Orca-T Boosts cGVHD-Free Survival vs Allo-HSCT in Advanced Hematologic Malignancies

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Treatment with the allogeneic immunotherapy Orca-T led to an improvement in moderate-to-severe chronic graft-vs-host disease (cGVHD)–free survival (cGFS) compared with standard-of-care allogeneic hematopoietic stem cell transplant (allo-HSCT) in patients with advanced hematologic malignancies, according to data from the phase 3 Precision-T trial (NCT05316701).

Data presented at the 51st Annual EBMT Meeting showed that patients treated with Orca-T (n = 93) experienced a 1-year cGFS rate of 78.0% (95% CI, 65.0%-86.6%) compared with 38.4% (95% CI, 26.2%-50.5%) in patients who underwent allo-HSCT (n = 94; HR, 0.26; 95% CI, 0.14-0.47; log-rank P < .00001).

Overall, the incidence of moderate-to-severe cGVHD was 12.6% (95% CI, 5.3%-23.1%) in the Orca-T arm vs 44.0% (95% CI, 31.3%-56.1%) in the allo-HSCT arm (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test P = .00002).

“[The improvement in cGFS] corresponds to a reduction in [the incidence of] moderate-to-severe cGVHD,” lead study author Everett Meyer, MD, PhD, said in a presentation of the data. “[The incidence of moderate-to-severe cGVHD] represents a significant reduction in late-term comorbidities and improved quality of life for our patients.”

Meyer is an associate professor of medicine (Blood and Marrow Transplantation and Cellular Therapy), of pediatrics (Stem Cell Transplantation) and of surgery (Abdominal Transplantation) at Stanford Medicine in California.

Orca-T Background and Precision-T Overview

Compared with conventional allo-HSCT, which utilizes an uncontrolled mix of more than 50 cell types, Orca-T features a defined population of stem cells, regulatory T cells (Tregs), and conventional T cells (Tcons) given over multiple days.

Precision-T enrolled patients 18 to 65 years of age with acute myeloid leukemia, myelodysplastic syndromes, acute lymphoblastic leukemia, or mixed phenotype acute leukemia who would have undergone standard allo-HSCT. Patients needed to be in complete remission (CR) or CR with incomplete count recovery.

Patients were randomly assigned to receive Orca-T or conventional allo-HSCT. In the experimental arm, patients underwent myeloablative conditioning on days –10 to –2. At day 0, they received an infusion of hematopoietic stem and progenitor cells, along with Tregs at a dose of 3 x 106 Tregs/kg; on day 2, Tcons were administered at 3 x 106 T cells/kg; and on day 3, tacrolimus was given alone at 5 to 10 ng/mL. Notably, no additional immunosuppressive therapies were given with Orca-T.

In the control arm, patients underwent myeloablative conditioning on days –10 to –2, followed by tacrolimus at 5 to 10 ng/mL on day –1, an infusion of the apheresis product at a dose of 108 to 109 T cells/kg on day 0, and methotrexate prophylaxis on days 1, 3, 6, and 11.

The trial’s primary end point was cGFS. Secondary end points included overall survival (OS), GVHD-free relapse-free survival (GRFS), and the incidence of moderate-to-severe cGVHD.

Among 93 patients randomly assigned to the Orca-T arm, 89 patients received the immunotherapy, 3 did not receive the treatment during the study, and 1 patient received tacrolimus and methotrexate. Eighty-eight patients, including those who died, completed trial follow-up; 3 patients withdrew and 2 did not complete follow-up for other reasons. The intention-to-treat (ITT) population included all 93 patients, and 88 were included in the safety population.

In the control arm, 93 of the 94 enrolled patients received tacrolimus and methotrexate; 1 patient received a haploidentical bone marrow transplant and post-transplant cyclophosphamide. Eighty-five patients in the control arm completed follow-up; 5 patients withdrew, and 4 did not complete follow-up for other reasons. All 94 patients were included in the ITT and safety populations.

Additional Efficacy and Safety Data

Findings also demonstrated that patients in the Orca-T arm achieved a 1-year OS rate of 93.9% (95% CI, 85.8%-97.4%) compared with 83.1% (95% CI, 72.9%-89.8%) for patients given conventional allo-HSCT (HR, 0.49; 95% CI, 0.20-1.22; log-rank P = .11823). The 1-year GRFS rates were 63.1% (95% CI, 50.1%-73.6%) and 30.9% (95% CI, 20.0%-42.5%), respectively (HR, 0.37; 95% CI, 0.23-0.60; log-rank P = .00003).

Among the 7 patients who died in the Orca-T arm, causes of death included GVHD (n = 1), infection (n = 2), and disease relapse (n = 4). In the 15 patients who died in the control arm, causes comprised organ failure (n = 4), GVHD (n = 5), infection (n = 3), and disease relapse (n = 3). The 1-year non-relapse mortality rates were 3.4% for Orca-T vs 13% for allo-HSCT. The 1-year RFS rates were 76% and 74%, respectively.

Regarding safety, grade 3 or higher infections occurred in 8.4% (95% CI, 3.6%-16%) of patients treated with Orca-T vs 16% (95% CI, 9.2%-25%) for those in the control arm.

Serious treatment-emergent adverse effects (AEs) occurred in 39% of patients in the Orca-T arm vs 56% of patients in the control arm. The 1-year incidence of grade 2 or higher acute GVHD (aGVHD) was 22% and 30%, respectively. The respective rates of 1-year grade 3 or higher aGVHD were 6.2% and 16%. Any-grade cGVHD was reported in 17% of patients in the Orca-T group vs 49% of patients in the allo-HSCT group.

AEs led to hospitalization in 27% of patients in the Orca-T arm vs 46% of patients in the allo-HSCT arm.

Primary graft failure was not observed in any patients in either arm; 1 patient (1.1%) in the Orca-T arm had secondary graft failure vs no patients in the control arm. The median time to neutrophil engraftment was 13 days for the Orca-T arm compared with 14 days for the allo-HSCT arm. The median time to platelet engraftment was 17 days and 18 days, respectively.

Meyer concluded by noting that Orca Bio—the developer of Orca-T—intends to use the data from Precision-T to support the filing of a biologics license application (BLA) to the FDA in 2025.

“Due to the success of this trial, the plan is [to submit a] BLA, and hopefully [FDA] approval [will follow],” he said.

Disclosures: Meyer reported receiving sponsored research support from Orca Bio for clinical and preclinical studies; he is not employed by or a representative of Orca Bio.

Reference

Meyer EH, Salhotra A, Gandhi AP, et al. Orca-T demonstrates improved survival free of chronic GvHD compared to conventional allogeneic hematopoietic stem cell transplant: a randomized phase 3 trial in advanced hematologic malignancies. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS15-01.