Table 6.

FDA benefit-risk Analysis of brexu-cel for R/R B-ALL.

Parameter	Summary
Unmet medical need	Adult patients with relapsed or refractory B-ALL do not survive without treatment with long-term survival of <1%. B-ALL after second or subsequent relapse or refractory to initial induction chemotherapy is highly resistant to salvage chemotherapy based on prior exposure to standard of care chemotherapy and allogeneic HSCT. R/R B-ALL has a poor prognosis with standard of care therapy including allogeneicHSCT and prognosis is influenced by disease biology, patient characteristics, and prior therapy.
Clinical benefit	Of 54 patients in the primary efficacy population, OCR rate was 65% (95% CI: 51, 77), and CR rate was 54% (95% CI: 40, 67). With a median follow-up of 7.1 months (0.03+, 16.07+), the median duration of CR was not reached. CR rate within 3 months of infusion of brexu-cel was 52% (95% CI: 38, 66).
Risks	• The USPI for brexu-cel has Warnings and Precautions for CRS, neurologic toxicity, HLH/MAS, serious infections, prolonged cytopenias, hypogammaglobulinemia, and secondary malignancies. • Of 78 patients in the safety population who were treated with brexu-cel: ­-  ARs in ≥20%, excluding laboratory terms, included fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. ­- Grade ≥3 ARs occurred in 97%; the most common grade ≥ 3 ARs of interest included prolonged cytopenias (61%), febrile neutropenia (35%), neurologic toxicities (35%), infections (30%), and CRS (26%). ­- Any grade of CRS occurred in 92% patients, neurologic toxicity in 87% ­- Serious ARs occurred in 79% patients and 5% of patients had fatal ARs which included cerebral edema and infections.
Uncertainties	• Long-term safety after treatment with brexu-cel, particularly for secondary malignancies, is undefined.
Conclusions	• The ZUMA-3 study provides substantial evidence of effectiveness in adult patients with r/r B-ALL, with an acceptable safety profile. • CRS and neurologic toxicity can be life-threatening or fatal, supporting boxed warnings in labeling and a REMS.