Tisagenlecleucel Misses EFS End Point in Aggressive B-cell Non-Hodgkin Lymphoma Trial

Treatment with the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) in patients with aggressive B-cell non-Hodgkin lymphoma after relapse or lack of response to first-line treatment, did not improve event-free survival (EFS) compared with the standard of care, missing the primary end point of the phase 3 BELINDA study, according to a press release issued by Novartis.¹

The safety profile of tisagenlecleucel in the study appeared to be consistent with prior reports.

“Patients with aggressive B-cell non-Hodgkin lymphoma who are refractory to first-line treatment are vulnerable and we are disappointed that the BELINDA study did not meet its primary endpoint in this setting,” said Jeff Legos, executive vice president and global head of Oncology & Hematology Development. “Kymriah continues to demonstrate durable responses for patients with certain advanced blood cancers in the third-line setting. We remain committed to accelerating the development of Kymriah and our next-generation CAR Ts and anticipate sharing early clinical results for these therapies at an upcoming medical meeting.”

BELINDA is a randomized, open-label study (NCT03570892) in which salvage chemotherapy, the standard of care, was challenged by tisagenlecleucel. The key secondary end points of the study included EFS per local investigator assessment, overall survival, overall response rate, duration of response, and time to response.

The patients included in the study had histologically confirmed, aggressive B-cell non-Hodgkin lymphoma that was relapsed or refractory to frontline therapy. Multiple subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, and follicular lymphoma were included. Patients were required to have an ECOG performance status of 0 or 1 and adequate organ function to enroll.

This primary end point result follows positive data observed with tisagenlecleucel as treatment of patients with relapsed/refractory follicular lymphoma in phase 2 ELARA clinical trial (NCT03568461). In the study, the CAR T-cell agent induces durable responses in patients with relapsed/refractory follicular lymphoma following treatment with at least 2 prior regimens.²

Tisagenlecleucel was administered as a single intravenous (IV) infusion in doses ranging from 0.6 to 6 x 10⁸ CAR-positive viable T cells. In the comparator arm, patients received lymphodepleting chemotherapy at 25 mg/m² by IV. The chemotherapy consisted of fludarabine daily for 3 days plus 250 mg/m², IV cyclophosphamide daily for 3 days or 90 mg/m², and IV bendamustine daily for 2 days.

At baseline, the patient population had a median age of 57.0 years (range, 29-73). The majority of patients had an ECOG performance status of 0 (57.7%). In terms of history, the median number of prior treatments was 4 (range, 2-13), and the majority of patients were refractory to at least 2 regimens (76.3%). Moreover, a total of 20.6% of patients had received prior treatment with a PI3K inhibitor.

At a median follow-up of 10.9 months, the objective response rate with 86.2%. Responses included complete responses in 66.0% of patients, meeting the study’s primary end point.

In terms of safety, all-grade and grade 3 or greater cytokine release syndrome (CRS) was observed in 48.5% in the tisagenlecleucel arm compared with 0% of the control. Any-grade and grade 3 or greater neurological adverse reactions occurred in 9.3% versus 1.0% of patients, respectively. There were no treatment-related mortalities were reported in the study.

Further evaluation of tisagenlecleucel in the BELINDA study data is ongoing and will be presented in the future.

“We were hopeful the BELINDA study would show that Kymriah could improve outcomes and the overall treatment experience for these patients in need. The study investigators will work together with Novartis in the coming weeks and months to understand the factors that contributed to this outcome,” said Michael R. Bishop, MD, professor of Medicine and director of the Hematopoietic Stem Cell Transplantation Program, University of Chicago Medicine and BELINDA Steering Committee chair.

_References:

_{1. Novartis provides update on BELINDA study investigating Kymriah® as second-line treatment in aggressive B-cell non-Hodgkin lymphoma. News release. August 24, 2021. Accessed August 24, 2021. https://bit.ly/3DieROm}

_{2. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: 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}