Kite/Gilead announces new ZUMA-1 cohort analysis of prophylactic corticosteroid use with Yescarta for relapsed or refractory large B-cell lymphoma.

Kite, a Gilead Company announced findings from a new analysis of the ZUMA-1 trial of Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) . Results were presented in an oral session at the Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy (ASTCT) and Center for International Blood & Marrow Transplant Research (CIBMTR) (Abstract #70). In a new ZUMA-1 safety management cohort (Cohort 6) , the primary objective was to assess the impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events. Patients with relapsed or refractory LBCL received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days. Corticosteroids and tocilizumab were started earlier, at lower grades of CRS and neurologic events, in Cohort 6 than in the ZUMA-1 pivotal cohorts (Cohorts 1 and 2). All 40 patients enrolled in Cohort 6 received at least one dose of corticosteroids. In the Cohort 6 primary analysis, no Grade greater than 3 CRS occurred. Grade greater than 3 neurologic events occurred in 13 percent of patients and no patients experienced Grade 5 neurologic events at the time of data cut-off. Median time to onset of any grade CRS was five days and any grade neurologic events was six days. Sixty-eight percent of patients had no CRS or neurologic events within 72 hours of Yescarta infusion. Ninety-five percent of patients in Cohort 6 responded to Yescarta, including 80 percent of patients who achieved a complete response; 63 percent of patients were in an ongoing response at the time of the data cut-off (median study follow-up of 8.9 months). The median duration of response has not yet been reached. A post-hoc propensity score-matching analysis was performed by selecting closely matched subgroups from Cohort 6 and pivotal cohorts based on pre-specified prognostic factors for patients with LBCL. This analysis provided a more robust comparison of the safety, efficacy and pharmacokinetic/pharmacodynamic profiles of Cohort 6 with pivotal cohorts. In this propensity score-matched subset, incidence of Grade greater than 3 CRS was lower in Cohort 6 (0 percent) than in matched patients from the pivotal cohorts (13 percent) and median time to CRS onset was delayed (5 days versus 2 days). Severity and onset of neurologic events were generally similar between cohorts after propensity score-matching. The propensity score-matching analysis suggested that response rates in Cohort 6 were comparable to those observed in the pivotal cohorts. “While previous analyses demonstrated a decrease in severity of CRS and neurologic events with earlier steroid intervention, this study suggests that prophylactic corticosteroids may also provide a benefit without compromising efficacy,” said Olalekan O. Oluwole, MBBS, MPH, ZUMA-1 Cohort 6 lead investigator and Associate Professor of Medicine, Vanderbilt University Medical Center. “With two-thirds of patients experiencing no CRS or neurologic events up to three days after Yescarta and a five day time to onset of CRS, it is highly encouraging that use of prophylactic steroids may play a significant role in reducing the severe side effects of CAR T.” Yescarta was the first CAR T-cell therapy to be approved by the FDA for the 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, and high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a risk evaluation and mitigation strategy (REMS) due to these risks. Prophylactic use of corticosteroids has not been approved by any regulatory agency in conjunction with Yescarta therapy. The safety and efficacy of this prophylactic adverse event management protocol requires further clinical investigation.