Orca-T Data With Survival, Tolerability Extends to Older Patients With Hematologic Cancers

Caspian H. Oliai, MD

Encouraging data with relapse-free survival (RFS), overall survival (OS), and nonrelapse mortality (NRM) regarding the high-precision cell therapy Orca-T was also matched in a population of patients with hematologic cancers aged 55 years and older, according to findings presented at the 2024 Transplantation & Cellular Therapy Meetings.¹

In results of a multicenter, single-arm, phase 1b trial (NCT04013685), the 1-year RFS rate was 82.3% (95% CI, 59.4%-93.0%) in the group of older patients compared with 84.8% (95% CI, 67.0%-93.5%) of patients who were between 18 and 55 years at a median follow-up of 12 months (range, 1.6-12).

Additionally, the 1-year OS rates were 95.5% (95% CI, 71.9%-99.3%) and 100% (95% CI, 100%-100%) in the older and younger patients, respectively. The 1-year NRM rates were 0% in both arms.

“Orca-T has the potential to be a reduced toxicity alternative to conventional allogeneic transplant,” lead study author Caspian H. Oliai, MD, medical director of the University of California Los Angeles (UCLA) Bone Marrow Transplantation Stem Cell Processing Center, of UCLA Jonsson Comprehensive Cancer Center, said in an oral presentation during the meeting. “Using Orca-T with myeloablative BFT conditioning has the potential to improve outcomes for older patients, based on a greater than 95% overall survival and 1 year transplant-related mortality [rate] of 0%.”

Older patients with hematologic cancers can often be ineligible for myeloablative conditioning (MAC) as their toxicity risk with transplant increases. Instead, they are often treated with reduced-intensity conditioning (RIC) treatments which, in turn, are associated with a higher relapse rate. In a phase 2 trial, results showed that with RIC in older patients, the 2-year cumulative incidence of relapse rate was 44% (95% CI, 35%-53%).²

Oliai emphasized that these data demonstrate an unmet need to develop a treatment strategy that lowers transplant-related mortality but does not reduce the curative potential of MAC, especially as it relates to graft-vs-host disease (GVHD).

Orca-T comprises both stem and immune cells derived from allogenic donors; its mechanism involves leveraging highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. Orca-T could potentially reduce allogeneic transplant-related toxicities through its multi-pronged approach for both disease and infection control.

“The Orca-T strategy uses a T-cell–reduced approach,” Oliai said. “This allows for single-agent GVHD prophylaxis, which again promotes natural immune reconstitution.”

For this analysis, investigators assessed the efficacy and safety of Orca-T in the patient population who were 55 years and older (n = 25) compared with patients aged between 18 and 55 years (n = 39) on the phase 1b trial. Patients either had acute myeloid leukemia (AML), acute lymphoblastic leukemia, or mixed-phenotype acute leukemia, in complete response (CR)/CR with incomplete count recovery; myelodysplastic syndrome (MDS), or chronic myeloid leukemia that was in chronic phase. All patients had an 8/8 related or unrelated matched donor, a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) of 4 or lower, a Karnofsky performance score of 70 or greater, and adequate organ function.

Patients were treated with MAC on days -10 to -2, which comprised intravenous busulfan (9.6 mg/kg), fludarabine (160 mg/m²), and thiotepa (10 mg/kg; BFT) before Orca-T administration on day 0 in the experimental arm. Hematopoietic stem cells and Tregs were given at 3 x 10⁶ Treg/kg on day 0 and Tcons at 3 x 10⁶ T cells/kg on day +2. Single-agent tacrolimus was then given on day +3 at 5 to 10 ng/mL.

In the standard arm, patients received tacrolimus on day -1 at 5 to 15 ng/mL, infusion of apheresis product at a cell dose of 10⁸ to 10⁹ T cells/kg, and methotrexate prophylaxis on days +1, +3, +6, and +11 posttransplant.

No methotrexate, PTCy, or other immunosuppressive treatments were given with Orca-T.

The primary end points were incidence of primary graft failure and incidence of severe acute GVHD.

The manufacturing process for Orca-T was done at a centralized GMP facility, where it was distributed and infused at US study sites. The vein-to-vein time was less than 72 hours for all patients, the majority being for less than 60 hours.

Regarding baseline characteristics, the median age in the older and younger cohorts was 59 and 47 years, respectively. Across both age groups, the median duration on study was 1 year. In the younger age group, 49% of patients were female, 13% were of Hispanic or Latino ethnicity, and most had AML (74%). In the 55-years-and-older group, 36% of patients were female, 12% were of Hispanic or Latino ethnicity, 44% had AML, and 32% had high-/very high-risk MDS. A baseline HCT-CI score of 0 was more common in the younger cohort (51%) and an HCT-CI score of 4 was more common in the older group (12%).

In the younger and older age groups, 64% and 36% of patients, respectively, had related matched donor relationships. Moreover, 64% and 48% had negative minimal residual disease, and 79% and 52% had an intermediate disease risk index score, respectively.

Further findings showed that OS was found to be similar in a broader phase 1b cohort of patients who received all conditioning regimens at 88.3% (95% CI, 71.8%-95.4%) and 96.2% (95% CI, 88.7%-98.8%) in the older and younger patients, respectively.

The 1-year disease-free survival rate was 86% in the cohort of older patients compared with 89% in patients who were between 18 and 55 years, at a median follow-up of 12 months (range, 1.6-12). The modified 1-year GVHD-free RFS rate was 77% and 86%, respectively.

Graft failure occurred in 1 patient in the younger age group; grade 4 infections occurred in 3 older patients. Grade 3 mucositis occurred in 1 younger and 1 older patient. Grade 3 or higher acute GVHD was reported in 1 older patient, moderate chronic GVHD in 3 younger patients and 2 older patients, and severe chronic GVHD in 1 older patient.

Regarding immune reconstitution, Oliai noted that the median donor chimerism at 3 months was greater than 90% in both older and young patients.

Additional data showed that 2 patients older than 65 years remain alive and did not have evidence of grade 3/4 acute GVHD, moderate-to-severe GVHD, or relapse.

Oliai concluded that the ongoing phase 3 Orca Precision T study (NCT05316701) comparing Orca-T with standard of care is currently enrolling patients.

Editor’s Note: Dr Oliai cited research funding from Orca Bio, Novartis Pharmaceuticals Corporation, Seagen Inc., Arog Pharmaceuticals, Kite (Gilead), AstraZeneca Pharmaceuticals, Jazz Pharmaceuticals, and Pfizer Inc.

References

1. Oliai C, Paintin J, Muffly LS, et al. Optimizing Outcomes with Myeloablative Conditioning in Older Patients: Efficacy and Safety of Precision Engineered Orca-T in Patients > 55 Years Old with Hematologic Malignancies. Presented at: 2024 Transplantation & Cellular Therapy Meetings; February 21-24, 2024; San Antonio, TX. Abstract 64.
2. Devine SM, Owzar K, Blum W, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015;33(35):4167-4175. doi:10.1200/JCO.2015.62.7273