On July 24, 2020, brexucabtagene autoleucel, a CD19-directed genetically modified autologous T-cell immunotherapy, was granted accelerated approval for the treatment of adult patients with relapsed or refractory mantle cell lymphoma.^1,2 Brexucabtagene autoleucel is approved with a Risk Evaluation and Mitigation Strategy due to the risk of cytokine-release syndrome (CRS) and neurologic toxicities.

Supporting Efficacy Data

Approval was based on findings in the multicenter phase II ZUMA-2 trial (ClinicalTrials.gov identifier NCT02601313).^2,3 In the trial, 74 patients who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton’s tyrosine kinase (BTK) inhibitor were to receive a single infusion of brexucabtagene autoleucel after lymphodepleting chemotherapy. The primary efficacy outcome measure was an objective response rate on Lugano 2014 criteria as assessed by an independent review committee.

Among the 74 patients who underwent leukapheresis, 68 received a single infusion of brexucabtagene autoleucel; of these patients, 60 were followed for at least 6 months for a response, qualifying them as efficacy-evaluable. Among the 60 efficacy-evaluable patients, 54 (90%) received 2 × 10⁶ chimeric antigen receptor (CAR)-positive viable T cells/kg; the remaining 6 patients received doses of 1.0, 1.6, 1.8, 1.8, 1.9, and 1.9 × 10⁶ CAR-positive viable T cells/kg. All treated patients received brexucabtagene autoleucel infusion on day 0 and were hospitalized until at least day 7.

Among the 60 efficacy-evaluable patients, median age was 65 years (range = 38–79 years), 85% were male, 93% were White, and 83% had stage IV disease. Of 20 patients with baseline bone marrow examinations, 10 were negative, 8 were positive, and 2 were indeterminate. The median number of prior therapies was three (range = 2–5), 43% had relapsed after or were refractory to autologous hematopoietic stem cell transplantation, 35% had relapsed after their last therapy for mantle cell lymphoma and 60% were refractory to their last therapy for mantle cell lymphoma, and 23% had blastoid mantle cell lymphoma. After leukapheresis and prior to administration of brexucabtagene autoleucel, 21 patients (35%) received bridging therapy, 16 (27%) received a BTK inhibitor, 9 (15%) received corticosteroids, and 4 (7%) received both.

Among the 60 patients evaluable for efficacy based on a minimum duration of 6 months of follow-up for a response, an objective response was observed in 52 (87%, 95 % confidence interval [CI] = 75%–94%), with complete remission in 37 (62%, 95% CI = 48%–74%). The estimated median duration of response was not reached (range = 0+ to 29.2+ months) after a median follow-up for duration of response of 8.6 months. The median time to a response was 28 days (range = 24–92 days).  Median duration of response was not reached (range = 1.9+ to 29.2+ months) in those with complete remission and 2.2 months (range = 0.0+ to 22.1+ months) in those with partial remission. Among all 74 patients who had undergone leukapheresis, an objective response was observed in 59 (80%), with complete remission in 41 (55%). Median duration of response was not reached (range = 0.0+ to 29.2+ months) in those with complete remission and was 2.2 months (range = 0.0+ to 22.1+ months) in those with partial remission.

How It Works

Brexucabtagene autoleucel is a CD19-directed genetically modified autologous T-cell immunotherapy. It binds to CD19-expressing cancer cells and normal B cells. Studies have 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.

How It Is Used

Brexucabtagene autoleucel must be administered at a certified health-care facility. Tocilizumab and emergency equipment must be available prior to infusion and during the recovery period. Patients must be monitored at the facility daily for at least 7 days following infusion for signs and symptoms of CRS and neurologic events. Patients should be instructed to remain within proximity of the facility for at least 4 weeks following infusion.

Each single infusion bag of brexucabtagene autoleucel contains a suspension of CAR-positive T cells in approximately 68 mL. The recommended dose of the agent is a single intravenous infusion of 2 × 10⁶ CAR-positive viable T cells/kg, with a maximum of 2 × 10⁸ CAR-positive viable T cells. The entire contents of the bag should be infused within 30 minutes.

A lymphodepleting regimen of cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m² should be administered on days 5, 4, and 3 before infusion. Patients should be premedicated with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to infusion. Prophylactic use of systemic corticosteroids should be avoided, since it may interfere with the activity of brexucabtagene autoleucel.

Product labeling provides detailed instructions on treatment and management of CRS and neurologic toxicity, including the use of tocilizumab and corticosteroids.

Safety Profile

In the ZUMA-2 study, the most common nonlaboratory adverse events of any grade (≥ 20% of patients) were pyrexia (94%), CRS (91%), hypotension (57%), encephalopathy (51%), fatigue (48%), tachycardia (45%), arrhythmia, infection-pathogen unspecified (43%), chills (41%), hypoxia (40%), cough (38%), tremor (38%), musculoskeletal pain (37%), headache (35%), nausea (35%), edema (35%), motor dysfunction, constipation (29%), diarrhea (28%), decreased appetite, dyspnea (24%), rash (22%), insomnia (21%), pleural effusion (21%), and aphasia (20%).

The most common grade ≥ 3 adverse events (≥ 10%) of patients were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, infection-pathogen unspecified, leukopenia, hypoxia, CRS, pyrexia, hyponatremia, hypertension, pneumonia, hypocalcemia, and lymphopenia. The most common grade 3 or 4 laboratory abnormalities were leukopenia (95%), neutropenia (95%), lymphopenia (86%), thrombocytopenia (63%), anemia (55%), and hypophosphatemia (30%).

Serious adverse events occurred in 66% of patients, the most common (≥ 2%) being encephalopathy, pyrexia, infection-pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections.

Brexucabtagene autoleucel has boxed warnings for CRS, including life-threatening reactions, and neurologic toxicities, including life-threatening reactions. Patients with active infection or inflammatory disorders should not receive brexucabtagene autoleucel. Severe or life-threatening CRS should be treated with tocilizumab or tocilizumab and corticosteroids. Neurologic reactions may occur concurrently with CRS or after CRS resolution. Patients should be monitored for neurologic toxicities after treatment, with supportive care and corticosteroids provided as needed. Brexucabtagene autoleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

Brexucabtagene autoleucel also has warnings/precautions for hypersensitivity reactions; severe infections; prolonged cytopenias, including grade ≥ 3 cytopenias for several weeks following administration; hypogammaglobulinemia; secondary malignancies; and effects on ability to drive and use machines. Patients should have complete blood cell counts monitored, be monitored for hypogammaglobulinemia, and receive replacement therapy. They should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks after treatment with brexucabtagene autoleucel. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. Available at https://www.fda.gov/drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma. Accessed August 4, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Tecartus (brexucabtagene autoleucel) suspension for intravenous infusion prescribing information. Available at https://www.fda.gov/media/140409/download. Accessed August 4, 2020.

3. Wang M, Munoz J, Goy A, et al: KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 382:1331-1342, 2020.