Patient-reported outcomes in phase III ZUMA-7 trial: axicabtagene versus standard of care in R/R LBCL

Introduction

Relapsed/refractory (R/R) large B-cell lymphoma (LBCL) is a high-risk lymphoma associated with poor prognosis and treatment outcomes. Additionally, around 50% of patients with R/R LBCL are ineligible for a second-line standard of care (SOC) high-dose chemotherapy and allogeneic stem cell transplantation. The introduction of CAR T-cell therapies such as axicabtagene ciloleucel (axi-cel) as a third-line therapy has greatly improved clinical practice in these populations; however, there has been a shift in treatment as recent data reveal the promising potential of CAR T-cell therapy as second-line therapy for the treatment of patients with R/R LBCL.¹

The Lymphoma Hub previously published an article on the primary analysis results of phase III ZUMA-7 trial (NCT03391466). Below, we summarize the recently published article by Elsawy M, et al. in Blood on patient-reported outcomes (PRO) of the ZUMA-7 trial.²

Study design

For the 296 people included in the QoL analysis set, eligible patients were:

• ≥18 years of age with histologically diagnosed LBCL per World Health Organization (WHO) 2016 criteria;
• R/R within 12 months of first-line chemoimmunotherapy, including an anti-CD20 monoclonal antibody and anthracycline-containing regimen; and
• anticipated to receive high-dose chemotherapy and allogenic stem cell transplantation if they achieved a successful response to initial chemoimmunotherapy.

The following PRO instruments were administered at baseline, Day 50, Day 100, Day 150, Month 9, every 3 months up until Month 24, or until disease progression, death, or new lymphoma therapy: European organization for research and treatment of cancer Quality of Life Questionnaire Core 30 (EORTCQLQ-C30), EuroQol 5-Dimension 5-Level (EQ-5D-5L), and the Work Productivity and Activity Impairment Questionnaire: General Health version 2.0 (WPAI:GH version v2.0).

The prespecified secondary endpoints were global health status and physical functioning by EORTC QLQ-C30, and visual analogue score (VAS) by EQ-5D-5L. Additional exploratory endpoints included other domains of EORTC QLQ-C30, EQ-5D-5L health index score, and WPAI:GH v2.0. Details of the assessments are summarized in Table 1.

Table 1. PRO instruments used to assess QoL in patients with LBCL*

EORTC QLQ-C30, European organization for research and treatment of cancer Quality of Life Questionnaire Core 30; EQ-5D-5L, EuroQol 5-Dimension 5-Level; VAS, visual analogue scale; WPAI:GH v2.0, Work Productivity and Activity Impairment Questionnaire: General Health version 2.0. *Data from Elsawy, et al.2 †Higher scores relate to a higher level of symptoms/ function.
Instrument	Details	Metric	Time period
EORTC QLQ-C30	30-item questionnaire consisting of a functional (physical, role, cognitive, emotional, and social), symptom (fatigue, pain, nausea, and vomiting), and global health status scale.	0–100†	1-week recall period
EQ-5D-5L	Two-part self-reported instrument, measuring health-related Qol in 2 parts: 1. EQ-5D-5L and 5Q-5D-5L-VAS 5Q-5D-5L: covers 5 dimensions mobility, self-care, usual activities, pain/discomfort, anxiety/depression across 5 severity levels (no problem; slight problems; moderate problems; severe problems; and extreme problems. 2. 5Q-5D-5L VAS: self-rated global health assessment.	5Q-5D-5L: health utility index – single global scale, where 0 signifies death and 1 represents perfect health VAS: 0-100, where 0 represents the worse health and 100 means the best health	On the assessment day
WPAI:GH v2.0	Measures work activity and productivity of employed patients across four areas: absenteeism (number of work hours missed), presenteeism (degree in which health impact work productivity), overall work impairment, and activity impairment.	Expressed as a percentage	7 days

Results

Baseline characteristics

Baseline characteristics for the 296 patients included in the QoL analysis set are summarized in Table 2.

Table 2. Selected baseline and demographic characteristics for axi-cel vs SOC cohort*

Axi-cel, axicabtagene ciloleucel; BCL2, B-cell lymphoma 2; BCL6, B-cell lymphoma 6; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HGBCL, high grade B-cell lymphoma; GCB, germinal center B-cell LBCL, large B cell lymphoma; IPI, international prognostic index; MYC, MYC gene; NOS, not otherwise specified; SOC, standard of care. *Data from Elsawy, et al.2
Characteristic, % (unless otherwise stated)	Axi-cel arm (n = 165)	SOC arm (n = 131)
Age group
<65 years	72.1	67.9
≥65 years	27.9	32.1
Sex
Female	38.8	27.5
Male	61.2	72.5
Observed baseline ECOG PS
0	53.9	61.8
1	46.1	38.2
Response to first-line therapy
Primary refractory	72.1	67.9
Relapse ≤6 months of first line                therapy	5.5	5.3
Relapse >6 and ≤12 months of first                line therapy	22.4	26.7
Second-line age-adjusted IPI total score
0–1	58.2	57.3
2–3	41.8	42.7
Disease type per investigator
DLBCL NOS	61.2	65.6
HGBL with or without MYC and                BCL2 and/or BCL6 rearrangement	22.4	13.0
Large-cell transformation from                follicular lymphoma	11.5	16.0
Other	4.8	5.3
Cell of origin (molecular subgroup)
GCB	52.7	42.7
Non-GCB	26.7	30.5
Not tested	20.6	26.7
Double-/triple-hit status per investigator
HGBL double hit	17.6	8.4
HGBL triple hit	3.6	8.4
Negative	61.8	58.0
Not tested	17.0	25.2

Patient-reported outcomes

A statistically significant and clinically meaningful difference between the mean change in scores from baseline was observed at Day 100 for the prespecified endpoints, favoring axi-cel over SOC (Table 3). Similarly, improvements in the mean change in EORTC global health status and 5Q-VAS scores from baseline were observed favoring axi-cel over SOC on Day 150. However, the difference was only clinically meaningful for EQ-5D-5L VAS. Overall, axi-cel surpassed the mean estimated scores at baseline by Day 150 for PROs compared to Month 9 or later for the SOC cohort.

Table 3. Estimated score differences from baseline to Day 100 and Day 150 for prespecified PRO*

EORTC QLQ-C30, European organization for research and treatment of cancer Quality of Life Questionnaire Core 30; EQ-5D-5L, EuroQol 5-Dimension 5-Level; PRO, patient-reported outcome; VAS, visual analogue scale; WPAI, Work Productivity and Activity Impairment. *Data from Elsawy, et al.2 †Unadjusted.
Prespecified PRO	Visit
	Day 100 (p value)†	Day 150 (p value)†
Primary endpoints
EORTC QLQ-C30 global health status/QoL	18.1 (p < 0.001)	9.8 (p = 0.0077)
EORTC QLQ-C30 physical functioning	13.1 (p < 0.001)	5.1 (p = 0.0940)
EQ-5D-5L VAS	13.7 (p < 0.001)	11.3 (p = 0.0002)
Secondary endpoints
EORTC QLQ-C30 role functioning	19.8 (p < 0.001)	15.1 (p = 0.0007)
EORTC QLQ-C30 emotional functioning	6.1 (p < 0.001)	4.8 (p = 0.0834)
EORTC QLQ–C30 cognitive functioning	5.0 (p < 0.001)	4.8 (p = nd)
EORTC QLQ–C30 social functioning	22.8 (p < 0.001)	16.9 (p < 0.001)
EORTC QLQ-C30 Fatigue	- 20.4 (p < 0.001)	-14.4 (p < 0.001)
EORTC QLQ-C30 nausea and vomiting	-12.0 (p < 0.001)	-3.0 (p = 0.1688)
EORTC QLQ-C30 pain	3.4 (p < 0.001)	6.2 (p = nd)
EORTC QLQ–C30 dyspnea	-16.9 (p < 0.001)	-13.8 (p = 0.0019)
EORTC QLQ-C30 insomnia	-10.5 (p < 0.001)	-4.7 (p = 0.2919)
EORTC QLQ-C30 appetite loss	-22.4 (p < 0.001)	-7.5 (p = 0.0537)
EORTC QLQ-C30 constipation	3.2 (p = 0.393)	5.7 (p = nd)
EORTC QLQ-C30 diarrhea	-17.6 (p = 0.460)	-1.8 (p = 0.6279)
EORTC QLQ-C30 financial difficulties	-3.0 (p = nd)	-7.9 (p = nd)
Exploratory endpoints
WPAI Absenteeism	–31.9 (p = 0.0056)	–24.0 (p = 0.0491)
WPAI Presenteeism	–3.5 (p = 0.7822)	–12.8 (p = nd)
WPAI Overall Work Impairment	-22.3 (p = 0.1311)	-13.2 (p < 0.0001)
WPAI Activities Impairment	–20.4 (p = 0.0056)	–9.7 (p = 0.0872)

Improvements were also seen in axi-cel over SOC for the secondary and additional exploratory endpoints for other domains of EORTC QLQ-C30, EQ-5D-5L index, and WPAI:GH. Mean differences in scores from baseline favored axi-cel over SOC on Day 100 for nausea and vomiting, diarrhea, insomnia, appetite loss, role, and social functioning by EORTC QLQ-C30, Day 150 for role functioning and fatigue by EORTC QLQ-C30, and Month 9 for EORTC QLQ-C30 dyspnea. For WPAI:GH, significantly lower abseentism and lower mean activities impairments were seen at Day 100 for axi-cel over SOC.

Conclusion

This comparative analysis of patient-reported outcomes in the ZUMA-7 study highlights the importance of QoL assessments and patient experiences to fully elucidate the therapeutic potential of treatments. Axi-cel showed a statistically significant, clinically meaningful improvement and a faster recovery rate to baseline QoL over SOC by Day 100 and Day 150 for multiple PRO scores. Despite some methodological issues, as well as disproportionality in sample sizes and patient characteristics in this study, sensitivity analyses have confirmed the success of axi-cel over SOC. With both higher efficacy and QoL outcomes over SOC, axi-cel shows its promising benefit as a future second-line treatment for patients with R/R LBCL.