In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 18, 2017, the chimeric antigen receptor (CAR) T-cell immunotherapy axicabtagene ciloleucel (Yescarta) was granted regular approval for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.1,2 Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma.
Axicabtagene ciloleucel is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.
Supporting Efficacy Data
Approval was based on a single-arm multicenter trial in 108 adult patients with aggressive B-cell non-Hodgkin lymphoma.2 Eligible patients had refractory disease to the most recent therapy or relapse within 1 year after autologous hematopoietic stem cell transplantation (HSCT). Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible.
After lymphodepleting chemotherapy, patients received a single infusion at a target dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose = 2 × 108 cells). Lymphodepleting chemotherapy consisted of cyclophosphamide at 500 mg/m2 and fludarabine at 30 mg/m2 given on the fifth, fourth, and third day before axicabtagene ciloleucel. All patients were hospitalized for axicabtagene ciloleucel infusion and for a minimum of 7 days afterward.
The median age of patients was 58 years, 67% were male, 89% were white, and all had an Eastern Cooperative Oncology Group performance status of 0 (43%) or 1 (57%). Overall, 76% had DLBCL, 16% had transformed follicular lymphoma, and 8% had primary mediastinal large B-cell lymphoma. The median number of prior therapies was 3 (range = 1–10); 77% had disease refractory to a second or greater line of therapy, and 21% had relapsed within 1 year of autologous HSCT.
Among the 101 patients evaluated for efficacy, objective response on independent central review occurred in 73 patients (72%), with a complete remission in 52 (51%). Median follow-up for response was 7.9 months. Median time to response was 0.9 months. Median response duration was 9.2 months in all patients, not reached in those with complete remission, and 2.1 months in those with partial remission.
How It Works
Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines, resulting in the killing of CD19-expressing cells.
How It Is Used
The target dose of axicabtagene ciloleucel is 2 × 106 CAR-positive viable T cells/kg, with a maximum of 2 × 108 CAR-positive viable T cells. A lymphodepleting regimen of cyclophosphamide at 500 mg/m2 and fludarabine at 30 mg/m2 is given on the fifth, fourth, and third day before axicabtagene ciloleucel infusion. Patients should be premedicated with oral acetaminophen at 650 mg and intravenous or oral diphenhydramine at 12.5 mg approximately 1 hour before infusion. Prophylactic use of systemic corticosteroids should be avoided, since they may interfere with the activity of axicabtagene ciloleucel. Axicabtagene ciloleucel should not be given to patients with active infection or inflammatory disorders.
Axicabtagene ciloleucel has boxed warnings for cytokine-release syndrome and neurologic toxicity. It also should not be given to patients with active infection or inflammatory disorders.
Axicabtagene ciloleucel infusion carries a high risk of cytokine-release syndrome and neurologic toxicities. The agent must be administered at a certified health-care facility. Severe or life-threatening cytokine-release syndrome must be treated with tocilizumab (Actemra) or tocilizumab and corticosteroids. Patients with neurologic toxicity should receive supportive care and/or corticosteroids as needed. Tocilizumab and emergency equipment must be available prior to infusion and during the recovery period. Patients should be monitored at least daily for 7 days following infusion for signs and symptoms of cytokine-release syndrome and neurologic toxicities at the certified health-care facility. Patients should be instructed to remain within proximity of the certified health-care facility for at least 4 weeks following infusion.
Product labeling provides detailed instructions on the management of cytokine-release syndrome and neurologic toxicities, including the use of tocilizumab and corticosteroid treatment. Patients experiencing grade ≥ 2 cytokine-release syndrome (eg, hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) and those with grade ≥ 2 neurologic toxicity should be monitored with continuous cardiac telemetry and pulse oximetry. Echocardiograms to assess cardiac function should be considered for patients experiencing severe cytokine-release syndrome, and intensive care supportive therapy should be considered for severe or life-threatening cytokine-release syndrome. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities. Nonsedating antiseizure medicines (eg, levetiracetam) should be considered for seizure prophylaxis for any grade ≥ 2 neurologic toxicities.
In the clinical trial, the most common adverse events of any grade included cytokine-release syndrome (94%), fever (86%), hypotension (57%), encephalopathy (57%), and tachycardia (57%), as well as (each ≥ 20%) fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmia. The most common grade ≥ 3 adverse events (≥ 10%) were febrile neutropenia, encephalopathy (29%), infections-pathogen unspecified (16%), fever (16%), hypotension (15%), cytokine-release syndrome (13%), hypoxia (11%), and lung infections. Serious adverse events occurred in 52% of patients. Tocilizumab treatment was used in 45% of patients after axicabtagene ciloleucel infusion. The most common grade ≥ 3 laboratory abnormalities were lymphopenia (100%), leukopenia (96%), neutropenia (93%), anemia (66%), thrombocytopenia (58%), and hypophosphatemia (50%).
Axicabtagene ciloleucel has boxed warnings for cytokine-release syndrome and neurologic toxicity, including fatal and life-threatening reactions. Axicabtagene ciloleucel should not be given to patients with active infection or inflammatory disorders. Neurologic toxicity has been observed to occur concurrently with cytokine-release syndrome or after cytokine-release syndrome resolution. Patients should be monitored for neurologic toxicities.
Axicabtagene ciloleucel also carries warnings/precautions for hypersensitivity reactions; serious infections; prolonged cytopenias, including grade ≥ 3 cytopenias for several weeks following infusion; hypogammaglobulinemia; secondary malignancies; and effects on ability to drive and use machines. Patients should refrain from driving or using machines for at least 8 weeks after treatment. Complete blood cell counts should be monitored. Patients should be monitored for hypogammaglobulinemia and receive replacement therapy when needed. Secondary malignancies should be reported to Kite at 1-844-454-KITE (5483). ■
1. U.S. Food and Drug Administration: FDA approves axicabtagene ciloleucel for large B-cell lymphoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm581296.htm. Accessed November 7, 2017.
2. Yescarta (axicabtagene ciloleucel) suspension for intravenous infusion prescribing information, Kite Pharma, Inc, October 2017. Available at https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm. Accessed November 7, 2017.