The approval was based on data from the phase 2 ELARA clinical trial, in which a complete response of more than 65% was observed.
The FDA has granted accelerated approval to tisagenlecleucel (Kymriah) for the treatment of adult patients with relapsed or refractory follicular lymphoma following 2 or more lines of systemic therapy.1
The regulatory decision is based on data from the phase 2 ELARA trial (NCT03568461), in which the CAR T-cell therapy produced an objective response rate (ORR) of 86.2%, with an independent review committee (IRC)–assessed complete response (CR) rate of 66.0%, meeting the primary end point of the trial.2 Notably, robust responses were noted in heavily pretreated patients.
"We are proud of today's FDA approval of a third indication for [tisagenlecleucel'. We hope this treatment option that has the potential for long-lasting results may help break the unrelenting cycle of treatment for patients with follicular lymphoma," Victor Bulto, president of Novartis Innovative Medicines US, stated in a press release. "We are on a mission to build on our pioneering work in cell therapy and continue to innovate for patient impact."
Adults who were at least 18 years of age; had grade 1, 2, or 3A follicular lymphoma; and relapsed/refractory disease were enrolled to the single-arm, international phase 2 trial. Patients could not have evidence of histological transformation, nor could they have received prior anti-CD19 therapy or have previously underwent allogeneic hematopoietic stem cell transplant (HSCT).
Patients first underwent a screening period that included apheresis and cryopreservation. After enrolling to the trial, patients had the option to receive bridging chemotherapy as tisagenlecleucel was manufactured. This was followed by restaging and lymphodepletion chemotherapy, which could have comprised fludarabine at 25 mg/m2 daily for 3 days plus cyclophosphamide at 250 mg/m2 daily for 3 days or bendamustine at 90 mg/m2 daily for 2 days. Participants then received tisagenlecleucel at doses that ranged from 0.6 x 108 CAR-positive viable T cells to 6.0 x 108 cells.
The primary end point was CR rate by IRC. Secondary end points comprised 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, 98 patients were enrolled to the trial, and all but 1 of these patients were infused with the CAR T-cell therapy. All who received tisagenlecleucel were determined to be evaluable for safety, and 94 patients were deemed to be 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.
Additional data presented during the 2021 ASCO Annual Meeting revealed that the median DOR was not yet reached with tisagenlecleucel. However, 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 experienced a partial response to treatment, 38.7% converted to CRs; all but 1 occurred between months 3 and 6. Moreover, the median time to the next anti-lymphoma therapy received 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. Additionally, the 6-month PFS rate was 76% (95% CI, 65%-84%).
Ninety-nine percent of patients experienced any-grade adverse effects (AEs) with the CAR T-cell product and 77.3% of AEs were suspected to be linked with tisagenlecleucel. 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 occurred 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.