General Information

Yescarta (axicabtagene ciloleucel) is a CD19-directed genetically modified autologous T cell immunotherapy.

Yescarta is specifically indicated for the treatment of the following:

• 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. 
• adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.
• adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy

Yescarta is supplied as a suspension for intravenous infusion. Each single infusion bag of Yescarta contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL. The target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells. 

Mechanism of Action

Yescarta (axicabtagene ciloleucel) a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that 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. This sequence of events leads to killing of CD19-expressing cells.

Side Effects

Adverse effects associated with the use of Yescarta may include, but are not limited to, the following:

• cytokine release syndrome
• fever
• hypotension
• encephalopathy
• tachycardia
• fatigue
• headache
• decreased appetite
• chills
• diarrhea
• febrile neutropenia
• infections-pathogen unspecified
• nausea
• hypoxia
• tremor
• cough
• vomiting
• dizziness
• constipation
• cardiac arrhythmias 

The Yescarta label comes with the following Black Box Warning:

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed. 

Clinical Trial Results

The FDA approval of Yescarta was based on the following:

The ZUMA-1 pivotal trial. The single-arm, open-label, multicenter trial evaluated the efficacy of a single infusion of Yescarta in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Following lymphodepleting chemotherapy, Yescarta was administered as a single intravenous infusion at a target dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose: 2 × 108 cells). The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously, both given on the fifth, fourth, and third day before Yescarta. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. All patients were hospitalized for Yescarta infusion and for a minimum of 7 days afterward. In this study, 72% of patients treated with a single infusion of Yescarta (n=101) responded to therapy (overall response rate) including 51% of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]). In the study, 13% of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31% experienced neurologic toxicities.

ZUMA-5, an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients (≥18 years old) with relapsed or refractory iNHL, who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was established on the basis of objective response rate (ORR) and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification. In the study, 91 percent of all FL patients (n=81 evaluable for efficacy analysis) responded to a single infusion of Yescarta, including 60 percent of patients who achieved a complete remission. Thirteen of the 25 patients who achieved a partial remission met imaging criteria for a complete remission without confirmation by negative bone marrow biopsy after treatment. Median DoR has not yet been reached. The FDA granted accelerated approval to Yescarta for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

ZUMA-7, a randomized, open-label, global, multicenter, study which evaluated Yescarta versus current standard of care (SOC) for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and ASCT in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. In the study, 359 patients were randomized to receive a single infusion of Yescarta or current SOC second-line therapy. Yescarta demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS) over SOC. EFS was defined as the time from randomization to the earliest date of disease progression, commencement of new lymphoma therapy, or death from any cause. Additionally, 2.5 times more patients receiving Yescarta (40.5%) were alive at two years without disease progression or need for additional cancer treatment, after their one-time infusion of Yescarta vs. SOC (16.3%), and the median EFS was four times greater (8.3 months vs. 2.0 months) with Yescarta versus SOC.