CAR-T effective as first-line therapy for high-risk large B-cell lymphoma
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First-line therapy with axicabtagene ciloleucel induced an objective response in 85% of patients with high-risk large B-cell lymphoma, according to phase 2 study results presented at the virtual ASH Annual Meeting and Exposition.
The autologous anti-CD19 chimeric antigen receptor T-cell therapy demonstrated substantial clinical benefit among this patient population and had a manageable safety profile, according to Sattva S. Neelapu, MD, professor and deputy chair of the department of lymphoma/myeloma in the division of cancer medicine at The University of Texas MD Anderson Cancer Center.
Axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 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.
The multicenter, open-label ZUMA-12 study is the first to evaluate CAR T-cell therapy as first-line therapy among patients with high‐risk large B-cell lymphoma, Neelapu told Healio.
“I think there are only advantages in using CAR-T earlier, as the T cells are expected to be more functional and more effective,” he said.
“Chemotherapy cures about 60% of patients with large B-cell lymphoma, but it is usually given over a 6-month period. CAR-T has the potential to achieve similar or better efficacy with a single infusion [and] therapy completed within a month,” he added.
ZUMA-12 enrolled 37 patients, including 32 (median age, 61 years; range, 23-86; 72% men) who underwent lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by an infusion of axi-cel at a dose of 2 × 106 CAR T cells/kg.
Eighty-eight percent of patients had stage III or stage IV disease, and all had at least one previous line of systemic therapy. Thirteen patients (41%) were aged 65 years or older.
Complete response according to investigator assessment using the Lugano classification staging system served as the study’s primary endpoint. Secondary endpoints included objective response rate, duration of response, EFS, PFS, OS and safety.
Median follow-up was 9.3 months (range, 0.9-18) among 27 patients eligible for the interim efficacy analysis and 9.5 months (range, 0.9-18) among 32 patients eligible for the safety analysis. The data cutoff date was Aug. 25, 2020.
Results showed an ORR of 85%, with a complete response rate of 74%. Eleven percent had a partial response to therapy and 15% had stable disease.
Nineteen patients (70%) had an ongoing response to therapy as of the data cutoff date. Five patients (19%) converted from a partial response or stable disease to a complete response.
Median duration of response, median PFS and median OS had not yet been reached.
“The expected complete response rate in this high-risk patient population with current standard-of-care chemoimmunotherapy is less than 50%,” Neelapu told Healio. “In the ZUMA-12 study, we observed a 74% complete response rate, which is a significant improvement.”
All patients experience at least one treatment-related adverse event. The most common grade 3 or greater treatment-related adverse events included encephalopathy (16%), increased alanine aminotransferase levels (9%) and decreased neutrophil count (9%).
One patient died during the study due to COVID-19.
All patients experienced cytokine release syndrome (CRS), including three patients (9%) with grade 3 CRS. Median time to CRS onset was 4 days (range, 1-10), with median duration of 6 days (range, 1-13). All cases of CRS were resolved.
Neurologic events occurred in 22 patients (69%), with eight patients (25%) having grade 3 or greater neurologic symptoms. Two patients (6%) had unresolved neurological events as of the data cutoff date.
Median time to onset of neurotoxicity was 9 days (range, 2-44), with median duration of 6 days (range, 1-54).
Neelapu said one of the perceived advantages of moving CAR-T to the first line of therapy is the belief that the cells used for the manufacturing will produce a more potent product.
“The fitness of the T cells could be affected by multiple lines of chemotherapy treatment,” he told Healio. “Therefore, CAR T cells generated from patients who received only two cycles of chemotherapy, as in this study, are likely to be more functional and exert superior efficacy.”
He said the hypothesis is supported by the data accumulated so far in the study. Neelapu and colleagues observed that peak CAR T-cell expansion was higher in ZUMA-12 than in ZUMA-1, the pivotal study of axi-cel that led to its FDA approval. The CAR T cells in ZUMA-12, however, used cells from patients who had received at least two previous lines of therapy.
Neelapu said demonstrating the superiority of CAR T-cell therapy for high-risk large B-cell lymphoma would require a large, randomized study.
“We hope to report the primary analysis of the trial sometime next year with data from 40 patients and with longer follow-up,” he told Healio. “If the response rates and durability are confirmed, it would provide support to design a randomized phase 3 study to compare axi-cel with the current standard of care of chemoimmunotherapy in this high-risk patient population with an unmet need.”
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