Two phase 3 randomized clinical trials involving 2 different chimeric antigen receptor (CAR) T-cell agents demonstrate the benefit of CAR T-cell therapy—specifically axicabtagene ciloleucel and lisocabtagene maraleucel—over current standard of care when used earlier in the treatment of patients with large B-cell lymphoma. The data from the 2 studies were reported at the 2021 American Society of Hematology annual meeting.
The ZUMA-7 Study
Axicabtagene ciloleucel is approved for the third-line therapy of patients with large B-cell lymphoma. ZUMA-7, a phase 3 clinical trial, examined the use of this CAR T-cell therapy in the second-line setting of patients with large B-cell lymphoma.1
At a 2-year follow-up, the median event-free survival (EFS) in patients randomized to axicabtagene ciloleucel was 8.3 months compared with 2 months in patients who were randomized to standard of care. The 24-month EFS rate was 40.5% in the axicabtagene ciloleucel arm versus 16.3% in the standard-of-care arm. At a median follow-up of 24.9 months, the EFS difference resulted in a 60% reduction in the hazard ratio with axicabtagene ciloleucel versus standard of care (95% confidence interval, 0.308-0.514; P <.0001).
These results herald a paradigm shift, emphasized Frederick L. Locke, MD, Vice Chair, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL.
“Axicabtagene ciloleucel should be a new standard for patients with second-line relapsed or refractory large B-cell lymphoma,” Dr Locke said. The finding “is remarkable and indicates that patients with lymphoma not responding to initial treatment or relapsing within 12 months should have the opportunity to get this therapy,” he suggested.
The ZUMA-7 study included 364 patients with early relapsed or refractory large B-cell lymphoma who were randomized to second-line axicabtagene ciloleucel after a conditioning chemotherapy regimen or to platinum-based chemoimmunotherapy, followed by high-dose therapy and an autologous transplant. All patients were eligible for transplant.
“By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy patients are exposed to, and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem-cell transplant,” said Dr Locke. Some 94% of patients in the axicabtagene ciloleucel arm received definitive therapy, and 36% in the standard-of-care arm underwent a transplant.
The study design did not include crossover between the 2 arms but allowed patients with disease progression to receive any therapy, including CAR T-cell therapy, as a third line or later. Ultimately, 56% of the patients who were randomized to standard of care later received CAR T-cell therapy when their cancer progressed.
The safety profiles were consistent with the known adverse events of each treatment. In the axicabtagene ciloleucel arm, 91% of the patients had grade ≥3 adverse events, including 42% serious events, compared with 83% and 40% in the standard-of-care arm. In addition, 1 treatment-related death occurred in the axicabtagene ciloleucel arm versus 2 deaths in the standard-of-care arm. The researchers will continue to follow patients for survival.
The TRANSFORM Study
The phase 3 TRANSFORM clinical trial included 184 patients with relapsed or refractory large B-cell lymphoma who were randomized either to second-line therapy with the CAR T-cell therapy lisocabtagene maraleucel (N = 92) or to standard of care (N = 92), which consisted of salvage chemotherapy. Responding patients received additional high-intensity chemotherapy, followed by stem-cell transplant.2
The interim analysis showed that the median survival of patients assigned to lisocabtagene maraleucel was 7.8 months longer than in patients who were randomized to standard of care. The median EFS was 10.1 months in the lisocabtagene maraleucel arm versus 2.3 months in the standard-of-care arm (hazard ratio, 0.35; P <.0001).
“Despite a relatively short follow-up period of just over 6 months, the positive results of this study suggest that CAR T-cell therapy has the potential to become the new standard of care for patients who do not respond to initial chemotherapy or who relapse within 12 months,” said Manali Kamdar, MD, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, Denver, who reported the results.
In addition to improving the EFS, lisocabtagene maraleucel extended the progression-free survival by 9 months compared with standard of care (P <.0001), and had a superior complete response rate (66% vs 39%, respectively; P <.0001) and overall survival rate (not reached vs 16.4 months, respectively; P = .0257).
Lisocabtagene maraleucel’s safety profile in this study was consistent with its previously reported adverse events, said Dr Kamdar. Overall, 50% of the patients in the CAR T-cell therapy arm had cytokine-release syndrome, with 1 grade 3. Neurologic events occurred in 11 patients, including 4 grade 3. No deaths were reported.
Furthermore, some patients were able to receive lisocabtagene maraleucel infusion in the outpatient clinic setting, Dr Kamdar emphasized.
“In my opinion, this is a breakthrough therapy, which has shown superiority over standard of care after decades, in terms of not just efficacy but also an extremely favorable safety profile,” she said. “We are extremely excited about the potential of this study to change the existing standard of care in these high-risk patients.”
- Locke FL, Miklos DB, Jacobson C, et al. Primary analysis of ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard-of-care therapy in patients with relapsed/refractory large B-cell lymphoma. Blood. 2021;138(suppl 1):Abstract 2.
- Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL): results from the randomized phase 3 Transform study. Blood. 2021;138(suppl 1):Abstract 91.