Quality-adjusted time without symptoms or toxicity: analysis of axicabtagene ciloleucel versus standard of care in patients with relapsed/refractory large b-cell lymphoma: Q-TWiST analysis of axi-cel versus standard of care

Background

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison, which partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (NCT03391466), a phase 3, randomized, open-label, multicenter study was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T-cell therapy, compared with standard of care (SOC; platinum-based salvage chemotherapy with autologous stem cell transplant [ASCT] consolidation) as a second-line treatment for relapsed/refractory large B-cell lymphoma (R/R LBCL), and met its primary endpoint of improved event-free survival (EFS).

Objective

To use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel vs SOC who were enrolled in ZUMA-7.

Study design

Pre-planned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade 3 or higher adverse events before event as defined in the EFS analysis (TOX), time without severe toxicity before event (TWiST), and time after event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat (ITT) cohort at median follow-up. A relative Q-TWiST gain of 10% was "clinically important" and 15% or more was "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up durations from 3 months to the maximum follow-up and subgroup analyses by age and relapse/refractory status were explored.

Results

At 23.5 months follow-up, the axi-cel cohort showed significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months vs 5.39 months, respectively. Mean TOX was 1.16 months vs 0.74 months, and mean REL was 6.02 months vs 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 (95% CI: 2.3, 5.2) months, representing a relative gain of 21.9%. This was reflected across all subgroups, with Q-TWiST gains estimated to be 3.1 (95% CI: 1.5, 4.9) and 5.2 (95% CI: 2.4, 7.9) months for those <65 and ≥65 years, respectively, and 3.2 (95% CI: 1.4, 4.9), 9.1 (95% CI: 3.9, 13.5), and 4.1 (95% CI: 1.1, 7.1) months for individuals with primary refractory disease, relapse within 6 months, and relapse between 6 and 12 months, respectively. The Q-TWiST gain for axi-cel was also statistically significant across follow-up durations, increasing from 0.2 (95% CI: 0.1, 0.3) months at 3 months' follow-up to 4.9 (95% CI: 2.4, 7.8) months at the maximum follow-up of 37.7 months.

Conclusions

Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence of benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

Authors M J Kersten, Y Qiao, R Shah, C Solem, J T Snider, C To, P Cheng, C Spooner, M-A Perales
Journal Transplantation and cellular therapy
Therapeutic Areas Oncology
Centers of Excellence Strategic Market Access
Year 2023
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