FDA Approves Yescarta, First CAR T-Cell Therapy for Lymphoma

Treatment targets relapsed or refractory large B-cell lymphoma

The second CAR T-cell therapy approved by the FDA targets a type of lymphoma with a grim prognosis, offering new hope to patients who have often relapsed after a string of earlier treatments. The U.S. list price: $373,000.

Axicabtagene ciloleucel (Yescarta, Gilead Sciences) became the first chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of adults with relapsed or refractory large B-cell lymphoma who have undergone two or more lines of systemic therapy. The indication includes diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma). The therapy is not indicated for the treatment of patients with primary central nervous system lymphoma.

“We believe this is only the beginning for CAR-T therapies,” said Arie Belldegrun, MD, FACS, the founder of the Gilead subsidiary, Kite, that won the approval. In CAR-T therapy for hematologic cancer, a patient’s own T cells are engineered to seek and destroy cancer cells. CAR-T therapy is manufactured specifically for each individual. Gilead and Kite are accelerating studies of CAR-T therapy in multiple blood cancers.

Yescarta has a boxed warning regarding the risks of cytokine release syndrome (CRS) and neurological toxicities. The FDA has approved a risk evaluation and mitigation strategy (REMS) for Yescarta that will inform and educate health care professionals about its associated risks. Training and certification on the REMS program will be an integral part of authorization for centers offering Yescarta. Kite expects to certify 16 centers quickly and is actively working to train more than 30 additional centers, with an eventual target of 70 to 90 centers across the United States.

DLBCL is the most common aggressive non-Hodgkin’s lymphoma, accounting for three out of every five cases. In the United States each year, approximately 7,500 patients with refractory DLBCL are eligible for CAR-T therapy. Historically, when treated with the current standard of care, patients with refractory large B-cell lymphoma had a median overall survival of approximately six months, with only 7% attaining a complete response. Currently, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes and greater unmet need, since nearly half of them either do not respond or relapse shortly after transplant.

“With CAR-T therapy, we are re-engineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Many of the patients that received CAR-T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”

Yescarta, a CD19-directed genetically modified autologous T-cell immunotherapy, will be manufactured in Kite’s facility in El Segundo, California. In the ZUMA-1 pivotal trial, Kite demonstrated a 99% manufacturing success rate with a median manufacturing turnaround time of 17 days, which is important to patients given the potential for rapid disease progression.

The approval of Yescarta is supported by data from the ZUMA-1 pivotal trial. In this study, 72% of patients treated with a single infusion of Yescarta (n = 101) responded to therapy (overall response rate), including 51% of patients who had no detectable cancer remaining (complete remission; 95% confidence interval [CI], 41–62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI, 8.1 months, not estimable [NE]).

In the study, 13% of patients experienced grade 3 or higher CRS and 31% experienced neurological toxicities. The most common (at least 10%) grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections (pathogen unspecified), hypotension, hypoxia, and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia, and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred.

Source: Gilead Sciences; October 18, 2017.