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The FDA has granted a priority review to tisagenlecleucel for use in adult patients with relapsed or refractory follicular lymphoma.
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.