FDA Grants Priority Review to Tisagenlecleucel for Relapsed/Refractory Follicular Lymphoma

FDA

The FDA has granted a priority review to tisagenlecleucel (Kymriah) for use in adult patients with relapsed or refractory follicular lymphoma. The regulatory agency also accepted a Type II Variation for the use of the CAR T-cell product in patients with relapsed/refractory follicular lymphoma following 2 prior lines of treatment.¹

The applications were supported by data from the phase 2 ELARA trial (NCT03568461), in which tisagenlecleucel elicited an objective response rate (ORR) of 86.2%, with an independent review committee (IRC)–assessed complete response (CR) rate of 66.0% in this population, meeting the primary end point.² Notably, robust responses were observed in heavily pretreated patients.

“This is an important milestone in our mission to bring [tisagenlecleucel] to adult patients with relapsed or refractory follicular lymphoma,” Jeff Logos, executive vice president and global head of Oncology & Hematology Development at Novartis. “Receiving orphan drug designation from the European Commission as well as priority review from the FDA underscores the unmet need and urgency for these patients. With [tisagenlecleucel] demonstrating impressive results in the ELARA trial, we are hopeful that we can offer a unique and potentially definitive treatment that minimizes the burden.”

Tisagenlecleucel is an autologous CD19-targeted CAR T-cell therapy that has previously been approved for use in relapsed/refractory pediatric and young adult acute lymphoblastic leukemia,³ and for relapsed/refractory large B-cell lymphoma following 2 or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.⁴

The single-arm, international phase 2 trial enrolled adults with at least 18 years of age; grade 1, 2, or 3A follicular lymphoma; and relapsed/refractory disease. Patients could not have evidence of histological transformation, nor could they previously have received anti-CD19 therapy or allogeneic hematopoietic stem cell transplant (HSCT).

First, patients underwent a screening period that comprised apheresis and cryopreservation. After enrolling to the trial, patients had the option to receive bridging chemotherapy as the CAR T-cell product was manufactured. This was followed by restaging and lymphodepletion chemotherapy, which could have consisted of fludarabine at a daily dose of 25 mg/m2 for 3 days plus cyclophosphamide at a daily dose of 250 mg/m2 for 3 days or bendamustine at a daily dose of 90 mg/m2 for 2 days. Participants then received the CAR T-cell therapy at doses ranging from 0.6 x 108 CAR-positive viable T cells to 6.0 x 108 cells.

The primary end point of the trial was CR rate by IRC and secondary end points include ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics.

As of a data cutoff of September 28, 2020, a total of 98 patients were enrolled to ELARA. All but 1 of these patients were infused with the CAR T-cell product and all who received tisagenlecleucel were evaluable for safety. Ninety-four patients were evaluable for efficacy.

The median follow-up for the 97 treated patients and the 94 patients in the efficacy set was 10.6 months (range, 4.3-19.7) and 10.9 months (range, 4.3-19.7), respectively.

The median age was 57.0 years (range, 29-73), with 24.7% of patients aged 65 years or older. Moreover, most patients had an ECOG performance status of 0 (57.7%), bulky disease at study entry (64.9%), stage III to IV disease at study entry (84.5%), and a FLIPI of 3 or higher at study entry (59.8%). The median number of prior lines of therapy was 4 (range, 2-13), with 27.8% of patients having received 5 or more prior lines of treatment.

Additionally, 36.1% previously underwent autologous HSCT, 78.4% of patients were refractory to the last line of therapy they received, 76.3% were refractory to 2 or more regimens, and 69.1% were double refractory. Previous therapies included anti-CD20 monoclonal antibodies and alkylating agents (64.9%), PI3K inhibitors (20.6%), and lenalidomide (Revlimid) and rituximab (Rituxan; 16.5%).

Additional data presented during the 2021 ASCO Annual Meeting showed that the median DOR was not yet reached with the CAR T-cell therapy. The probability for a responding patient to continue to respond at 6 months or longer was 79% (95% CI, 66%-87%). Of 31 patients who achieved a partial response, 38.7% converted to CRs; all but 1 occurred between months 3 and 6. The median time to the next anti-lymphoma therapy was not yet reached.

The median PFS (95% CI, 12.1–not evaluable [NE]) and the median OS (95% CI, NE–NE) were both not yet reached. The PFS rate at 6 months with tisagenlecleucel was 76% (95% CI, 65%-84%).

Additionally, cellular kinetic parameters for the CAR T-cell product were estimated using transgene levels in peripheral blood (n = 94). In responding patients, the persistence of CAR transgene was noted for up to 370 days; in non-responding patients, persistence was observed for 187 days. The persistence was anticipated to increase with additional follow-up.

Regarding safety, 99.0% of patients experienced any-grade adverse effects (AEs) with the CAR T-cell product and 77.3% of AEs were suspected to be associated with the treatment. Moreover, 41.2% of patients experienced a serious AE with 28.9% of them suspected to be related to the study drug. Additionally, 76.3% of patients reported grade 3 or 4 AEs, with 45.4% of these effects thought to be drug related. Toxicities were managed by tocilizumab (Actemra) in 34% of patients and corticosteroids in 6.4%.

Three deaths were reported on the trial, with all attributed to the study indication.

Additionally, 48.5% of patients experienced cytokine release syndrome (CRS) and 9.3% had neurological adverse reactions. The median onset for CRS was 4.0 days (range, 1-14) and all cases were low grade.

Previously, tisagenlecleucel was granted an orphan medicinal product designation by the European Commission for follicular lymphoma.

References

1. Novartis receives priority review by US FDA and filing acceptance by EMA for Kymriah to treat patients with relapsed or refractory follicular lymphoma. News release. Novartis. October 27, 2021. Accessed October 28, 2021. https://bit.ly/3jMIPla
2. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (tisa-cel) in adult patients (pts) with relapsed/refractory follicular lymphoma (r/r FL): primary analysis of the phase 2 Elara trial. J Clin Oncol. 2021;39(suppl 15):7508. doi:10.1200/JCO.2021.39.15_suppl.7508
3. FDA approval brings first gene therapy to the United States. News release. FDA. August 30, 2017. Accessed October 28, 2021. https://bit.ly/3bjqPuf
4. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed October 28, 2021. https://bit.ly/2WlsomW