Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant Cyclophosphamide Patients

BACKGROUND

Allogeneic hematopoietic stem cell transplant (alloHSCT) is the only curative option for many patients with high-risk hematologic malignancies. However, the utilization and efficacy of alloHSCT remain limited by toxicity and complications like graft versus host disease (GvHD). Post-transplant cyclophosphamide (PTCy) is often used as a prophylaxis against GvHD, but may increase infections, organ damage and hospitalizations. Despite the advances in GvHD prophylaxis regimens, there is a continued need for improvements in overall survival (OS).

Orca-T is an investigational allogeneic T-cell immunotherapy. Whereas PTCy is routinely employed in a triple-agent regimen, Orca-T leverages highly purified, polyclonal donor regulatory T cells with single-agent tacrolimus to control GvHD. Preliminary outcomes with Orca-T including engraftment, GvHD, RFS, NRM have been previously reported (Salhotra et al. 2023). Here, we retrospectively compare long-term follow up from a subset of phase 1b (NCT04013685) Orca-T patients to a similar subset of patients from the CIBMTR registry who received PTCy.

METHODS

To date, 154 patients have been treated with Orca-T in the phase 1b trial. Patients were heterogeneous with respect to disease type, DRI risk, active disease status, donor type, and conditioning regimen. Nearly all phase 1b patients are past the protocol defined schedule of assessments. Up to date OS data were collected from participating centers in July 2024. For comparison to PTCy, data were obtained from the CIBMTR.

For a more interpretable comparison, we identified criteria for disease and treatment characteristics consistent with the phase 3 Precision-T protocol and applied them to phase 1b Orca-T patients to create the subset Ph1b’, and to CIBMTR data to create the PTCy registry cohort. Specifically, both cohorts included only patients with a diagnosis of AML, ALL or MDS. Patients with active disease or low DRI score were excluded, and only patients treated with a MAC regimen and 8/8 HLA-matched donor cells were included. Additional inclusion criteria for the Ph1b’ cohort were treatment between 2019-2024 and use of Bu/Flu/TT, TBI/Cy, or TBI/etoposide MAC regimen, consistent with the phase 3 protocol. Additional criteria for the PTCy registry cohort were age <66, treatment between 2019-2021, and use of PTCy + tacrolimus + mycophenolate as GvHD prophylaxis. Statistical analyses of OS were performed in R. A log-rank test was used to test the null hypothesis that there is no difference in survival between groups.

RESULTS

Orca-T was produced in a centralized GMP facility, distributed, and infused in 17 centers across the U.S. All patients enrolled in study received their product and were successfully infused.

Ph1b’ patients (n=77) had a median age of 49 (range 19-70 years) and a median follow up (f/u) time of 33 months (range 5-54 months). The PTCy registry cohort (n=293) had a median age of 48 (range 19-65 years) and a median f/u time of 24 months (range 0-53 months). Patients with related donors constituted 31% of Ph1b’ and 14% of the PTCy registry cohort. A majority of patients had HCT-CI scores of 0-2: 60% among Ph1b’ patients and 61% in the PTCy registry cohort. Among Ph1b’ patients, 93%, 79%, and 29% had >1, >2, and >3-year f/u, respectively, while 80%, 57%, 24% of the PTCy registry cohort had >1, >2, and >3-year f/u, respectively.

The OS rates (and 95% CIs) for the Ph1b’ and the PTCy patients at all time points are included below (p=0.0021):

• 1-year: 96% (88%-99%) for Orca-T vs 82% (78%-87%) for PTCy
• 2-year: 88% (78%-94%) for Orca-T vs 73% (68%-79%) for PTCy
• 3-year: 86% (73%-92%) for Orca-T vs 67% (61%-74%) for PTCy

Median f/u for all phase 1b patients (n=154) was 30 months (range 0-54); The 1-, 2-, and 3-year OS estimates were 88% (95% CI 78%-92%), 80% (72%-86%) and 76% (67%-83%), respectively.

CONCLUSIONS

Orca-T exhibits promising long-term OS in the phase 1b patient population. An observational study of Orca-T phase 1b and PTCy patients from the CIBMTR registry demonstrated higher OS for Orca-T patients. Outcomes available for this study were limited to OS and retrospective/registry data. Further analysis is needed to identify the specific clinical factors such as infection, relapse and organ toxicity including cardiotoxicity that may account for the differences in OS. A phase 3 prospectively randomized trial comparing Orca-T to Tac/MTX pharmacological GvHD control recently completed enrollment.