On January 31, the FDA approved an update to the prescribing information for axicabtagene ciloleucel (Yescarta) to include use of prophylactic corticosteroids across all approved indications. Axicabtagene ciloleucel is now the first and only chimeric antigen receptor (CAR) T-cell therapy with information in the label to help physicians manage and potentially prevent treatment side effects.
Basis of Label Update
The label update is based on the results of a new safety management cohort (Cohort 6) of the pivotal ZUMA-1 study, which was designed to assess the impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab and prophylactic levetiracetam on the incidence and severity of cytokine-release syndrome and neurologic events. In the cohort, no grade ≥3 cytokine-release syndrome events occurred in any patients, compared to 13% (14 of 108) in the pivotal Cohorts 1/2. Grade ≥ 3 neurologic events occurred in 13% of patients at the time of data cutoff, and one patient experienced a late-onset grade 5 event following the data cutoff (13% [5 of 39] of patients in Cohort 6 compared to 31% [33 of 108] in the pivotal Cohorts 1/2). Cohort 6 showed a median time to cytokine-release syndrome onset of 5 days (with a range from 1–15 days) and a median time to neurotoxicity onset of 6 days (with a range from 1–274 days) in patients that experienced these complications.
Recently published additional data showed 68% of patients had no cytokine-release syndrome or neurologic events within 72 hours of axicabtagene ciloleucel infusion (27 of 40). Helping to address the potential concern that steroid use might impact efficacy, the Cohort 6 1-year update presented at the 2021 American Society of Hematology Annual Meeting & Exposition suggested that Cohort 6 toxicity management strategy can improve certain adverse events without compromising the activity of axicabtagene ciloleucel. Patients in Cohort 4 and Cohort 6 were found to have received median cumulative steroid doses that were lower than those used in matched Cohorts 1/2 who received steroids to manage cytokine-release syndrome or neurologic events when they occurred, according to another recently published report.
The ZUMA-1 study also included Cohort 4, which was added to the FDA label in May 2021 and evaluated the earlier treatment with corticosteroids and/or tocilizumab and prophylactic levetiracetam. Cohort 6 builds on this growing knowledge regarding how to manage and minimize side effects gained over many years of developing axicabtagene ciloleucel. Cohort 6 evaluated 39 patients with relapsed or refractory large B-cell lymphoma. Patients received dexamethasone at 10 mg orally once daily for 3 days, starting prior to axicabtagene ciloleucel infusion. In Cohort 6, corticosteroids and tocilizumab were started earlier, at lower grades of cytokine-release syndrome and neurologic events, than in the ZUMA-1 pivotal cohorts (Cohorts 1 and 2). All 39 patients received three prophylactic doses of corticosteroids.
The axicabtagene ciloleucel prescribing information does not specify a treatment setting, whether in the hospital or in nearby outpatient offices with close monitoring. It is up to a patient’s physician to determine the most appropriate treatment setting for their care based on individual circumstances. The axicabtagene ciloleucel label update may help physicians manage potential complications and determine the appropriate setting for care of their patients.
