Obe-cel CAR-T induces ‘deep, durable responses’ in B-cell ALL
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Key takeaways:
- Sixty-one percent of responders remained in remission as of the data cutoff date.
- Three percent of patients developed grade 3 or higher CRS.
CHICAGO — Seventy-six percent of adults with relapsed or refractory B-cell acute lymphoblastic leukemia achieved complete response to treatment with obecabtagene autoleucel, interim results of the pivotal phase 2 FELIX trial showed.
Individuals treated with the investigational chimeric antigen receptor T-cell therapy exhibited low levels of cytokine release syndrome and neurotoxicity, according to results presented at ASCO Annual Meeting.
“The results were really heartening to us,” Claire Roddie, PhD, FRCPath, MBChB, MRCP, associate professor in hematology-oncology at University College London, said during a presentation. “There were deep, durable responses in this study cohort.”
Background, methodology
The development of CD19-directed CAR T-cell therapy has revolutionized treatment of relapsed B-cell ALL.
“Obe-cel is a unique autologous CD19 CAR with a fast off-rate CD19-binding domain,” Roddie said. “And it was designed that way to mitigate for the safety and persistence concerns we had with other CD19 CAR T cells.”
Obecabtagene autoleucel (AUTO1; Autolus Therapeutics) — commonly called obe-cel — is a CD19-directed CAR T-cell therapy previously evaluated in a phase 1 study in adults and younger individuals with B-cell ALL. The FDA granted regenerative medicine advanced therapy designation to obe-cel in May 2022 for treatment of adults with relapsed or refractory B-cell ALL.
The phase 2 multicenter FELIX trial enrolled 112 patients, 94 (median age, 50 years; range, 20-81; 50% women) of whom received treatment with obe-cel.
The study population included 25 patients (26.6%) with Philadelphia chromosome-positive disease. Twenty-nine patients (30.9%) received at least three previous lines of therapy.
Study participants underwent preconditioning lymphodepletion followed by two doses of obe-cel using a split dosing method.
The approach adjusted dosing to maximize therapeutic benefit based on the recipient’s tumor burden before preconditioning and severity of treatment-related toxicity after the first infusion.
Overall response rate as determined by complete response (CR) or CR with incomplete blood count recovery (CRi) by central independent review committee assessment served as the study’s primary endpoint. Secondary endpoints included duration of response, EFS, OS, minimal residual disease (MRD)-negativity rate and safety.
Key findings
Median follow-up was 9.5 months (range, 1.9-19), with a data cutoff date of March 16.
Investigators reported a 76% (95% CI, 66-84) ORR for the study, comprising a CR rate of 54.3% and CRi rate of 21.3%.
Sixty-one percent of treatment responders remained in remission as of data cutoff without use of additional anticancer therapy.
Ninety-seven percent of patients achieved MRD-negative status as determined by flow cytometry.
Researchers reported a median response duration of 14.1 months (95% CI, 5.9 to not estimable).
Seventy-one patients (75.5%) experienced treatment-related cytokine release syndrome. Three (3.2%) experienced grade 3 or higher symptoms.
Twenty-four patients (25.5%) developed immune effector cell-associated neurotoxicity syndrome (ICANS). Six of the seven patients who experienced grade 3 or higher ICANS had bone marrow blast levels greater than 20% during an evaluation prior to preconditioning lymphodepletion.
Other common grade 3 or higher treatment-related toxicities included neutropenia (36.2%), thrombocytopenia (25.5%), febrile neutropenia (25.5%) and anemia (19.1%).
Clinical implications
The results should be viewed within the context of treating a high-risk population, Roddie said.
“Despite all of these odds being stacked against the product, obe-cel was able to achieve CR or CRi in 76% of infused patients,” she said. “Those responses were deep, MRD-negative responses, and I think we also need to acknowledge that this is a safe product to give to those older, comorbid patients, with very low levels of grade 3 CRS or ICANS.”
Perspective
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Lee Greenberger, PhD
The interim analysis of the FELIX study showed treatment with the CD19-directed CAR T-cell therapy obe-cel led to promising responses in a group of adults with relapsed or refractory B-cell ALL. In fact, we saw response rates quite similar to other FDA-approved autologous CD19-directed CAR T-cell therapies.
The results also revealed an apparent reduction in any-grade CRS and ICANS events. This outcome would indicate that obe-cel is more tolerable than conventional CAR-T. However, a head-to-head analysis is necessary to confirm this finding because this reduction in CRS and ICANS events could be associated with better overall care or even patient selection.
I also wonder if the manufacturing time — currently 21 days with obe-cel — can be shortened and done in a way that does not sacrifice treatment efficacy and safety.
Overall, these findings represent a promising development with some questions left to be answered. I am intrigued to see what the PFS and OS data are when available in the coming years.
Collapse
Roddie C, et al. Abstract 7000. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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