammaglobulinemia were 11% vs 1%; no grade 3 or worse hypogammaglobulinemia events were reported in either arm.
Cytopenia was common in both arms: the rates of any grade, and grade 3 or worse cytopenias were 80% and 75%, respectively, with each treatment. Lastly, the rates of infections were 45% vs 32%, with axi-cel and SOC, for any grade events. The rates of grade 3 or worse infections were 16% vs 12%, respectively.
In the axi-cel arm, 30% (n = 51) of patients died because of progressive disease, 5% (n = 8) because of a grade 5 AE during the protocol-specific reporting period, and 1% (n = 2) because of a new or secondary malignancy. Eight percent (n = 13) of these patients passed away for an unspecified reason and 1% (n = 1) experienced a definitive therapy-related mortality.
Among patients in the SOC arm, 42% (n = 71) died because of progressive disease, and 1% (n = 2) because of a grade 5 AE; 11% (n = 18) died because of an unspecified reason and 3% (n = 2) experienced a definitive therapy-related mortality.
1. Westin JR, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. J Clin Oncol. 2023;41(suppl 17):LBA107. doi:10.1200/JCO.2023.41.17_suppl.LBA107
2. Westin JR, Oluwole OO, Kersten MJ; ZUMA-7 Investigators. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. Published June 5, 2023. doi:10.1056/NEJMoa2301665