FDA Issues CRL for Tabelecleucel in EBV+ Lymphoproliferative Disease

The CRL did not identify any deficiencies related to the manufacturing, efficacy, or safety outlined in the BLA, and no new clinical trials were requested.

The FDA has given a complete response letter (CRL) to the biologics license application (BLA) submitted for tabelecleucel (Ebvallo) as a monotherapy treatment for adult and pediatric patients with Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease who have received at least 1 prior therapy which included an anti-CD20 containing therapy, according to a news release from the drug’s developer, Atara Biotherapeutics.1

The CRL was solely related to observations as part of a pre-license inspection of a third-party manufacturing facility for tabelecleucel. Furthermore, the CRL did not identify any deficiencies related to the manufacturing, efficacy, or safety of the agent in the BLA, and the FDA did not request any new clinical trials.

The FDA previously accepted a biologics license application (BLA) for tabelecleucel to treat patients with EBV-positive post-transplant lymphoproliferative disease in July 2024.2

The BLA for tab-cel was supported by findings from the phase 3 ALLELE trial (NCT03394365), in which investigators evaluated the allogenic EBV-specific T-cell immunotherapy in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease who progressed after treatment with rituximab (Rituxan) with or without chemotherapy. Updated findings were presented in an oral presentation at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition.3

Results from the trial reveal that the updated overall response rate (ORR) was 50.7% (n = 38/75; 95% CI, 38.9%-62.4%) among all patients. Additionally, ORR was similar among patients who previously underwent solid organ transplant (SOT) at 51.0% (n = 25/49; 95% CI, 36.3%-65.6%) vs those who underwent hematopoietic stem cell transplant (HCT) the ORR was 50.0% (n = 13/26; 95% CI, 29.9%-70.1%).

“We are working closely with our partner Pierre Fabre Laboratories, the FDA, and the third-party manufacturer to address the feedback to support marketing approval for tabelecleucel,” Cokey Nguyen, PhD, president and chief executive officer of Atara Biotherapeutics, said in the news release. “Once the third-party manufacturer GMP compliance issues have been adequately addressed, we will file for a resubmission, which we would expect to be potentially approved within six months of resubmission. Atara and its partner Pierre Fabre remain confident in the potential of tabelecleucel and are committed to bringing this potential first-in-class medicine to US patients with EBV+ [post-transplant lymphoproliferative disease] who have limited treatment options and significant unmet need.”

A total of 75 patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease were enrolled to receive tab-cel and included in the analysis as of the data cut-off date of October 9, 2023. Of those 75 patients, 49 received prior solid organ transplant (SOT), and 26 received prior hematopoietic stem cell transplant (HCT).

Patients in the ALLELE trial received 2 x 106 cells/kg of tabelecleucel on days 1, 8, and 15 administered in 35-day cycles for up to 5 years. The median time from EBV-positive post-transplant lymphoproliferative disease to initial tabelecleucel dosing was 4.6 months (range, 0.6-190.5). Additionally, the median number of prior therapies was 1.0 (range, 1-5), with prior therapies including rituximab (Rituxan) monotherapy (n = 65; 86.7%), chemotherapy-containing regimens (n = 35; 46.7%), and rituximab plus chemotherapy (n = 28; 37.3%).

In the trial, the primary end point was ORR per independent oncologic response adjudication. Key secondary end points included time to response and time to best response, progression-free survival in responders, overall survival in responders vs those without a response, and rates of allograft loss in the SOT cohort.

In the HCT and SOT groups, serious treatment-emergent adverse effects (TEAEs) were reported in 65.4% and 61.2% of patients. Fatal TEAEs were reported in 19.2% and 18.4% of the respective groups, although none were reported to be treatment-related. There were no reported incidences of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Additionally, no events of graft-versus-host disease or organ rejection were related to tab-cel treatment.

References

1. Atara Biotherapeutics provides regulatory and business update on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed January 17, 2025. https://tinyurl.com/2sutywn9
2. Atara Biotherapeutics announces U.S. FDA acceptance and priority review of the Biologics License Application for tabelecleucel (tab-cel®) for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease. News Release. Published July 17, 2024. Accessed January 17, 2025. https://tinyurl.com/4h4wps4j
3. Ghobadi A, Baiocchi R, Beitinjaneh AM, et al. Updated clinical results: a multicenter, open-label, phase 3 study of tabelecleucel for solid organ or allogeneic hematopoietic cell transplant recipients with Epstein-Barr virus-driven post transplant lymphoproliferative disease after failure of rituximab or rituximab plus chemotherapy. Blood. 2024;144(suppl 1):70. doi:10.1182/blood-2024-198159