Tisagenlecleucel Approaches EU Approval for Relapsed/Refractory Follicular Lymphoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion recommending the approval of tisagenlecleucel (Kymriah) for use in adult patients with relapsed/refractory follicular lymphoma following 2 lines of systemic treatment.¹

The recommendation is based on findings from the phase 2 ELARA trial (NCT03568461), which showed that at a median follow-up of 16.59 months (interquartile range, 13.8-20.21), the CAR T-cell therapy elicited an objective response rate (ORR) of 86.2% (95% CI, 77.5%-92.4%), meeting the primary end point of the trial.² The complete response (CR) rate achieved with tisagenlecleucel was 69.1% (95% CI, 95% CI, 58.8%-78.3%).

“Follicular lymphoma patients will often relapse, many having shorter responses to treatment with each subsequent line of therapy,” Catherine Thieblemont, MD, PhD, professor of hematology in the Paris VII – University, France, and head of the Hemato-Oncology Unit of St-Louis Hospital, stated in a press release. “If approved, [tisagenlecleucel] may offer an effective new option with potentially definitive results for these patients with a highly favorable safety profile.”

The single-arm, international trial enrolled patients with relapsed/refractory follicular lymphoma that was grade 1, 2, or 3A and who did not have evidence of histological transformation or follicular lymphoma 3B.³ Patients needed to be at least 18 years of age, and they could not have previously received anti-CD19 therapy or have undergone allogeneic hematopoietic stem cell transplant (HSCT).

Study participants underwent screening, apheresis, and cryopreservation prior to enrollment on ELARA. Then, they had the option to receive bridging therapy as the CAR T-cell therapy was being manufactured. This was followed by restaging and receipt of lymphodepleting chemotherapy, which was comprised of intravenous (IV) fludarabine at a daily dose of 25 mg/m² IV for 3 days plus IV 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.

Patients were then given a single IV infusion of tisagenlecleucel at a dose ranging from 0.6 x 10⁸ to 6 x 10⁸ CAR-positive viable T cells. Subsequently, patients underwent their first efficacy assessment at month 3.

The primary end point of the trial was CR rate by independent review committee and Lugano classification 2014, and key secondary end points included ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics.

As of March 29, 2021, 97 of 98 enrolled patients received the CAR T-cell therapy, and 94 patients were evaluable for efficacy.

Earlier data shared at the 2021 ASCO Annual Meeting showed that the median age of all patients who were infused with tisagenlecleucel was 57.0 years (range, 29-73), and 24.7% of patients were aged 65 years or older. Moreover, 57.7% of patients had an ECOG performance status of 0, 64.9% had bulky disease at study entry, 84.5% of patients had stage III to IV disease at study entry, and 59.8% of patients had a FLIPI score of 3 or higher at study entry. The median number of prior therapies received was 4 (range, 2-13), and 27.8% of patients had received 5 or more prior lines of treatment.

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

Eighteen percent of patients received the CAR T-cell therapy in the outpatient setting, 44% of patients received bridging therapy for stabilization, and the median infused dose of tisagenlecleucel was 2.06 x 10⁸ CAR-positive viable T cells.

Additional findings presented during the meeting showed that the median DOR had not yet been reached, and the probability for a responding patient to continue to respond to treatment for at least 6 months was 79% (95% CI, 66%-87%). Notably, 12 of the 31 PRs reported with the treatment were noted to convert to CRs, and all but 1 was observed between month 3 and month 6. Moreover, the median time to the next anti-lymphoma treatment received had not yet been reached.

The median PFS (95% CI, 12.1–not evaluable [NE]) and median OS (95% CI, NE-NE) had not yet been reached either. The 6-month PFS rate with tisagenlecleucel was 76% (95% CI, 65%-84%).

Regarding safety, 99.0% of patients experienced any-grade adverse effects (AEs), with 77.3% of cases suspected to be related to the CAR T-cell therapy. Additionally, serious AEs occurred in 41.2% of patients, with 28.9% of these cases suspected to be associated with tisagenlecleucel. Three patients died, and they were noted to be due to study indication.

Investigators managed AEs with tocilizumab (Actemra) in 34% of patients, and corticosteroids in 6.4% of patients.

AEs of special interest included cytokine release syndrome (CRS) and neurological adverse reactions. All-grade CRS was reported in 48.5% of patients, and all-grade neurological toxicities were experienced by 9.3% of patients, with 1.0% of patients experiencing grade 3 or higher neurological AEs.

Other toxicities of special interest included infections (all grade, 18.6%; grade 3 or higher, 5.2%), tumor lysis syndrome (1.0%; 1.0%), prolonged depletion of B cells and/or agammaglobulinemia (all grade, 10.3%), neutropenia (30.9%; 27.8%), anemia (24.7%; 13.4%), and thrombocytopenia (16.5%; 9.3%).

Previously, in October 2021, the FDA granted a priority review to tisagenlecleucel for use in adult patients with relapsed or refractory follicular lymphoma based on data from ELARA.⁴

References

1. Novartis receives positive CHMP opinion for Kymriah CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma in Europe. News release. Novartis Pharma AG; March 25, 2022. Accessed March 25, 2022. https://yhoo.it/37UJ2zD
2. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022;28(2):325-332. doi:10.1038/s41591-021-01622-0
3. 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
4. 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 March 25, 2022. https://bit.ly/3jMIPla