FDA Issues Complete Response Letter for Tab-cel in EBV+ PTLD

• A complete response letter (CRL) has been issued by the FDA in response to the biologics license application (BLA) seeking the approval of tabelecleucel (tab-cel; Ebvallo) for the treatment of Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease (PTLD).

• This indication is for adult and pediatric patients 2 years of age or older with EBV–positive PTLD who have received 1 or more prior therapy, including an anti-CD20 containing regimen.
• In the CRL, no deficiencies related to manufacturing, clinical efficacy, or safety data in the BLA were identified.

The FDA has issued a CRL to the BLA seeking the approval of tab-cel for the treatment of adult and pediatric patients aged 2 years and older with EBV–PTLD who have received 1 or more prior therapy, including an anti-CD20 containing regimen.¹

In July 2024, the FDA accepted the BLA seeking the approval of tabelecleucel for this patient population. The application was also granted priority review and was given a Prescription Drug User Fee Act target action date of January 15, 2025.²

The CRL stemmed from findings during a routine pre-license inspection of a third-party manufacturing facility for tab-cel. No issues were identified regarding the manufacturing process, clinical efficacy, or safety data included in the BLA. Additionally, the FDA did not require any additional clinical studies to support the agent’s potential approval.

“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,” said Cokey Nguyen, PhD, president and chief executive of Atara, in a press release.¹ “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 6 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-positive PTLD who have limited treatment options and significant unmet need.”

“We are disappointed by the delay and are willing to work with Atara on appropriate next steps to bring tabelecleucel to US patients that suffer from this deadly rare disease with no approved therapies,” added Eric Ducournau, chief executive officer of Pierre Fabre Laboratories, in the press release.¹

Red blood cells flowing realistically, 3D rendering: © Kodjovi - stock.adobe.com

The initial BLA was supported by data from the phase 3 ALLELE trial (NCT03394365).³ The global, multicenter, open-label study evaluated tab-cel for the treatment of patients with EBV-positive PTLD who were refractory to or relapsed after treatment with rituximab (Rituxan), with or without chemotherapy, following hematopoietic stem cell transplantation (HSCT) or solid organ transplant.³ Enrollment was open to patients with an ECOG performance status of 0, 1, 2, or 3.

Patients were treated with tab-cel given via intravenous infusion at a dose of 2.0 x 10⁶ cells/kg on days 1, 8, and 15. They then underwent clinical and radiographic assessment around day 28. After treatment, patients were assessed for their disease every 3 months for up to 24 months. Survival status assessment also was performed every 6 months for up to 5 years.

The primary end point of the trial was overall response rate (ORR). Secondary end points of the trial were time to response (TTR), time to best response, overall survival (OS) in responders, OS in nonresponders, progression-free survival (PFS) in responders, and rates of allograft loss/rejection episodes.

According to updated findings of the study, which were presented at the 2024 ASH Annual Meeting & Exposition, at the data cutoff date of October 9, 2023, 75 patients were enrolled, treated with tab-cel, and included in the full analysis set. The ORR among the 75 patients treated with tab-cel was 50.7% (95% CI, 38.9%-62.4%). This included a 28.0% complete response rate.⁴

The median TTR for these patients was 1.1 months (range, 0.6-9.0) and the estimated median duration of response was 23.0 months (95% CI, 12.1-not estimable [NE]). The median PFS was 23.9 months and the 12-month PFS rate was 74.2%. Further, the median OS was 18.4 months (95% CI, 6.9-NE) and the 12-month OS rate was 55.7%.

For safety, serious treatment-emergent adverse events (TEAEs) and fatal TEAEs were seen in 65.4% and 19.2% of patients after hematopoietic stem cell transplant and 61.2% and in 18.4% of patients following solid organ transplant, respectively. No fatal TEAEs were deemed to be treatment-related.

Overall, the safety profile of tab-cel was favorable and consistent with previously reported data. There were no cases of tumor flare reactions, infusion reactions, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, marrow rejection, or transmission of infectious diseases reported. In addition, no graft-vs-host disease or organ rejection AEs were deemed related to tab-cel.

REFERENCES

1. Atara Biotherapeutics provides regulatory and business update on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed January 16, 2025. https://tinyurl.com/yuc4d6jy

2. Atara Biotherapeutics announces US 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. Atara Biotherapeutics, Inc. July 17, 2024. Accessed January 16, 2025. https://tinyurl.com/mpbjp5bu

3. Mahadeo KM, Baiocchi R, Beitinjaneh A, et al. Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial. Lancet Oncol. 2024;25(3):376-387. doi:10.1016/S1470-2045(23)00649-6

4. 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