Axicabtagene Ciloleucel Shows QoL Benefit as Second-Line LBCL Therapy

Mahmoud Elsawy, MD, MSc

Investigators observed a clinically meaningful quality of life (QoL) improvement due to axicabtagene ciloleucel (axi-cel; Yescarta), an autologous anti-CD19 CAR T-cell therapy, at day 100 compared with standard of care (SOC) as a second-line treatment of patients with relapsed/refractory large B-cell lymphoma (LBCL), based on a QoL analysis of the phase 3 ZUMA-7 trial (NCT03391466) that was presented at the 2021 ASH Annual Meeting and Exposition.

Using the patient-reported outcome (PRO) instruments EORTC QLQ-C30, EQ-5D-5L, and Work Productivity and Activity Impairment: General Health (WPAI), investigators reported patients treated with axi-cel (n = 165) in the QoL analysis set assessed at day 100 achieved a statistically significant difference in mean change of scores from baseline in favor of axi-cel vs SOC (n = 131).¹ Patients had a change from baseline in favor of axi-cel at day 100 in the prespecified PRO end points for EORTC QLQ-C30 physical functioning (P < .0001), EORTC QLQ-C30 global health status/QoL (P < .0001), and EQ-5D-5L visual analog scale (VAS; P < .0001).

“Sensitivity analyses controlling for covariates and patterns of missingness showed similar results with retained significance at day 100,” said Mahmoud Elsawy, MD, MSc, an assistant professor in the Division of Hematology at Dalhousie University in Halifax, Nova Scotia. “[Furthermore] the mean estimated scores for the axi-cel arm returned to or exceeded the scores at baseline by day 100 to day 150 vs month 9 or later in the SOC arm.”

EORTC QLQ-C30 is a cancer-specific 30-item questionnaire that includes global health status and functional and symptom scales. The questionnaire has functional scales for physical, role, emotional, cognitive, and social functioning. Symptom scales include fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.

EQ-5D-5L is a general questionnaire with 5 QoL domains plus a global assessment. The domains include mobility, self-care, usual activities, pain/discomfort, and anxiety and depression. The VAS provides a rating of global assessment of the patient’s state of health on the day of assessment.

WPAI measures work productivity and activity impairment. The instrument has scales for absenteeism, presenteeism, overall work impairment, and activity impairment.

Eligible adult patients underwent an initial disease assessment prior to treatment and were reassessed at day 50, 100, 150, and month 9, then every 3 months thereafter from randomization up to 24 months or at the time of an event-free survival (EFS) event, whichever occurred first. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 physical functioning, EORTC QLQ-C30 global health status/QoL, and EQ-5D-5L VAS) were tested using a mixed-effect model with repeated measures at day 100 and subsequent time points if previous time points were found to be statistically insignificant.

Investigators defined clinically meaningful change as 10 points for each EORTC QLQ-C30 score, 7 points for the EQ-5D-5L VAS score, and 0.06 for the EQ-5D-5L index. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed.

Axi-cel showed a favorable statistically significant change from baseline (P < .05) at day 100 in the EORTC QLQ-C30 scales for nausea and vomiting, diarrhea, insomnia, and appetite loss. Statistically significant changes from baseline were also seen in role functioning at days 100 and 150. Social functioning, fatigue, and dyspnea measures all moved favorably in a statistically significant manner for axi-cel at day 100, day 150, and month 9.

Regarding the WPAI PRO instrument, investigators reported that patients treated with axi-cel had statistically significant (P < .05) lower mean absenteeism, and lower mean activities impairment at day 100 compared with those receiving SOC treatment.

ZUMA-7 enrolled a total of 359 adult across 77 sites in the United States, Canada, Europe, and Israel. Patients were randomized 1:1 to receive either conditioning chemotherapy plus axi-cel or SOC investigator-selected platinum-based chemotherapy for at least 2 cycles. Responding patients in the SOC arm proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) and nonresponding patients were given additional treatment off of study protocol.

Patients with relapsed/refractory LBCL who a maximum of 1 year removed from their first-line therapy were eligible for the trial. Eligible patients also needed to intend to proceed to HDT-ASCT. Optional steroid-bridging therapy was permitted.

The primary end point of the trial was EFS by blinded central review. The key secondary end points were objective response rate and overall survival. Additional secondary end points included progression-free survival, safety, and PROs.

Baseline patient demographics for patients included in the QoL analysis set were comparable. Among the 165-patient axi-cel group, 28% were at least 65 years old vs 32% in the SOC group (n = 131). Most patients in both arms were primary refractory (72% vs 68%, respectively) and were negative for double/triple hit status per investigator (62% vs 58%, respectively). Investigators noted a second-line age-adjusted International Prognostic Index score of 2 or 3 in 42% of the axi-cel arm and 43% of the SOC arm.

“Score comparisons at later timepoints warrant cautious interpretation because attrition due to disease progression, new lymphoma therapy, or death was disproportionately higher on the SOC arm and may select patients with the best outcomes,” Elsawy said. “[Nonetheless] the superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line relapsed/refractory LBCL.”

_Reference:

_{1. Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in a phase 3, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel (axi-cel) versus standard of care therapy in patients with relapsed/refractory large b-cell lymphoma (ZUMA-7). Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 430.}