A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis.

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T­cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open­label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma.

BACKGROUND: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914). METHODS: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 106 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate. RESULTS: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5-98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients-most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019). CONCLUSION: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options. TRIAL REGISTRATION: JapicCTI-183914.

Inhaled Laninamivir Octanoate as Prophylaxis for Influenza in Children.

BACKGROUND: A single 20-mg dose of inhaled laninamivir octanoate is an effective treatment of influenza. However, the efficacy of laninamivir octanoate for the prevention of influenza in children <10 years of age has not yet been established. METHODS: We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine whether the efficacy of a single 20-mg dose of inhaled laninamivir octanoate to prevent the development of influenza was superior to that of placebo as prophylaxis for influenza in pediatric (<10 years) household members of index cases. Eligible subjects without influenza, in contact with an influenza-infected index case living in the same household, were blindly randomly assigned in a 1:1 ratio to receive 20 mg of laninamivir octanoate or placebo. The primary end point was the proportion of subjects who developed clinical influenza during a 10-day period. RESULTS: A total of 343 subjects were randomly assigned, with 341 subjects included in the full analysis set for the primary analysis. The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups. CONCLUSIONS: A single 20-mg dose of inhaled laninamivir octanoate was effective and well tolerated as prophylaxis for influenza.