FDA Grants Priority Review to Tisagenlecleucel for R/R Follicular Lymphoma

The FDA has accepted and granted priority review to a biologics license application (BLA) for tisagenlecleucel (Kymriah) as a potential treatment for relapsed or refractory follicular lymphoma (FL) after 2 lines of therapy, announced Novartis, in a press release.¹

The BLA is supported by findings from the pivotal phase 2 ELARA clinical trial for which results were presented during the 2021 American Society of Clinical Oncology Annual Meeting. In the study, tisagenlecleucel elicited robust responses in heavily pretreated patients with relapsed or refractory FL, meeting the primary end point of complete response rate (CRR) in ELARA. Further, the result showed a tolerable safety profile.^1,2

“This is an important milestone in our mission to bring Kymriah to adult patients with relapsed or refractory follicular lymphoma. 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 Kymriah demonstrating impressive results in the ELARA trial, we are hopeful that we can offer a unique and potentially definitive treatment that minimizes the burden,” said Jeff Legos, executive vice president, Global Head of Oncology & Hematology Development, Novartis, in a press release.¹

In the single arm, multicenter, open-label phase 2 trial, 97 patients with relapsed/refractory FL were evaluated on treatment with tisagenlecleucel dosed at 6-6 ×108 CAR + viable T cells after lymphodepleting chemotherapy. The secondary end points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival, safety, and cellular kinetics.²

At baseline, the population had a median age of 57 years (range, 29-73). Stage III to IV disease was observed in 85% of patients at baseline, 60% had a FLIPI score of 3 or higher, 65% had bulky disease, and 42% had a lactate dehydrogenase above the upper limit of normal. In terms of prior treatment, the study population had a median of 4 prior lines of therapy (range, 2-13). Seventy-eight percent of patients were refractory to their last treatment, and 60% progressed within 2 years of receiving initial anti-CD20-based therapy.

In the 94 patients evaluable for response, the CRR was 66% (95% CI, 56%-76%). The ORR observed with tisagenlecleucel in the study was 86% (95% CI, 78%-92%), and notably both the primary and key secondary end points were comparable across the key high-risk subgroups evaluated in the study.

The estimated DOR rate at 6 months was 95% (95% CI, 82%-98%), and the estimated PFS rate at 6 months was 76% (95% CI, 65%-84%).

In terms of safety, grade 3 or higher adverse events (AEs) were seen in 65% of patients within 8 weeks after infusion of tisagenlecleucel. The most common AEs observed with neutropenia in 28% of patients and anemia in 13%. Cytokine release syndrome (CRS) of any grade occurred in 49% of patients, but notably, no cases were grade 3. There were 3 deaths in the study due to progressive disease.

An analysis of the cellular kinetics of tisagenlecleucel showed that for up to 370 days the persistence of CAR transgene was observed in responding patients and it was seen for up to 187 days in non-responders. There was a comparable chance of achieving a response across dose quartiles, and there was no correlation between dose of tisagenlecleucel and the probability of patients experiencing a CRS or neurologic event.

Outside of the FL space, tisagenlecleucel is already FDA approved to treat relapsed/refractory acute lymphoblastic leukemia in pediatric and young adult patients up to age 25, as well as those with relapsed/refractory diffuse large B-cell lymphoma.¹

_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 27, 2021. https://bit.ly/3bdIK5w}

_{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(15): 7508-7508. doi: 10.1200/JCO.2021.39.15_suppl.7508}