Orca-T Is Associated With Retrospective OS Improvement vs Post-Transplant Cyclophosphamide in Advanced Hematologic Malignancies

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Findings from a retrospective analysis revealed that the allogeneic T-cell immunotherapy Orca-T was associated with an improvement in overall survival (OS) compared with post-transplant cyclophosphamide in patients with advanced hematologic malignancies. Data were presented at the 51st Annual EBMT Meeting.¹

The retrospective analysis included selected patients who received Orca-T during a phase 1b trial (NCT04013685) and a cohort of registry-derived patients given post-transplant cyclophosphamide. Findings showed that patients treated with Orca-T (n = 77) experienced 1-, 2-, and 3-year OS rates of 96% (95% CI, 88%-99%), 88% (95% CI, 78%-94%), and 86% (95% CI, 73%-92%), respectively. In the post-transplant cyclophosphamide cohort, these respective rates were 82% (95% CI, 78%-87%), 73% (95% CI, 68%-79%), and 67% (95% CI, 61%-74%).

“The increased survival was maintained through 1-, 2-, and 3-year comparisons,” lead study author Arpita P. Gandhi, MD, MS, said in a presentation of the data. “Historically, T-cell reduction has provided graft-vs-host disease [GVHD] control but higher [rates of] infection and lower survival. Orca-T exhibited low [rates of] GVHD, low infections, and high survival in the context of a single-arm phase 1b trial.”

Gandhi is an assistant professor of medicine in the Division of Hematology/Medical Oncology in the School of Medicine at Oregon Health & Science University in Portland.

Setting the Stage for the Retrospective Analysis

In the phase 1b study evaluating Orca-T, investigators enrolled patients 18 to 75 years of age with high-risk hematologic malignancies in complete response (CR), including acute myeloid leukemia (AML), acute lymphoblastic leukemia, high- or very high–risk myelodysplastic syndrome (MDS), or myelofibrosis. Patients needed to be eligible for myeloablative conditioning; have a hematopoietic cell transplantation–specific comorbidity index score of 4 or less; have a Karnofsky performance status of at least 70; and have adequate organ function.

In the single-arm study, patients underwent myeloablative conditioning on days –10 to –2 prior to receiving Orca-T. Infusion of the immunotherapy comprised hematopoietic stem and progenitor cells at a dose of 3 x 10⁶ on day 0; conventional T cells at a dose of 3 x 10⁶ on day +2; and single-agent tacrolimus at a target dose of 5 to 10 ng/mL on day +3. Notably, patients did not receive methotrexate, post-transplant cyclophosphamide, or other immunosuppressive therapies.

The trial’s primary end points were the rate of dose-limiting toxicities and the incidence of primary graft failure through day +28.

Previously reported data from the study showed that evaluable patients (n = 150) achieved 1-, 2-, and 3-year OS rates of 88% (95% CI, 83%-94%), 80% (95% CI, 74%-87%), and 76% (95% CI, 69%-84%), respectively. Two percent of patients experienced primary graft failure, and no patients had secondary graft failure. Moderate-to-severe GVHD was reported in 13% of patients, and 5% had grade 3 or higher acute GVHD. Infections included grade 1 to 3 (28%), grade 4 (5%), and grade 5 (1%). The non-relapse mortality rate was 9%.

Building the Retrospective Cohorts

To conduct the retrospective analysis, investigators selected cohorts of patients from the Orca-T phase 1b study (n = 154) and patients from a post-transplant cyclophosphamide comparator arm (n = 2585). The groups evaluated in the analysis were selected based on date of treatment, HLA match status, age, disease type, conditioning, and GVHD prophylaxis, which created the final Orca-T (n = 77) and post-transplant cyclophosphamide (n = 293) arms.

Among patients included in the retrospective analysis, the median age was 49 years (interquartile range [IQR], 39-58) in the Orca-T arm vs 48 years (IQR, 37-58) in the post-transplant cyclophosphamide arm. The majority of patients were male (Orca-T, 57%; post-transplant cyclophosphamide, 57%), had myeloid malignancies such as AML or MDS (70%; 72%), had intermediate-risk disease (65%; 64%), were in first CR (60%; 63%), had matched-unrelated donors (52%; 85%), were White (68%; 84%), and were not Hispanic or Latino (75%; 82%). The median follow-up was 33 months (range, 5-54) for the Orca-T arm and 24 months (range, 0-53) for the post-transplant cyclophosphamide arm.

Additional Retrospective Data

Further data from the retrospective analysis demonstrated that age had no significant impact on OS. In patients 50 years of age or younger, the 1-year OS rates were 95% (95% CI, 88%-100%) for Orca-T (n = 39) vs 86% (95% CI, 81%-92%) for post-transplant cyclophosphamide (n = 170). In those over 50 years of age, the 1-year OS rates were 97% (95% CI, 92%-100%) for Orca-T (n = 38) vs 77% (95% CI, 70%-85%) for post-transplant cyclophosphamide (n = 123).

The 1-year non-relapse mortality rate was 2% for the Orca-T group compared with 8% for the post-transplant cyclophosphamide group. The 1-year relapse-free survival rate was 83% and 71% for Orca-T and post-transplant cyclophosphamide, respectively.

Orca-T was further investigated vs conventional allogeneic hematopoietic stem cell transplant in patients with advanced hematologic malignancies the phase 3 Precision-T trial (NCT05316701), and findings from the study showed that Orca-T led to an improvement in the rate of moderate-to-severed chronic GVHD, meeting the trial’s primary end point.² Full data from Precision-T will be presented on Tuesday at the 51st Annual EBMT Meeting.

References

1. Gandhi AP, Srour SA, Oliai C, et al. Observational comparison of overall survival between phase 1b Orca-T and registry-based post-transplant cyclophosphamide patients. Presented at: 51st Annual EBMT Meeting; March 30 to April 2, 2025; Florence, Italy. Abstract OS3-04.
2. Orca Bio announces positive results from the pivotal phase 3 study of investigational Orca-T compared to allogeneic stem cell transplant for the treatment of hematologic malignancies. News release. Orca Bio. March 17, 2025. Accessed March 31, 2025. https://orcabio.com/orca-bio-announces-positive-results-from-the-pivotal-phase-3-study-of-investigational-orca-t-compared-to-allogeneic-stem-cell-transplant-for-the-treatment-of-hematologic-malignancies/