FDA Expends Approval for CAR-T Therapy, Tisagenlecleucel

New indication concerns treatment of adult patients with relapsed or refractory DLBCL

On 1 May 2018, the US Food and Drug Administration (FDA) approved tisagenlecleucel (Kymriah®, Novartis Pharmaceuticals Corp.) for intravenous infusion in 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) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. 

FDA granted this application priority review, breakthrough therapy designation, and orphan product designation. Full prescribing information is available  here

Kymriah® is a CD19-directed genetically modified autologous T cell immunotherapy. It is a second approved indication by FDA for this product. On 30 August 2017, FDA granted regular approval to Kymriah® for the treatment of paediatric and young adult patients up to 25 years of age with B-cell precursor acute lymphoblastic leukaemia (ALL) that is refractory or in second or later relapse. 

The FDA also approved in August 2017 tocilizumab (ACTEMRA, Genentech Inc.) for the treatment of patients 2 years of age or older with cytokine release syndrome (CRS) that occurs with CAR T cell therapy. To ensure all hospitals and their associated clinics are aware of how to manage the risks of CRS and neurological toxicities, Kymriah® is available through a Risk Evaluation and Mitigation Strategy programme. 

Kymriah® is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. In paediatric and young adult patients with r/r B-cell ALL, dosage is based on the patient weight reported at the time of leukapheresis: in patients 50 kg or less, 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight; and in patients above 50 kg, 0.1 to 2.5 x 108 CAR-positive viable T cells. Dose in adult patients with r/r DLBCL is 0.6 to 6.0 x 108 CAR-positive viable T cells.  

Kymriah® is not indicated for treatment of patients with primary central nervous system lymphoma. 

JULIET pivotal study

The FDA approval of Kymriah® in adult patients with r/r DLBCL is based on the pivotal, single-arm, open-label, multicentre phase II JULIET clinical trial (NCT02445248). It 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, Austria, France, Germany, Italy, Norway and the Netherlands. 

Eligible patients must have been treated with at least two prior lines of therapy, including an anthracycline and rituximab, or relapsed following autologous haematopoietic stem cell transplant. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy. In the JULIET trial, patients were infused in the inpatient and outpatient setting. 

In this Novartis-sponsored study, Kymriah® showed an overall response rate of 50% (95% confidence interval [CI], 38% - 62%), with 32% of patients achieving a complete response and 18% achieving a partial response 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), grade 3/4 CRS, defined by the Penn Grading Scale, occurred in 23% of patients. Grade 3/4 neurologic events occurred in 18% of all infused patients, which were managed with supportive care. Encephalopathy was seen as severe or life-threatening in 11% of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral oedema have occurred. 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 (>20%) adverse events in the JULIET study are CRS, infections, pyrexia, diarrhoea, nausea, fatigue, hypotension, oedema and headache.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

Novartis is also committed to bringing Kymriah® to patients outside the US. In January 2018, Novartis announced that the European Medicines Agency granted accelerated assessment to the Marketing Authorisation Application for Kymriah® for the treatment of children and young adults with r/r B-cell ALL and for adult patients with r/r DLBCL who are ineligible for autologous stem cell transplantation. Accelerated assessment is granted to therapies which may provide a significant improvement in the safety and effectiveness of the treatment of a serious disease, and the designation is intended to expedite the standard review time. Novartis plans additional regulatory submissions for Kymriah® in paediatric and young adult patients with r/r B-cell ALL and adult patients with r/r DLBCL beyond the US and EU in 2018.