FDA approves Kymriah for large B-cell lymphoma as second indication for CAR-T therapy.- Novartis.

The FDA has approved Kymriah (tisagenlecleucel) suspension, from Novartis, for intravenous infusion for its second indication - the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Kymriah is not indicated for the treatment of patients with primary central nervous system lymphoma.

The FDA approval of Kymriah in adult patients with r/r DLBCL is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET was conducted in collaboration with Penn, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.

In this study, Kymriah showed an overall response rate (ORR) of 50% (95% confidence interval [CI], 38% - 62%), with 32% of patients achieving a complete response (CR) and 18% achieving a partial response (PR) in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response. In all patients infused with Kymriah (n=106), severe or life-threatening (grade 3/4) CRS, defined by the Penn Grading Scale -a rigorous scale for grading this reaction-, occurred in 23% of patients.

There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred. Eighteen percent of all infused patients experienced grade 3/4 neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR-T therapies, was seen as severe or life-threatening in 11% of patients. Grade 3/4 cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25%. The most common (more than 20%) adverse events (AEs) in the JULIET study are CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema and headache.

Comment: CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. Kymriah became the first chimeric antigen receptor T cell (CAR-T) therapy to receive regulatory approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Kymriah is now the only CAR-T cell therapy to receive FDA approval for two distinct indications in non-Hodgkin lymphoma (NHL) and B-cell ALL.