CAR T-Cell Therapy for High-Risk Lymphoma Makes Case as Standard-of-Care Treatment

CAR T-Cell Therapy for High-Risk Lymphoma Makes Case as Standard-of-Care Treatment
Burkitt's lymphoma cells, a cancer of the lymphatic system, monoclonal B-cell tumor, 3D illustration

Data from three separate clinical studies, released at the American Society Hematology (ASH) conference in December by researchers from the MD Anderson Cancer Center, showed enhanced response in patients with high-risk lymphoma when treated with axicabtagene ciloleucel (axi-cel) chimeric antigen receptor (CAR) T-cell therapy.

Axi-cel is an autologous anti-CD19 CAR T-cell therapy that has been developed by pharmaceutical company Kite, a Gilead Sciences company. The therapy, marketed under the name Yescarta, first gained FDA approval in 2017 for certain forms of large B-cell lymphoma (LBCL) and has since won approval for two other indications: for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy; and in primary mediastinal large B-cell lymphoma.

The new data for axi-cel studied efficacy in three additional indications. The Phase II ZUMA-5 trail studied its effects in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) in patients who have failed two or more prior lines of therapy. The Phase II ZUMA-12 trial expanded the findings of the ZUMA-1 trial which provided the basis for its original approval in studied patients with high-risk LBCL—a patient population where roughly 50% of patients do not achieve long-term disease remission with typical treatment approaches like chemo-immunotherapy.

Perhaps the most notable findings came from the Phase III ZUMA-7 trial which looked at its efficacy as a second line treatment in LBCL. This trial, led by Jason Westin, associate professor of Lymphoma and Myeloma, at MD Anderson, found that axi-cel showed a clinically significant advantage in event-free survival (EFS) relative to standard of care (SOC) high-dose chemotherapy with autologous stem cell transplant.

According to Westin, these results continue the progress CAR T-cell therapies are making beyond their deployment as therapeutic agents used after the failure of at least two lines of therapy—moving these treatments from the realm of palliative care, to potentially curative.

“The ZUMA-7 trial found that axi-cel was superior to high dose chemotherapy and autologous stem cell transplant for patients with aggressive lymphoma after only one prior therapy,” Westin told Inside Precision Medicine. “These results are paradigm changing—moving treatment of first relapse from the 25-year-old precedent of autologous stem cell transplant to the newer CAR T-cell therapy—but only if treating physicians refer their patients to centers with CAR T-cell expertise before starting chemotherapy.”

The ZUMA-7 trial was the first randomized Phase III trial of CAR T-cell therapy. It enrolled 359 patients with R/R LBLC to receive second-line therapy with either axi-cel (170 patients) or standard of care (179 patients).

At 24.9 months median follow-up, the researchers reported median EFS was significantly longer with axi-cel versus standard of care. Median EFS was 8.3 months for axi-cel compared to 2 months for SOC treatment. The overall response rate for axi-cel was 83% compared to 50% in SOC, with a corresponding complete response rate of 65% and 32%.

The safety of axi-cel was manageable and consistent with third-line therapy. Treatment-emergent adverse events occurred in 155 patients receiving axi-cel and in 140 patients in the SOC cohort. In those treated with axi-cel, grade 3 cytokine release syndrome occurred in 11 patients and grade 3 neurologic events occurred in 36 patients.

Westin noted that while the two Phase II ZUMA studies reported high response rates and improved survival outcomes for patients who did not achieve early response from chemotherapy, it is not yet poised to change standard of care in these instances until they have confirmed these data in a randomized trail comparing response rates.

That said, there continue to be other areas ripe for research into the efficacy of this therapy. “There are many trials exploring existing and novel CAR T-cell products in patients with lymphomas, however the upcoming trials which combine CAR T-cells with other immune facing targeted therapies are highly anticipated,” Westin added.