Orca-T improves chronic graph-versus-host disease free in patients with a broad range of demographic and clinical variables: Results of randomized, Phase 3 trial Free

BACKGROUND Orca-T is an investigational allogeneic T-cell immunotherapy using purified donor regulatory T cells to prevent graft-versus-host disease (GvHD). The randomized phase 3 Precision-T trial (NCT05316701) showed improved moderate-to-severe chronic GvHD-free survival with Orca-T versus standard-of-care transplantation with tacrolimus plus methotrexate prophylaxis. This analysis examines outcomes in prespecified patient subgroups from Precision-T.

METHODS In the phase 3 randomized controlled trial, 88 patients received Orca-T and 94 patients received Tac/MTX. Orca-T was produced in a centralized GMP facility and administered in 19 centers across the U.S. Patients were ≤65 years old; had a diagnosis of AML, ALL, MPAL, or MDS with intermediate or high disease risk index (DRI) scores. Patients received a myeloablative conditioning (MAC) regimen (busulfan/fludarabine/thiotepa [BFT] or a TBI-based regimen) and had an 8/8 HLA-matched donor. In this analysis, subgroups of these patients were identified based on differences in demographic and pre-treatment clinical variables including recipient age and sex, donor type, disease type, disease risk, and conditioning regimen. cGFS (the primary endpoint) and GRFS (survival free of aGVHD grades 3-4, moderate-to-severe cGVHD, and relapse) (a secondary endpoint) were compared between treatment groups for each of the subsets. Statistical analyses were performed in R. Log-rank tests and Gray's tests were used to assess survival and cumulative incidence, respectively.

RESULTS Per the statistical analysis plan (SAP), the 56th cGFS event triggered a primary analysis of the phase 3 study at a median follow-up of 9 months. The study population had a median age of 43.5 years (range 19 to 65) and 35% were 50 to 65 years old. Primary diseases included AML (53%), ALL (30%), mixed phenotype acute leukemia (MPAL; 3%) and high-risk MDS (14%). Donors were 8/8 HLA-matched (53% sibling, 47% unrelated).

In the intention to treat cohorts, Orca-T had a significantly higher cGFS rates at 1-year of 78% (95% CI: 65%, 87%) for Orca-T and 38% (95% CI: 26%, 51%) for Tac/MTX with a hazard ratio 0.26; 95% CI: 0.14, 0.47, p <0.00001). The hazard ratio for GRFS also favored Orca-T at 0.37 (0.23, 0.60). A total of 94% Orca-T patients were alive at 1 year vs 83% of Tac/MTX patients (hazard ratio 0.49; 95% CI 0.20, 1.22, p=0.12).

One-year relapse-free survival was comparable between groups (76% for Orca-T vs. 74% for Tac/MTX) while non-relapse mortality favored Orca-T (3.4% vs. 14%, respectively).

Subset analyses for several demographic and clinical variables were analyzed, for which the hazard ratios and 95% confidence intervals for cGFS and GRFS were as follows:

• cGFS

>

• 26 (0.14-0.48)

• 24 (0.11-0.54) for ≤50 years, 0.30 (0.12-0.76) for >50 years

• 24 (0.10-0.56) for men, 0.32 (0.14-0.77) for women

• 32 (0.14-0.77) for related, 0.21 (0.09-0.48) for unrelated

• 27 (0.13-0.56) for AML, 0.28 (0.06-1.41) for ALL, 0.25 (0.05-1.33) for MDS

• 21 (0.10-0.44) for intermediate, 0.52 (0.17-1.61) for high

• 35 (0.18-0.67) for BFT, 0.07 (0.01-0.50) for TBI-based

• GRFS

• 37 (0.23, 0.59)

• 34 (0.18-0.63) for ≤50 years, 0.44 (0.21-0.91) for >50 years

• 32 (0.17-0.63) for men, 0.47 (0.24-0.92) for women

• 52 (0.28-0.98) for related, 0.24 (0.11-0.50) for unrelated

• 39 (0.22-0.69) for AML, 0.35 (0.12-1.02) for ALL, 0.35 (0.09-1.41) for MDS

• 33 (0.19-0.57) for intermediate, 0.59 (0.24-1.47) for high

47 (0.28-0.79) for BFT, 0.15 (0.04-0.51) for TBI-based

Notably, overall survival and NRM were similar for patients aged 51-65 as in the entire safety population. For the patients >50y: one-year rates of overall survival were 93.6% (77%, 98%) for Orca-T patients (n=31) versus 80% (61%, 91%) for Tac/MTX patients (n=32), HR = 0.48 (0.12, 1.89), and one-year rates of NRM were 6.4% (1.1%, 19%) with Orca-T vs 16% (5.7%, 31%), HR=0.49 (0.11, 2.06) with Tac/MTX.

CONCLUSIONS Orca-T demonstrated improved clinical outcomes overall and across subgroups with varied demographic and clinical features. These data suggest that the benefit of Orca-T extends to older patients and those with high-risk disease.