Atara Reports Positive Results from Pivotal Phase 3 Trial Tab-cel at ASH
December 14, 2021
Atara Biotherapeutics reported positive efficacy and safety results from its late-stage study of tab-cel for the treatment of an ultra-rare type of cancer that occurs in a small number of transplant patients known as post-transplant lymphoproliferative disorder.
PTLD is a specific lymphoma linked with the proliferation of B-cells that are infected by Epstein-Barr virus (EBV). Most people are infected with EBV, but they are usually asymptomatic. Immune-suppressants administered to avoid transplant rejection can cause T-cells from controlling B-cells, causing them to run amok and lead to lymphoma. About half of patients with PTLD die within two years.
The phase 3 multicenter ALLELE study demonstrated a 50 percent Objective Response Rate (ORR) for patients treated with tabelecleucel (tab-cel) who had Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD) following solid organ transplant (SOT) or hematopoietic cell transplant (HCT), with a one-year survival rate of 89.2 percent for patients responding to tab-cel compared with 32.4 percent for non-responders. At least 11 of 19 responders had a Duration of Response (DOR) that lasted more than six months with median time to response in all patients of just 1.1 months.
The findings, along with combined long-term survival data from phase 2 and multicenter Expanded Access Protocol (EAP) studies of tab-cel were featured as oral presentations at the 63rd American Society of Hematology (ASH) Annual Meeting.
“Patients with EBV+ PTLD face a poor prognosis with survival measured in weeks to months if initial treatment is unsuccessful. There are no approved treatment options for this devastating disease, underscoring the critical unmet need that exists,” said Jakob Dupont, head of Global Research & Development at Atara. “Our conviction that tab-cel, recently filed with the EMA, is a potential first-in-class treatment option for transplant recipients that develop EBV+ PTLD is validated by almost 90 percent of patients responding to treatment surviving after one year, and a similar two-year survival benefit of over 86 percent in patients who achieved a complete or partial response from phase 2 and EAP studies.”
Poor patient survival in relapsed or refractory EBV+ PTLD underscores the significant need for effective, safe, and fast-acting new therapeutic options were highlighted in two additional posters presented at ASH. Patients suffer from poor median survival of 0.7 months (n=81) and 4.1 months (n=86) for HCT and SOT, respectively, reported in EBV+ PTLD patients for whom rituximab ± chemotherapy failed.
Tab-cel is an off-the-shelf, allogeneic T-cell immunotherapy in development for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD). It is derived from blood cells from healthy donors in which the B-cells are separated from the T-cells. The T-cells are activated to be responsive to EBV antigens. The final product is a population of T-cells that are specific and selective for EBV that targets only EBV-infected cells. Because it is allogeneic, Atara says it will be safe to use in patients in different diseases since the T cells will not attack other cells in the body, only those infected with EBV.
In the ongoing phase 3 ALLELE study, 38 evaluable patients as of May 2021 — 24 EBV+ PTLD patients following SOT after failure of rituximab ± chemotherapy and 14 EBV+ PTLD patients following HCT after failure of rituximab monotherapy — were treated with tab-cel and had the opportunity for a six-month follow-up after response. The median age of evaluable patients for both SOT and HCT was 52.9 years (3.2–81.5) who had tried anywhere from one to five prior systemic treatments including rituximab monotherapy, chemotherapy or immunotherapy.
As measured by independent oncologic response adjudication (IORA) assessment, an ORR of 50 percent was observed for both HCT and SOT groups. For patients with EBV+ PTLD following SOT, an ORR of 50.0 percent was observed and similarly, for patients with EBV+ PTLD following HCT, an ORR of 50.0 percent was observed, with a best overall response of Complete Response (26.3%) or Partial Response (23.7%). The median time to response (TTR) in all patients was 1.1 months. In the study, 11 of 19 responders had a duration of response (DOR) lasting more than six months and median DOR has not yet been reached. Of the remaining eight responders, four had events due to IORA-assessed progressive disease or death and four patients were alive and censored for the DOR at the time of the data cut.
Patients responding to tab-cel had longer survival compared to the non-responders, with a median overall survival not evaluable and a one-year survival rate of 89.2 percent versus non-responders’ overall survival of 5.7 months and one-year survival rate of 32.4 percent.
Safety was consistent with previously published data, and no new safety signals or concerns were reported. There were no reports of tumor flare reaction, infusion reactions, cytokine release syndrome, transmission of infectious diseases, including cytomegalovirus, and no events of graft versus host disease (GvHD) or organ rejection related to tab-cel. Overall, tab-cel was well-tolerated in treatment-refractory and immunocompromised patients.
Atara also reported combined long-term survival data from phase 2 and multicenter EAP studies of tab-cel in a second oral presentation. Results show that across studies, patients who responded to tab-cel for treatment of EBV+ PTLD experienced a long-term survival benefit with a median overall survival of 54.6 months reported in all patients (n=76). Importantly, patients who achieved a partial response with tab-cel derived similar overall survival benefit to those who achieved a complete response. Treatment was well tolerated in refractory and immunocompromised patients and there were no fatal events reported related to tab-cel.
These data support the recent EMA-validated Marketing Authorization Application for tab-cel as the first off-the-shelf allogeneic T-cell therapy ever to be reviewed by a regulatory agency. The EMA’s Committee for Medicinal Products for Human Use (CHMP) granted tab-cel Accelerated Assessment and an EU approval decision is anticipated for second half of 2022.
Tab-cel has been granted Breakthrough Therapy Designation for EBV+ PTLD following allogeneic HCT by the U.S. Food and Drug Administration and PRIME designation by the European Medicines Agency for the same indication. Tab-cel has orphan drug designation in the United States and European Union.
Author: Rare Daily Staff
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