Axicabtagene Ciloleucel Highly Effective as Second-Line Treatment for Patients With Relapsed, Refractory LBCL

By Cameron Kelsall, MD /alert Contributor
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Second-line treatment with axicabtagene ciloleucel significantly improved event-free survival (EFS) and response rates in patients with relapsed or refractory large B-cell lymphoma (LBCL) in comparison to standard treatments, according to phase 3 study results published in The New England Journal of Medicine

“Standard-care second-line treatment in the curative setting for patients with relapsed or refractory LBCL is high-dose chemotherapy with autologous stem-cell transplantation if the disease is responsive to salvage chemoimmunotherapy,” wrote Frederick Locke, MD, vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center (Tampa, FL), and colleagues. “Patients whose disease does not respond to salvage chemotherapy and those who are not considered to be candidates for high-dose chemotherapy with autologous stem-cell transplantation have poor outcomes.”

The US Food and Drug Administration previously approved axicabtagene ciloleucel, a CD19–directed chimeric antigen receptor T-cell therapy, for the treatment of patients with relapsed or refractory LBCL after two prior systemic therapies. Locke and colleagues sought to determine its efficacy as a second-line treatment in this patient population.

The researchers randomly assigned 359 adult patients with relapsed or refractory LBCL to receive a single infusion of axicabtagene ciloleucel (n = 180) or to investigator’s choice chemoimmunotherapy (n = 179), which was defined as the standard of care. Responding patients in the standard-of-care arm were permitted to proceed to high-dose chemotherapy and autologous transplant.

EFS by blinded central review served as the study’s primary endpoint. Secondary endpoints included investigator-assessed EFS, progression-free survival (PFS) and adverse events.

Median follow-up was 24.9 months. Among the study participants, the median age was 59 years (range, 21-81), with 30% of patients (n = 109) aged 65 years or older. In total, 74% of the cohort had primary refractory disease, and 79% had stage III or stage IV LBCL.

Treatment with axicabtagene ciloleucel resulted in a significant EFS improvement by blinded central review (median, 8.3 months vs. 2 months), as well as a significantly higher 24-month EFS (41% vs. 16%; hazard ratio for event or death, 0.4; 95% CI, 0.31-0.51; P < .001).

The response rate for treatment with axicabtagene ciloleucel was 83%, compared with 50% for standard-of-care treatment (P < .001). Axicabtagene ciloleucel also provoked a more robust complete response rate (65% vs. 32%).

The overall survival rate for axicabtagene ciloleucel was not reached in the interim analysis, and was 35.1 months for standard-of-care treatment (hazard ratio for death, 0.73; 95% CI, 0.53-1.01). The estimated 2-year overall survival rates were 61% and 52%, respectively. In total, 72 patients in the axicabtagene arm and 81 patients in the standard-of-care arm died of any cause; deaths related to progressive disease were observed in 52 patients and 65 patients, respectively.

Median PFS favored axicabtagene ciloleucel over standard of care (14.7 months vs. 3.7 months; hazard ratio for progression or death; 0.49; 95% CI, 0.37-0.65). The 24-month PFS estimates were 46% and 27%, respectively.

In total, 91% of patients in the axicabtagene ciloleucel arm (n = 155) and 83% of patients in the standard-of-care arm (n = 140) experienced grade 3 or higher adverse events, of which neutropenia was the most common (69% vs. 41%). Rates of serious adverse events were similar (50% vs. 46%). Infections of any grade were observed in 41% of the axicabtagene arm and in 30% of the standard-of-care arm (grade ≥3, 14% vs. 11%).

Seven patients in the axicabtagene arm experienced fatal adverse events. The researchers deemed one death from hepatitis B virus reactivation related to axicabtagene. One fatal case each of cardiac arrest and acute respiratory distress syndrome were observed in the standard-of-care arm, both of which were deemed related to high-dose chemotherapy.

In total, 11 patients assigned axicabtagene experienced grade 3 or higher cytokine release syndrome, and 36 patients experienced grade 3 or higher neurological toxicities. The researchers observed no deaths caused by cytokine release syndrome or neurotoxicity.

The researchers reported a median time to peak CAR T-cell levels of 7 days (range, 2-233) post-infusion, with a median peak level of 25.84 cells per cubic millimeter. CAR T cells remained detectable at 24 months post-infusion in 12 patients.

“Axicabtagene ciloleucel appears to be a viable alternative to a regimen of chemoimmunotherapy, high-dose chemotherapy, and autologous stem-cell transplantation for the second-line treatment of relapsed or refractory LBCL,” the researchers concluded.



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