Earlier Use of CAR T-Cell Therapy Approved for Relapsed Large B-cell Lymphoma Patients

Patients with large B-cell lymphoma (LBCL) who did not respond to initial treatment or relapsed within a year may now receive the CAR T-cell product axicabtagene ciloleucel (Yescarta) as a second-line therapy, following approval by the U.S. Food and Drug Administration (FDA) based on results of a recent clinical trial.

Until now, the standard of care for patients with refractory or relapsed LBCL has been second-line chemotherapy, and for responding patients, subsequent high-dose chemotherapy and autologous stem cell transplantation. CAR T-cell therapies like axicabtagene ciloleucel, or “axi-cel” were reserved for third line use for patients who either did not respond sufficiently to second-line chemotherapy or who had relapsed following high dose chemotherapy and autologous stem cell transplantation.

Dr. Caron Jacobson photographed for Paths of Progress Spring Summer 2017. Photo by Sam Ogden.

However, in the Zuma 7 clinical trial, whose results were reported last December, Yescarta given as second-line therapy proved superior to the current standard of care, reducing the risk of disease progression, death, or the need for a new therapy by 60.2%. At two years, 40.5% of patients treated with Yescarta were still alive and didn’t require additional cancer treatment or experience cancer progression, versus 16.3% for the control arm.

“We observed a clear improvement with axi-cel, as compared with standard care, in event-free survival and the percentage of patients with a response,” said the authors of a report in the New England Journal of Medicine. Caron Jacobson, MD, MMScmedical director of the Immune Effector Cell Therapy Program at Dana-Farber is third author of the report.

“This is a terrific advance for our patients who either don’t go into remission or relapse early after first-line chemotherapy,” says Jacobson. “These patients have a very low chance of benefiting from second-line chemotherapy but prior to the new approval they would not have been eligible for CAR T cells until they had failed to respond to chemotherapy. Now, we don’t need to administer ineffective therapy just to get them to their CAR T-cells in the end anyway,” Jacobson added.

The estimated 18-month event-free survival rate was 41.5% in the axicabtagene ciloleucel arm of the Zuma-7 trial and 17.0% in the standard therapy arm. The estimated median event-free survival was 8.3 months and 2.0 months, respectively. Differences in overall survival did not reach statistical significance with limited follow-up for this endpoint. Additionally, many patients who progressed on the standard of care arm went on to receive CAR T-cells in the non-trial setting under the existing FDA label for these therapies.

Challenges of large B-cell lymphoma

Large B-cell lymphoma is an aggressive, fast-growing form of non-Hodgkin lymphoma, affecting about seven of 100,000 people in the United States annually, mostly middle-aged or older adults. With appropriate treatment, about two-thirds of patients can be cured. However, patients who relapse or don’t respond to first-line therapy have a poor prognosis. Most patients in this situation are unable to receive high-dose chemotherapy and qualify for a bone-marrow or stem cell transplant.

YESCARTA uses an anti-CD19 extracellular domain to target and bind to CD19 on the surface of healthy and cancerous B cells. Image from Yescarta.

Yescarta, or axi-cel, manufactured by Kite Pharma, is made by removing the patient’s immune T-cells and sending them to the company’s laboratories, where they are engineered to equip them with a chimeric antigen receptor (CAR) that enables them to target the patient’s cancer. The CAR T cells are then re-infused into the patient’s circulation, where they seek out and attack cancer cells throughout the body.

Following the FDA’s approval on April 1 of Yescarta in the second-line setting, “referring physicians and patients can immediately begin accessing Yescarta CAR T-cell therapy for this new indication through Kite’s 112 authorized treatment centers across the U.S,” including Dana-Farber Brigham Cancer Center, the company said in a statement.

The safety of Yescarta treatment was described as manageable. However, the treatment caused high-grade adverse events in the vast majority of patients, though few had fatal effects. The incidence of cytokine release syndrome and neurologic events, which are known CAR T-cell side effects but not expected side effects of chemotherapy and autologous stem cell transplant, was higher in the axi-cel group.