On December 2, 2024 Autolus Therapeutics plc (Nasdaq: AUTL), an early-commercial stage biopharmaceutical company developing next-generation programmed T cell therapies, reported that the New England Journal of Medicine has published data from the pivotal Phase 1b/2 FELIX study of obecabtagene autoleucel (obe-cel) in relapsed/refractory (r/r) adult B-cell Acute Lymphoblastic Leukemia (ALL) (Press release, Autolus, DEC 2, 2024, View Source [SID1234648731]). The data demonstrate high rates of durable responses with low incidence of grade ≥3 immune-related toxicity.
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"With its low rates of serious side effects coupled with compelling long-term survival data and durable responses, obe-cel offers real hope for adult lymphoblastic leukemia patients," said Dr. Claire Roddie, MD, PhD, FRCPath, Lead investigator of the FELIX study and Associate Professor of Haematology at the University College London (UCL) Cancer Institute. "Obe-cel’s durable responses were particularly observed in patients with low-intermediate bone marrow burden, including patients who did not receive consolidative allo-Stem Cell Transplant and there could be an opportunity to use obe-cel as earlier-line consolidation."
"Adult ALL is an extremely aggressive cancer and patients with this disease historically suffer from poor outcome," said Elias Jabbour, MD, U.S. lead investigator of the FELIX study and professor of Leukemia, ALL Section Chief, at The University of Texas MD Anderson Cancer Center, Houston, Texas. "The clinical benefit and improvements in survival demonstrated by obe-cel have the potential to redefine the standard of care in the adult relapsed/refractory B-ALL setting."
Of the 153 r/r B-ALL patients enrolled patients in the FELIX study, 127 (83.0%) received at least one obe-cel infusion and were evaluable. Eligible patients underwent leukapheresis, and bridging therapy, except blinatumomab, was permitted at the investigator’s discretion. Obe-cel was administered in a bone marrow (BM) burden adjusted split dose following lymphodepletion, with a BM mandated prior to lymphodepletion to guide dosing. The second obe-cel dose was given in the absence of severe/unresolved toxicity.
The primary end point was overall remission (CR/CRi). In the pivotal cohort of patients, (cohort IIA (n=94)), the CR/CRi for patients who received at least one infusion of obe-cel was 76.6% Across all infused patients (n=127), of the 91/127 with ≥5% BM blasts pre-lymphodepletion, the CR/CRi was 74.7%. Median response duration for all infused patients was 21.2 months. Median event-free survival (EFS) was 11.9 months and the estimated 6- and 12-month event-free survival rates were 65.4% and 49.5%, respectively. BM burden pre-lymphodepletion correlated with median event-free survival; patients with low (<5% BM blasts), intermediate (≥5–≤75% blasts), and high (>75% blasts) BM burden had event-free survival rates at 12 months of 68.0%, 54.9% and 25.0%, respectively.
Median overall survival (OS) was 15.6 months and estimated 6- and 12-month overall survival rates were 80.3% and 61.1%, respectively. BM burden pre-lymphodepletion correlated with overall survival; patients with low, intermediate, and high BM burden had an overall survival rate at 12 months of 71.5%, 58.7% and 55.0%, respectively. BM burden before enrollment also influenced event-free and overall survival.
Of the 127 patients infused (pooled across all study cohorts), 99 patients responded. Of the responders, 18 patients (18.2%) proceeded to allo-Stem Cell Transplant (allo-SCT) while in remission at a median of 101 days post-obe-cel infusion. In 6/18 (33.3%), this was a second allo-SCT. Of 11 patients who had persisting CAR T cells before allo-SCT, and who had samples available post, none had CAR T cells detected following allo-SCT. There was no difference in event-free and overall survival observed between patients who received allo-SCT and those who did not.
Median duration of CAR T persistence by droplet digital PCR (ddPCR) in peripheral blood was 17.8 months.
Obe-cel was associated with minimal immunotoxicity. CRS and Immune effector cell-associated neurotoxicity syndrome (ICANS) rates (Grade ≥3) were 2.4% and 7.1%, respectively. Overall, 87 (68.5%) patients developed CRS, and 29 (22.8) developed ICANS. Severe ICANS post-obe-cel were seen as largely limited to patients with high BM burden pre-lymphodepletion. Intensive care unit (ICU) admissions occurred in 20 (15.7%) patients for a median of 5.5 days (range,1−37) of which 7/20 were admitted due to immunotoxicity management (5 ICANS, 2 CRS).
Obe-cel was approved by the Food & Drug Administration (FDA) under the brand name AUCATZYL (obecabtagene autoleucel) on November 8, 2024. Marketing authorization applications (MAAs) for obe-cel [in adult r/r ALL] are being reviewed by the regulators in both the EU and the UK, with a submission to the European Medicines Agency (EMA) accepted in March 2024, and a submission accepted by the UK MHRA in August 2024.