Obe-Cel Produces Durable Remissions in Adult R/R B-ALL

The autologous CAR T-cell therapy obecabtagene autoleucel (obe-cel; Aucatzyl) generated durable responses in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to updated data from the phase 1b/2 FELIX trial (NCT04404660) published in the New England Journal of Medicine.1

Findings showed that at a median follow-up of 20.3 months, patients with morphologic disease at baseline who were enrolled in the pivotal cohort 2A and received at least 1 infusion of obe-cel (n = 97) achieved an overall remission rate (ORR) of 77% (95% CI, 67%-85%). ORR comprised complete remission (CR) and CR with incomplete hematologic recovery (CRi); the CR rate in cohort 2A was 55% (95% CI, 45%-66%), and the CRi rate was 21% (95% CI, 14%-31%). Based on these results, the prespecified null hypotheses for an ORR of no more than 40% (P < .001) and a CR of no more than 20% (P < .001) were rejected.

In cohort 2A, obe-cel generated a median duration of response (DOR) of 14.1 months (95% CI, 8.2-not evaluable [NE]) and a median event-free survival (EFS) of 9.0 months (95% CI, 6.1-15.0).

Among all patients who received at least 1 obe-cel infusion across all portions of the study (n = 127), the ORR was 78% (95% CI, 70%-85%), which included CR rate of 57% and a CRi rate of 20%. The median DOR was 21.2 months (95% CI, 11.6-NE), and the median EFS was 11.9 months (95% CI, 8.0-22.1). The estimated 6- and 12-month EFS rates were 65.4% and 49.5%, respectively.

“Adult ALL is an extremely aggressive cancer and patients with this disease historically suffer from poor outcomes,” Elias Jabbour, MD, US lead investigator of the FELIX study and a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, stated in a news release.2 “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.”

In November 2024, the FDA approved obe-cel for the treatment of adult patients with relapsed or refractory B-cell precursor ALL, based on data from FELIX.3

FELIX Design and Patient Enrollment

Investigators for the multicenter, international, pivotal registration FELIX study enrolled patients at least 18 years of age with relapsed/refractory CD19-positive B-ALL.1 Specifically, patients needed to have primary refractory disease without a CR after 2 cycles of induction chemotherapy; disease in first relapse if first remission was no more than 12 months; relapsed/refractory disease after 2 or more lines of systemic therapy; or relapsed/refractory disease after allogeneic stem cell transplant (alloSCT) if transplant occurred at least 3 months prior to the infusion of obe-cel. Notably, patients with CD19-positive, Philadelphia chromosome (Ph)–positive ALL were allowed to enroll if they were intolerant to or experienced disease progression after 2 lines of any TKI or 1 line of a second-generation TKI, or if TKIs were contraindicated.

Other key inclusion criteria for all patients consisted of an ECOG performance status of 0 or 1; and adequate renal, hepatic, pulmonary, and cardiac function.

Within both phases of the study, individual cohorts also had specific inclusion criteria, which were as follows:

• Cohort 1A (phase 1b): Presence of a bone marrow blast level of at least 5% at screening
• Cohort 1B (phase 1b): Minimal residual disease (MRD)–positive disease
• Cohort 2A (phase 2): Presence of bone marrow blast levels of at least 5% at screening
• Cohort 2B (phase 2): Patients in at least second CR/CRi with MRD-positive disease and bone marrow blast levels of less than 5% at screening
• Cohort 2C (phase 2): Patients with isolated extramedullary disease, with or without MRD

Enrolled patients underwent leukapheresis, and during the manufacturing of obe-cel, bridging therapy was permitted at investigator discretion, except for blinatumomab (Blincyto). Starting at day –6, patients underwent lymphodepleting chemotherapy featuing 30 mg/m2 of fludarabine per day for 4 days and 500 mg/m2 of cyclophosphamide per day for 2 days.

Obe-cel administration featured a split-dose infusion on day 1 and day 10. Dose levels were guided by bone marrow burden at the start of lymphodepletion. Patients who had a bone marrow blast level of 20% or less at day –6 received the first infusion of obe-cel at a target dose of 100 x 106 CAR T cells; the second infusion was given at a target dose of 310 x 106 CAR T cells if patients did not experience grade 2 or higher cytokine release syndrome (CRS) or any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) following the first dose.

Patients who had a bone marrow blast level of more than 20% at day –6 received obe-cel at 10 x 106 CAR T cells on day 1. If they did not experience grade 2 or higher CRS or any-grade ICANS, these patients received the second dose at 400 x 106 CAR T cells on day 10.

The CR/CRi rate in cohort 2A served as the trial’s primary end point. CR rate in cohort 2A was a key secondary end point. Other secondary end points included DOR, EFS, MRD-negative remission, overall survival (OS), progression-free survival, relapse-free survival, safety, alloSCT, and overall remission without alloSCT or other subsequent therapies.

Between both phases of the study, 217 patients were screened, and 153 individuals were enrolled. Twenty-six patients did not receive at least 1 infusion of obe-cel due to death (n = 15), manufacturing-related issue with patient leukapheresate (n = 7), adverse effects (AEs; n = 2), physician withdrawal (n = 1), and progressive disease (n = 1). In total, 127 patients received at least 1 dose of obe-cel across phase 1b (n = 16) and phase 2 (n = 111).

Among all patients who received at least 1 infusion, the median age was 47.0 years (range, 20-81), and 20% of patients were at least 65 years of age. Most patients were male (52%), White (74%), not Hispanic or Latino (63%), and had an ECOG performance status of 1 (60%).

Patients received a median of 2.0 prior lines of therapy (range, 1-6); 10% of patients were refractory to all prior anticancer therapy, 25% were refractory to first-line treatment, and 52% were refractory to their most recent therapy. Forty-seven percent of patients experienced disease relapse within 12 months after receipt of first-line therapy. Prior treatments included blinatumomab (42%); inotuzumab ozogamicin (Besponsa; 31%); both blinatumomab and inotuzumab ozogamicin (17%); and alloSCT (44%).

The median bone marrow blast level was 40.0% (range, 0%-100%). Twenty-three percent of patients had extramedullary disease, 28% had Ph-positive disease, and 88% had no lymphoblasts in the cerebrospinal fluid, irrespective of white blood cell count.

In patients who received obe-cel, 92.9% also underwent bridging therapy prior to infusion. Bridging therapies included chemotherapy alone (63.0%); chemotherapy plus a TKI (7.9%); chemotherapy plus inotuzumab ozogamicin (7.1%); inotuzumab ozogamicin alone (7.1%); a TKI alone 7 (5.5%); glucocorticoids alone (1.6%); and rituximab (Rituxan) alone (0.8%).

Most patients (59.8%) received obe-cel at 10 x 106 CAR T cells as the first infusion. Notably, 94.5% of patients who underwent the first infusion also received the second. Reasons for not receiving the second infusion (n = 7) included grade 3 ICANS (n = 2) and grade 3 CRS (n = 1), death due to a cerebrovascular incident (n = 1), manufacturing-related issue (n = 1), and rapid disease progression (n = 2). In cohort 2A, 88 of 94 patients (94%) received both doses.

Additional Efficacy Data

Among the overall population who received at least 1 infusion of obe-cel and had a bone marrow blast level of at least 5% prior to lymphodepletion (n = 91), the ORR was 75% (95% CI, 64%-83%). In responders within this population who had MRD data available (n = 62/68), 94% (n = 58/62) were MRD negative following treatment with obe-cel.

MRD data were available for most patients with bone marrow blast levels of less than 5% who did not have extramedullary disease before lymphodepletion (n = 28/29); in this subgroup, 96% of patients achieved an MRD-negative remission. In patients with bone marrow blast levels of less than 5% and extramedullary disease before lymphodepletion (n = 7), 71%cleared their extramedullary disease after receiving obe-cel.

ORRs were consistent between patient subgroups; however, patients with a bone marrow blast level higher than 75% before lymphodepletion experienced an ORR of 65% (95% CI, 48%-79%) compared with 82% (95% CI, 69%-92%) for patients who had a bone marrow blast level of 5% to 75% prior to lymphodepletion.

Accounting for patients who did not receive at least 1 infusion of obe-cel, the ORR was 64.3% (95% CI, 54.7%-73.1%) for cohort 2A (n = 112) and 64.7% (95% CI, 56.6%-72.3%) for the overall trial population (n = 153).

Among all responders in the intention-to-treat population (n = 99), 18% underwent subsequent alloSCT at a median of 101 days (range 38-421) following the infusion of obe-cel; 6 transplants were given to patients who had undergone alloSCT prior to enrolling on the trial. No patients with persisting CAR T cells prior to alloSCT (n = 11) had CAR T cells detected after transplant. Transplant was not associated with differences in EFS or OS.

Thirty-one percent of responders experienced disease relapse. Specifically, morphologic relapse was observed in 19% of patients (n = 6/31) with a bone marrow blast level of less than 5% at lymphodepletion; 29% (n = 12/42) of patients with a bone marrow blast level of 5% to 75%; and 50% (n = 13/26) of patients with bone marrow blast levels greater than 75%. Other relapses included isolated extramedullary relapse (n = 5), including central nervous system disease (n = 2); and bone marrow relapse with concomitant extramedullary presentation at the time of relapse (n = 3).

Patients who received at least 1 infusion of obe-cel experienced a median OS of 15.6 months (95% CI, 12.9-NE); the estimated 6- and 12-month OS rates were 80.3% and 61.1%, respectively.

Notably, bone marrow burden prior to lymphodepletion correlated with OS; the estimated 12-month OS rates for patients with low, intermediate, and high bone marrow burden were 72% (95% CI, 53%-84%), 59% (95% CI, 44%-71%), and 55% (95% CI, 38%-69%), respectively.

Safety Findings

Any-grade CRS occurred in 68.5% of patients who received at least 1 dose of obe-cel, and the rate of grade 3 or higher CRS was 2.4%. The median time to onset of CRS was 8 days (range, 1-23), and the median duration of CRS was 5 days (range, 1-21).

The respective rates of any-grade and grade 3 or higher ICANS in the obe-cel–treated population were 22.8% and 7.1%. The median time to onset of and median duration of ICANS was 12 days (range, 1-31) and 8 days (range, 1-53), respectively. Among patients who experienced grade 3 or higher ICANS (n = 9), 56% had a bone marrow blast level of greater than 75% before lymphodepletion, and 44% had a bone marrow blast level of 5% to 75%. No instances of grade 3 or higher ICANS were reported in patients with bone marrow blast levels of less than 5% prior to lymphodepletion.

After the infusion of obe-cel, 15.7% of patients were admitted to an intensive care unit, and the median stay was 5.5 days (range, 1-37). Seven of these admissions were for the management of ICANS (n = 5) or CRS (n = 2).

Febrile neutropenia was observed in 24.4% of patients. Infections led to 5 deaths, including neutropenic sepsis (related to obe-cel, n = 1; not related to obe-cel, n = 1), sepsis (not related to obe-cel, n = 2), and abdominal infection (not related to obe-cel, n = 1). One other death (acute respiratory distress syndrome with ongoing ICANS) was deemed related to obe-cel.

“With its low rates of serious [AEs] coupled with compelling long-term survival data and durable responses, obe-cel offers real hope for adult [patients with ALL],” Claire Roddie, MD, PhD, FRCPath, lead investigator of FELIX and an associate professor of hematology at the University College London Cancer Institute, stated in a news release.2 “Obe-cel’s durable responses were particularly observed in patients with [low-to-intermediate] bone marrow burden, including patients who did not receive consolidative alloSCT, and there could be an opportunity to use obe-cel as earlier-line consolidation.”

References

1. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia. N Engl J Med. 2024;391(23):2219-2230. doi:10.1056/NEJMoa2406526
2. Autolus Therapeutics announces publication of data from the FELIX study of obe-cel in r/r adult B-ALL patients in the New England Journal of Medicine. News release. Autolus Therapeutics. December 2, 2024. Accessed January 3, 2025. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-publication-data-felix-study-obe
3. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed January 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute