CAR-T confers durable clinical benefit in high-risk indolent non-Hodgkin lymphoma
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More than 90% of patients with advanced-stage indolent non-Hodgkin lymphoma had an objective response to treatment with axicabtagene ciloleucel, according to data presented at the virtual ASH Annual Meeting and Exposition.
Investigators presented the primary analysis of the phase 2 ZUMA-5 trial, which evaluated the efficacy and safety of axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) — an autologous anti-CD19 chimeric antigen receptor T-cell therapy — among patients with relapsed or refractory, advanced-stage indolent NHL.
The promising efficacy results were coupled with a manageable safety profile, according to the investigators.
“Advanced-stage indolent B-cell lymphomas are largely incurable with conventional therapies,” Caron A. Jacobson, MD, assistant professor of medicine at Harvard Medical School and medical director of the immune effector cell therapy program at Dana-Farber Cancer Institute, said during a presentation. “In particular, available third-line therapies rarely lead to complete responses and response duration is, on average, just about 1 year.”
Axicabtagene ciloleucel, also known as axi-cel, has been approved by the FDA for adults with relapsed or refractory large B-cell lymphoma after two or more lines of therapy. Kite Pharma has submitted a supplemental biologics license application to the FDA for axi-cel for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma after at least two lines of therapy.
The application was supported by data from ZUMA-5, which included 146 patients (median age, 61 years; range, 34-79; 57% men) who received axi-cel. The efficacy analysis presented at ASH included 104 patients with median follow-up of 17.5 months (range, 1.4-31.6) as of data cutoff on March 12. Eighty-four of the patients had follicular lymphoma, whereas 20 had marginal zone lymphoma.
All patients had a median three (range, 1-10) previous lines of therapy, and 86% had stage III or stage IV disease. Two-thirds of patients (68%) were refractory to their previous line of treatment.
“This was a heavily pretreated and relatively high-risk population,” Jacobson said.
Patients received a lymphodepleting chemotherapy regimen that included cyclophosphamide and fludarabine, followed by an infusion of axi-cel dosed at 2 × 106 CAR T cells/kg.
CAR T cells were successfully manufactured for all patients enrolled in the study. Manufacturing turnaround time was a median 17 days from leukapheresis to delivery at the study site.
Objective response rate assessed by independent radiology review committee served as the primary endpoint. Secondary endpoints included complete response rate, duration of response, PFS, OS and adverse events.
Efficacy results showed an ORR of 92% (95% CI, 85-97), with a complete response rate of 76% (95% CI%, 67-84). Patients with follicular lymphoma had an ORR of 94%, with a complete response rate of 80%. Patients with marginal zone lymphoma had an ORR of 85% and a complete response rate of 60%.
“Although longer follow-up is needed, these responses appear to be durable,” Jacobson said.
Sixty-four percent of patients with follicular lymphoma had an ongoing response to therapy as of data cutoff. Median duration of response, median PFS and median OS had not been reached. Researchers reported a 1-year duration of response rate of 71.7% (95% CI, 60.7-80.1), a 1-year PFS rate of 73.7% (95% CI, 63.3-81.6) and a 1-year OS rate of 92.9% (95% CI, 85.6-96.5).
Safety results showed 99% of patients treated with axicabtagene ciloleucel experienced at least one adverse event. The most common treatment-related adverse events were pyrexia (85%), neutropenia (64%) and hypotension (49%). Grade 3 or higher adverse events, experienced by 86% of patients, included cytopenias (70%) and infections (16%).
Three patients died during the study — two of causes unrelated to their disease or the study treatment and one “of multisystem organ failure in the context of (cytokine release syndrome),” according to Jacobson.
Eighty-two percent of patients developed cytokine release syndrome (CRS), including all 22 patients with marginal zone lymphoma and 97 patients (78%) in the follicular lymphoma group. Ten patients (7%) had grade 3 or greater CRS, with a median time to onset of 4 days (range, 1-15) and a median duration of 6 days (range, 1-27).
Most patients (60%) experienced neurologic toxicity, which was more common among patients with marginal zone lymphoma than follicular lymphoma (77% vs. 56%). Nineteen percent of patients had grade 3 or greater neurotoxicity, including 41% of those with marginal zone lymphoma and 15% of those with follicular lymphoma.
Median time to onset of neurotoxicity was 7 days (range, 1-177), with a median duration of 14 days (range, 1-452).
Jacobson said based on the safety results, particularly among patients with follicular lymphoma, her group plans to further evaluate axi-cel as a possible outpatient therapy for this patient population.
Perspective
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Catherine Bollard, MD
These results present CAR-T as a viable treatment option for some patients who have not responded to other therapies.
The field needs more long-term follow-up in the real-world setting to see what the true PFS ... is for these patients. The work of Jacobson and colleagues is laudable and with longer follow-up will lead to more robust data. More data will allow us to draw effective comparisons with historic survival data.
It's really exciting to see this data in the setting of lymphoma and I think it is possible to move this type of therapy up to an earlier stage in the disease treatment process.
George Washington University
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Jacobson C, et al. Abstract 700. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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