Clinical Trial of Tisagenlecleucel in Aggressive B-cell Non-Hodgkin Lymphoma Fails to Meet Primary Endpoint

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy already indicated for B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma.

Updated findings from the BELINDA study have found that tisagenlecleucel (Kymriah; Novartis) failed to meet its primary endpoint of event-free survival among patients with aggressive B-cell non-Hodgkin lymphoma who had primary refractory disease or who relapsed within 12 months of first-line treatment, according to a Novartis press release.

“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 and hematology development at Novartis, in the press release. “Kymriah continues to demonstrate durable responses for patients with certain advanced blood cancers in the third-line setting.”

The phase 3, randomized, open label, multicenter study evaluated the efficacy of tisagenlecleucel compared with standard-of-care salvage chemotherapy followed by high-dose chemotherapy and stem cell transplant in responding patients. The safety profile was consistent with the established profile of tisagenlecleucel.

The trial enrolled patients from more than 73 sites in 18 countries worldwide and had a primary endpoint of event-free survival, which was defined as the time from the date of randomization to the date of the first documented disease progression or stable disease at or after the week 12 assessment, or death at any time. Secondary endpoints included event-free survival, overall survival, overall response rate, duration of response, time to response, and safety. Patients in the control arm had the opportunity to cross over to receive tisagenlecleucel upon progression.

The drug is a CD19-directed genetically modified autologous T cell immunotherapy. It is already indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. It is also indicated for adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma and diffuse large B-cell lymphoma arising from follicular lymphoma.

Tisagenlecleucel can cause severe or life-threatening adverse effects, including cytokine release syndrome and neurological toxicities. Patients with cytokine release syndrome may experience symptoms such as difficulty breathing, fever, chills, severe nausea, vomiting or diarrhea, severe muscle or joint pain, low blood pressure, or dizziness.

Patients with neurological toxicities can experience altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Because of these risks, tisagenlecleucel is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

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

REFERENCE

Novartis provides update on BELINDA study investigating Kymriah as second-line treatment in aggressive B-cell non-Hodgkin lymphoma. News release. Novartis; August 24, 2021. Accessed August 25, 2021. https://www.novartis.com/news/media-releases/novartis-provides-update-belinda-study-investigating-kymriah-second-line-treatment-aggressive-b-cell-non-hodgkin-lymphoma