
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01432-7
10.1016/j.esmoop.2024.103663
103663
Original Research
Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials
Lordick F. 1
Van Cutsem E. 2
Shitara K. 3
Xu R.-H. 45
Ajani J.A. 6
Shah M.A. 7
Oh M. @AstellasUS
8
Ganguli A. @AstellasUS
8
Chang L. @AstellasUS
8
Rhoten S. 9
Bhattacharya P. @AstellasUS
8
Matsangou M. @AstellasUS
8
Park J.W. @AstellasUS
8
Pophale R. @AstellasUS
8
Ranganath R. @AstellasUS
8
Kang Y.-K. ykkang@amc.seoul.kr
10∗†
1 Department of Medicine and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany
2 Digestive Oncology, University Hospitals Gasthuisberg, Leuven, and KULeuven, Leuven, Belgium
3 Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan
4 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou
5 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
6 The University of Texas, MD Anderson Cancer Center, Houston
7 Weill Cornell Medical College, New York City
8 Astellas Pharma Global Development, Inc., Northbrook
9 IQVIA, San Francisco, USA
10 Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea
∗ Correspondence to: Prof. Yoon-Koo Kang, Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea. Tel: +82-2-3010-3230 ykkang@amc.seoul.kr
† Present address: 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of Korea.

14 8 2024
8 2024
14 8 2024
9 8 103663© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies.

Materials and methods

Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW.

Results

The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies.

Conclusions

Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.

Highlights

• Key PRO domains of interest were GHS/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting.

• In SPOTLIGHT and GLOW combined, there were no clinically meaningful changes from baseline with zolbetuximab + chemotherapy.

• Change from baseline trends for key PRO domains were similar with zolbetuximab + chemotherapy and placebo + chemotherapy.

• Nausea/vomiting worsened in early cycles but later returned to baseline levels without clinically meaningful deterioration.

• Zolbetuximab + chemotherapy improved PFS and OS without negatively affecting HRQoL compared with placebo + chemotherapy.

Key words

gastric adenocarcinoma
gastroesophageal junction adenocarcinoma
CLDN18.2
zolbetuximab
patient-reported outcomes
quality of life
==== Body
pmcIntroduction

Gastric and gastroesophageal junction (G/GEJ) adenocarcinoma are currently among the most common cancers worldwide.1,2 The standard first-line (1L) therapy for locally advanced (LA) unresectable or metastatic G/GEJ (mG/GEJ) adenocarcinoma is platinum- and fluoropyrimidine-based chemotherapy.1,3, 4, 5, 6 The median overall survival (OS) in patients receiving these treatments is ∼1 year.1,3, 4, 5, 6 Targeted therapies, including trastuzumab [anti-human epidermal growth factor receptor 2 (HER2) antibody], and immunotherapies, including nivolumab [anti-programmed cell death 1 receptor (PD-1) antibody], can improve survival when combined with chemotherapy and are approved as 1L therapy in many countries.1,3, 4, 5, 6, 7, 8, 9 However, most tumors in patients with LA unresectable or mG/GEJ adenocarcinoma are HER2-negative, and only a subset of patients with tumors with high expression of programmed cell death ligand 1 (PD-L1) benefit from immunotherapies.8, 9, 10, 11, 12 Additional targeted therapies are needed to treat patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma.1,13

Patients with advanced G/GEJ adenocarcinoma experience a high symptom burden, including stomach/abdominal pain, appetite loss, fatigue, and anxiety, which worsen during disease progression.14,15 1L chemotherapy alone can maintain or improve patient-reported global health status/quality of life (GHS/QoL) scores, and improve symptoms including stomach pain and appetite loss over time.14,15 The addition of biomarker-based therapies, including trastuzumab and nivolumab, to chemotherapy has demonstrated a significantly delayed deterioration in health-related QoL (HRQoL) compared with chemotherapy alone.16,17

Claudin 18 isoform 2 (CLDN18.2) is a tight junction protein expressed in normal gastric epithelial cells.18,19 CLDN18.2 is retained in G/GEJ adenocarcinoma and may become more exposed on G/GEJ adenocarcinoma cells following malignant transformation, making it accessible to targeted antibodies.18, 19, 20, 21, 22, 23, 24 Zolbetuximab is a first-in-class chimeric monoclonal immunoglobulin G1 antibody that targets and binds CLDN18.2, leading to antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.20,21,25, 26, 27, 28, 29 Zolbetuximab has shown promising antitumor efficacy in phase I, II, and III studies in patients with G/GEJ adenocarcinoma.20,21,23,27, 28, 29, 30 Additionally, zolbetuximab plus chemotherapy demonstrated significantly delayed deterioration in patient-reported GHS/QoL scores compared with chemotherapy alone in the phase II FAST study, although patients experienced increased nausea and vomiting (N/V) during the first eight treatment cycles compared with baseline.31

The global, randomized, phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies of patients with previously untreated, HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive [defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining as determined by central immunohistochemistry using the VENTANA CLDN18 (43-14A) RxDx Assay (for Investigational Use Only; VMSI/Roche)] demonstrated prolonged progression-free survival (PFS) and OS with the addition of 1L zolbetuximab to chemotherapy [a modified folinic acid, 5-fluorouracil, and oxaliplatin regimen (mFOLFOX6) or a capecitabine and oxaliplatin regimen (CAPOX), respectively] versus placebo plus chemotherapy.27,28 This analysis of patient-reported outcomes (PROs) from the SPOTLIGHT and GLOW studies assesses patient perspectives on the experienced benefits and side-effects of 1L zolbetuximab plus chemotherapy.

Materials and methods

Study design and patients

Full details of the study designs of SPOTLIGHT and GLOW have been published previously and are briefly described here (Supplementary Figure S1A, available at https://doi.org/10.1016/j.esmoop.2024.103663).27,28

In SPOTLIGHT, patients were randomly assigned 1 : 1 to receive zolbetuximab (loading dose of 800 mg/m2 on cycle 1 day 1, followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6 for four 42-day cycles (Supplementary Figure S1A, available at https://doi.org/10.1016/j.esmoop.2024.103663). Patients without disease progression continued beyond four cycles with zolbetuximab or placebo; patients also continued with folinic acid and 5-fluorouracil at investigator’s discretion.27

In GLOW, patients were randomly assigned 1 : 1 to receive zolbetuximab (same treatment schedule as SPOTLIGHT) or CAPOX (capecitabine, days 1-14 of each cycle; oxaliplatin, every 3 weeks) or placebo plus CAPOX for eight 21-day cycles (Supplementary Figure S1A, available at https://doi.org/10.1016/j.esmoop.2024.103663). Patients without disease progression continued beyond eight cycles with zolbetuximab or placebo; patients also continued with capecitabine at investigator’s discretion.28

Health-related quality-of-life outcomes and assessments

PROs were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30; version 3) and Oesophago-Gastric Module (QLQ-OG25; plus STO22 Belching subscale in GLOW), Global Pain (GP), and 5-level EQ-5D (EQ-5D-5L). PRO assessments were completed by patients using an electronic tablet device; if completion by patients was not possible, assessments were administered to patients by site personnel using an electronic tablet device. Assessments were completed at screening, every 3 weeks while on treatment before any antiemetic or study drug treatment and before discussion of patient disease status, at treatment discontinuation, and 30 days and 90 days after treatment discontinuation (Supplementary Figure S1B and C, available at https://doi.org/10.1016/j.esmoop.2024.103663).

The EORTC QLQ-C30 is a 30-item cancer-specific instrument consisting of five functional scales (physical, role, emotional, social, and cognitive), nine symptom scales and items (fatigue, nausea and vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a GHS/QoL scale. Scores are standardized on a numerical 0-100 scale. For functional scales and the GHS/QoL scale, higher scores indicate better functioning. For symptom scales and items, higher scores indicate worsened symptoms. The assessment evaluates a patient’s experience over the preceding 7 days.

The EORTC QLQ-OG25 is a 25-item G/GEJ cancer-specific instrument consisting of six scales (dysphagia, eating restrictions, reflux, odynophagia, pain and discomfort, and anxiety) and 10 items (eating in front of others, dry mouth, trouble with taste, body image, trouble swallowing saliva, choked when swallowing, trouble with coughing, trouble talking, weight loss, and hair loss). Scores are standardized on a numerical 0-100 scale. For symptom scales and items, higher scores indicate worsened symptoms. Two items from the EORTC QLQ-STO22 Belching subscale (belching, bile or acid coming in mouth) were administered following the QLQ-OG25 assessment in GLOW. The assessment evaluates a patient’s experience over the preceding 7 days.

GP is an instrument with a single assessment of overall pain (physical, psychological, and clinical impacts of pain, and interference with daily activities) on a numerical scale from 0 to 10. A higher score indicates a higher degree of pain.32 The assessment evaluates a patient’s experience over the preceding 24 h.

The EQ-5D-5L is a standardized instrument to measure health outcomes consisting of the general EQ visual analog scale (VAS) to rate health status (ranging from 0 mm representing ‘worst imaginable health state’ to 100 mm representing ‘best imaginable health state’), and the descriptive system addressing five domains (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression) each rated on five levels. The assessment evaluates a patient’s experience on the day of the assessment.

In SPOTLIGHT and GLOW, PRO assessments were focused on the effects of treatment on GHS/QoL, physical functioning (PF), and abdominal pain and discomfort, which were pre-specified and identified as clinically meaningful to patients based on PRO results from the FAST study and a symptom burden study.28 N/V were identified as key adverse events in SPOTLIGHT and GLOW safety analyses as measured by Common Terminology Criteria for Adverse Events version 4.03, and were assessed here to provide additional patient perspectives.27,28

Statistical analysis

PRO endpoints were assessed in the full analysis set (FAS) in SPOTLIGHT and GLOW, which included all randomly assigned patients. PRO results were analyzed individually for each study as pre-specified analyses and pooled across SPOTLIGHT and GLOW in a combined FAS as exploratory analyses. Scores were summarized for visits with ≥10% of patients having non-missing data in either treatment arm, excluding study discontinuation and safety follow-up visits.

PROs assessment compliance rates represented the proportion of patients who completed assessments out of the number of patients expected to complete assessments (equal to the number of patients still on treatment or undergoing follow-up at any given timepoint). Additional details are provided in the Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2024.103663.

EORTC QLQ-C30 and QLQ-OG25 assessments were scored according to the EORTC scoring manual.33

The change from baseline in PRO assessment scores was evaluated as a secondary endpoint. Model-adjusted least squares mean (LSM) change in score from baseline and associated 95% confidence intervals (CIs) were reported at each postbaseline assessment. The LSM change in score from baseline at each postbaseline assessment was modeled as a linear function of treatment arm (zolbetuximab versus placebo), assessment timepoint, baseline PRO score, and trial stratification factors (region, Asia versus non-Asia; number of metastatic sites, 0-2 versus ≥3; prior gastrectomy, yes versus no) as fixed effects and between baseline PRO score and assessment timepoint, and treatment arm and assessment timepoint as interaction terms. The timeframes for reporting LSM change from baseline were selected to minimize the impact of missing data given the median PFS reported in SPOTLIGHT and/or GLOW.27,28 The within-group threshold for clinically meaningful changes from baseline was 10 points for the EORTC QLQ-C30 and QLQ-OG25 assessments. The LSM change in score from baseline was compared between treatment arms in each study using a restricted maximum likelihood-based mixed model repeated measures approach. All domains from the QLQ-C30 were analyzed except for financial difficulties. All domains from the QLQ-OG25 were analyzed except for bile or acid coming in mouth from the STO22 Belching subscale administered in GLOW.

Time to confirmed deterioration (TTCD), defined as the time from randomization to first clinically meaningful deterioration of at least one within-patient threshold unit compared to baseline as confirmed at a next scheduled assessment or followed by drop-out resulting in missing data, was evaluated as a key secondary endpoint for GHS/QoL, PF, and abdominal pain and discomfort, and as an exploratory analysis for N/V. Time to first definitive deterioration (TTDD), defined as the time from randomization to the first deterioration of at least one within-patient threshold unit compared to baseline and observed at all timepoints thereafter or followed by drop-out resulting in missing data, was evaluated as an exploratory analysis. The derivations of within-patient thresholds for clinically meaningful change from baseline and the thresholds are described in the Supplementary Methods and in Supplementary Table S1, respectively, available at https://doi.org/10.1016/j.esmoop.2024.103663. The primary analyses of TTCD and TTDD treated death as a censored event; sensitivity analyses treated death as an event of interest. The Kaplan–Meier method was used to estimate the distribution of TTCD and TTDD, and a stratified Cox proportional hazards model adjusted by stratification factors (defined above) was used to estimate the hazard ratio (HR) and corresponding 95% CIs.

Using the within-patient primary thresholds for clinically meaningful change, a responder analysis was carried out to assess the proportion of patients whose assessment scores improved, remained stable, or worsened from baseline for the four key PRO domains. The timepoints for the responder analyses were selected to minimize the impact of missing data given the median PFS reported in SPOTLIGHT or GLOW.27,28

Patients with non-missing baseline assessments were censored at the last available PRO assessment. Patients without a baseline or postbaseline PRO assessment, or whose baseline PRO scores did not allow for further deterioration (not including death or disease progression), were censored at randomization. Missing PRO assessment data were not imputed.

All analyses were conducted using SAS version 9.4 or higher (SAS Institute; Cary, NC).

Trial oversight

The study protocols and all amendments were approved by the appropriate independent ethics committee or institutional review board at each participating institution. Patients provided written informed consent before participating in the trial. All authors attest that the trial was conducted in accordance with the Declaration of Helsinki and the standards of Good Clinical Practice and vouch for the fidelity of the trial to the protocol and the accuracy and completeness of the reported data.27,28 All authors had access to study data and were involved in the writing, review, and editing of the manuscript. The manuscript was written by the authors with the assistance of a medical writer funded by the study sponsor. The trials were registered at ClinicalTrials.gov: NCT03504397 (SPOTLIGHT), NCT03653507 (GLOW).

Results

Baseline characteristics

This study reports results for the combined and individual populations from the SPOTLIGHT and GLOW studies. The combined FAS population consisted of 1072 patients: 537 patients in the zolbetuximab plus chemotherapy arms (SPOTLIGHT, 283; GLOW, 254) and 535 patients in the placebo plus chemotherapy arms (SPOTLIGHT, 282; GLOW, 253). Demographic and baseline characteristics were well balanced between treatment arms in both SPOTLIGHT and GLOW (combined population, Table 1; individual study populations, Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103663).Table 1 Demographics and baseline characteristics in the combined FAS population across SPOTLIGHT and GLOW

Characteristic	Zolbetuximab + chemotherapy (n = 537)	Placebo + chemotherapy (n = 535)	
Median age, years (range)	61.0 (22-83)	60.0 (20-86)	
Male sex,an (%)	335 (62.4)	331 (61.9)	
Race,bn (%)			
 Asian	254 (49.5)	255 (50.9)	
 White	234 (45.6)	224 (44.7)	
 American Indian or Alaska Native	9 (1.8)	8 (1.6)	
 Black	5 (1.0)	2 (0.4)	
 Native Hawaiian or other Pacific Islander	0	0	
 Other	11 (2.1)	12 (2.4)	
 Missing	24	34	
Region, n (%)			
 Asia	245 (45.6)	247 (46.2)	
 Non-Asia	292 (54.4)	288 (53.8)	
Organs with metastases, n (%)			
 0-2	408 (76.0)	407 (76.1)	
 ≥3	129 (24.0)	128 (23.9)	
Prior gastrectomy, n (%)			
 Yes	159 (29.6)	157 (29.3)	
 No	378 (70.4)	378 (70.7)	
Primary tumor site, n (%)			
 Stomach	438 (81.6)	419 (78.3)	
 GEJ	99 (18.4)	116 (21.7)	
Lauren Classification,bn (%)			
 Diffuse	169 (31.6)	217 (40.9)	
 Intestinal	106 (19.8)	107 (20.2)	
 Mixed	51 (9.5)	34 (6.4)	
 Unknownc	125 (23.4)	104 (19.6)	
 Other	84 (15.7)	69 (13.0)	
 Missing	2	4	
ECOG PS score,bn (%)			
 0	233 (43.8)	223 (42.2)	
 1	298 (56.0)	305 (57.8)	
 2d	1 (0.2)	0	
 Missinge	5	7	
Measurable disease,fn (%)			
 Yes	406 (75.6)	416 (77.8)	
 No	131 (24.4)	119 (22.2)	
ECOG PS, Eastern Cooperative Oncology Group performance status; FAS, full analysis set; GEJ, gastroesophageal junction.

a Sex was reported by study site staff through an interactive response technology system with options ‘male’ or ‘female.’

b Percentages were calculated excluding patients with missing data.

c Patients with Lauren classification ‘unknown’ had adenocarcinoma without Lauren classification.

d Baseline measurements were reported at cycle 1 day 1, at which time these patients had an ECOG PS score of 2; these patients had a score of 1 at screening and were, thus, eligible for enrollment.

e Baseline measurements were reported at cycle 1 day 1; patients reported as ‘Missing’ did not receive any treatment, thus no baseline was defined per statistical analysis plan. However, at screening these patients had an ECOG PS score of 0 or 1 and were, thus, eligible for enrollment.

f Based on central assessment.

Questionnaire compliance

In SPOTLIGHT and GLOW, compliance rates were mostly >70% for visits with ≥10% patients in either treatment arm completing the EORTC QLQ-C30, EORTC QLQ-OG25, or EQ-5D-5L assessments (Supplementary Tables S3-S5, available at https://doi.org/10.1016/j.esmoop.2024.103663). The compliance rates for the GP instrument were mostly >70% for visits with ≥10% patients in either treatment arm.

HRQoL change from baseline over time

Baseline scores for the EORTC QLQ-C30 and EORTC QLQ-OG25 were well balanced between the zolbetuximab plus chemotherapy arms and the placebo plus chemotherapy arms (combined population, Table 2; individual study populations, Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2024.103663).Table 2 Baseline PRO scores across SPOTLIGHT and GLOW

Parameter	Zolbetuximab + chemotherapy (n = 537)	Placebo + chemotherapy (n = 535)	
GHS/QoL			
 n	499	500	
 Mean (SD)	66.45 (20.08)	64.77 (20.07)	
Physical functioning			
 n	499	500	
 Mean (SD)	81.66 (18.84)	81.09 (19.47)	
Nausea/vomiting			
 n	499	500	
 Mean (SD)	13.03 (21.40)	16.17 (23.79)	
Abdominal pain and discomfort			
 n	499	498	
 Mean (SD)	25.32 (25.38)	25.90 (26.46)	
GHS, global health status; PRO, patient-reported outcome; QoL, quality of life; SD, standard deviation.

In the combined populations from SPOTLIGHT and GLOW, LSM change from baseline showed mostly overlapping CIs in the zolbetuximab plus chemotherapy arms and the placebo plus chemotherapy arms for the key PRO domains of EORTC QLQ-C30 GHS/QoL, PF, and N/V and QLQ-OG25 abdominal pain and discomfort over 49 weeks of treatment (combined population, Figure 1; individual study populations, Supplementary Figures S2 and S3, available at https://doi.org/10.1016/j.esmoop.2024.103663). No clinically meaningful deteriorations in LSM change from baseline were observed within either treatment arm for the key PRO domains over 49 weeks (Figure 1). Scores for abdominal pain and discomfort improved over 49 weeks relative to baseline within both treatment arms. Scores for N/V initially worsened relative to baseline but returned to baseline following the first 6-8 zolbetuximab treatments (i.e. 18-24 weeks); over the first 24 weeks, the LSM change from baseline ranged from a high of 9.13 points at week 4 to a low of 2.30 points at week 22 in the zolbetuximab arm and from a high of 2.70 points at week 4 to a low of −3.46 points at week 19 in the placebo arm (with positive change from baseline representing worsened symptoms).Figure 1 LSM changes from baseline in PRO scores across SPOTLIGHT and GLOW. (A) GHS/QoL. (B) Physical functioning. (C) Abdominal pain and discomfort. (D) Nausea/vomiting. Dashed lines represent the within-group thresholds for clinically meaningful deterioration. Per EORTC assessments, positive LSM change from baseline indicates improvement in GHS/QoL and physical functioning; negative LSM change from baseline indicates improvement in abdominal pain and discomfort and nausea/vomiting. CI, confidence interval; EORTC, European Organisation for Research and Treatment of Cancer; GHS, global health status; LSM, least squares mean; PRO, patient-reported outcome; QoL, quality of life.

In SPOTLIGHT, no clinically meaningful deteriorations in LSM change from baseline were observed within either treatment arm for GHS/QoL, PF, or abdominal pain and discomfort over 61 weeks (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2024.103663). A clinically meaningful LSM change from baseline in N/V scores was observed in the zolbetuximab arm at week 1, but N/V scores in both treatment arms returned to baseline levels after the first 3 zolbetuximab treatments (i.e. 9 weeks). A summary of LSM change from baseline for additional domains is provided in the Supplementary Results, available at https://doi.org/10.1016/j.esmoop.2024.103663.

In GLOW, no clinically meaningful deteriorations in LSM change from baseline were observed within either treatment arm for GHS/QoL, PF, abdominal pain and discomfort, or N/V over 49 weeks (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2024.103663). A summary of LSM change from baseline for additional domains is provided in the Supplementary Results, available at https://doi.org/10.1016/j.esmoop.2024.103663.

In both SPOTLIGHT and GLOW, a higher proportion of patients experienced nausea than vomiting (Supplementary Figures S4 and S5, available at https://doi.org/10.1016/j.esmoop.2024.103663). In both studies, the difference between the proportion of patients who experienced nausea in early cycles compared with baseline was also greater than the difference between the proportion of patients who experienced vomiting in early cycles compared with baseline.

Time to deterioration

In the combined populations from SPOTLIGHT and GLOW, overall TTDD results based on the primary thresholds for clinically meaningful deterioration (treating death as a censored event) were similar between the zolbetuximab plus chemotherapy arms and the placebo plus chemotherapy arms for GHS/QoL, PF, abdominal pain and discomfort, and N/V (Figure 2). Compared with the placebo arms, patients in the zolbetuximab arms demonstrated numerically delayed TTDD for abdominal pain and discomfort, and early worsening of N/V.Figure 2 Kaplan–Meier plots of TTDD based on primary threshold across SPOTLIGHT and GLOW.a,b(A) GHS/QoL. (B) Physical functioning. (C) Abdominal pain and discomfort. (D) Nausea/vomiting. Black horizontal lines represent the median threshold.aDeaths were treated as censored events.bTTDD was defined as the time from randomization to the first deterioration of ≥1 within-patient threshold unit compared to baseline and observed at all timepoints thereafter or followed by drop-out resulting in missing data. CI, confidence interval; GHS, global health status; HR, hazard ratio; NR, not reached; QoL, quality of life; TTDD, time to first definitive deterioration.

In SPOTLIGHT and in GLOW, overall, TTCD and TTDD results in each study based on the primary threshold for clinically meaningful deterioration (treating death as a censored event) were similar between the zolbetuximab and placebo arms for GHS/QoL, PF, abdominal pain and discomfort, N/V, GP, and EQ VAS (Table 3; Supplementary Figures S6 and S7, available at https://doi.org/10.1016/j.esmoop.2024.103663). Overall, TTCD and TTDD based on the primary thresholds (treating death as an event of interest) or the sensitivity thresholds (treating death as either a censored event or an event of interest) were also similar between treatment arms (Supplementary Table S7, available at https://doi.org/10.1016/j.esmoop.2024.103663).Table 3 TTCDa and TTDDb by primary threshold across SPOTLIGHT and GLOW studiesc

Instrument	Domain		TTCD,a months, median (95% CI)	TTDD,b months, median (95% CI)	
SPOTLIGHT	GLOW	SPOTLIGHT	GLOW	
Zolbetuximab + mFOLFOX6	Placebo + mFOLFOX6	Zolbetuximab + CAPOX	Placebo + CAPOX	Zolbetuximab + mFOLFOX6	Placebo + mFOLFOX6	Zolbetuximab + CAPOX	Placebo + CAPOX	
QLQ-C30	GHS/QoL	Median (95% CI)	15.44 (6.90-22.83)	11.83 (8.74-15.08)	9.69 (7.39-NC)	7.49 (6.11-9.86)	21.06 (18.20-NC)	20.90 (15.11-NC)	21.42 (11.73-NC)	10.41 (7.92-NC)	
HR (95% CI)	1.17 (0.89-1.53)	0.85 (0.64-1.13)	1.05 (0.75-1.47)	0.77 (0.56-1.06)	
Physical functioning	Median (95% CI)	10.71 (6.01-NC)	12.32 (9.26-NC)	8.31 (5.88-19.81)	7.92 (6.47-11.10)	30.32 (15.01-NC)	20.50 (13.90-NC)	18.76 (13.37-NC)	9.59 (7.79-NC)	
HR (95% CI)	1.31 (1.00-1.71)	1.00 (0.76-1.32)	1.21 (0.88-1.64)	0.76 (0.56-1.03)	
Nausea/vomiting	Median (95% CI)	8.25 (4.47-17.97)	15.08 (8.74-29.57)	5.52 (3.78-9.17)	11.89 (7.69-NC)	NR (22.83-NC)	20.90 (18.30-29.57)	NR (21.19-NC)	NR (12.94-NC)	
HR (95% CI)	1.30 (0.99-1.70)	1.48 (1.12-1.96)	0.97 (0.66-1.42)	1.11 (0.76-1.61)	
QLQ-OG25	Abdominal pain and discomfort	Median (95% CI)	19.35 (15.77-NC)	15.61 (12.32-NC)	19.81 (9.53-NC)	12.94 (10.41-NC)	NR	27.40 (16.43-NC)	NR (19.81-NC)	25.82 (13.34-NC)	
HR (95% CI)	1.07 (0.79-1.46)	1.01 (0.73-1.41)	0.87 (0.58-1.31)	0.84 (0.57-1.24)	
Global Pain		Median (95% CI)	18.89 (15.18-NC)	18.40 (13.37-NC)	11.73 (8.18-NC)	26.51 (12.02-NC)	27.17 (23.33-NC)	28.75 (18.40-NC)	NR (13.63-NC)	26.51 (NC-NC)	
HR (95% CI)	0.92 (0.67-1.26)	1.31 (0.95-1.82)	0.83 (0.56-1.23)	1.15 (0.79-1.69)	
EQ-5D-5L	EQ VAS	Median (95% CI)	6.83 (4.40-16.79)	9.36 (6.97-15.08)	7.20 (5.62-11.30)	6.51 (4.96-7.79)	18.66 (12.78-30.82)	15.11 (12.25-NC)	13.83 (12.62-NC)	8.84 (6.80-15.41)	
HR (95% CI)	1.20 (0.93-1.55)	0.93 (0.71-1.21)	1.04 (0.78-1.40)	0.74 (0.55-0.99)	
Bold values indicate P < 0.05 in log-rank test for differences between treatment arms. Hazard ratios <1 favor the zolbetuximab treatment arms.

CAPOX, capecitabine and oxaliplatin regimen; CI, confidence interval; EQ-5D-5L, 5-level EQ-5D; EQ VAS, EQ visual analog scale; GHS, global health status; mFOLFOX6, modified folinic acid, 5-fluorouracil, and oxaliplatin regimen; NC, not calculable; NR, not reached; QLQ-C30, Quality of Life of Cancer Patients Core Questionnaire; QLQ-OG25, Quality of Life of Cancer Patients Questionnaire, Oesophago-Gastric Module; QoL, quality of life; TTCD, time to confirmed deterioration; TTDD, time to first definitive deterioration.

a TTCD was defined as the time from randomization to the first clinically meaningful deterioration of ≥1 within-patient threshold unit compared to baseline as confirmed at the next scheduled assessment or followed by drop-out resulting in missing data.

b TTDD was defined as the time from randomization to the first deterioration of ≥1 within-patient threshold unit compared to baseline and observed at all timepoints thereafter or followed by drop-out resulting in missing data.

c Deaths were treated as censored events.

Responder analysis

Overall, the proportion of patients with worsened, stable, or improved scores for GHS/QoL, PF, abdominal pain and discomfort, and N/V were similar between the zolbetuximab plus chemotherapy arms and the placebo plus chemotherapy arms in SPOTLIGHT (Supplementary Figure S8, available at https://doi.org/10.1016/j.esmoop.2024.103663) and in GLOW (Supplementary Figure S9, available at https://doi.org/10.1016/j.esmoop.2024.103663). In SPOTLIGHT, at week 49, a greater proportion of patients had stable scores for PF in the placebo arm (n/n = 31/51, 60.78%) compared with the zolbetuximab arm (n/n = 31/66, 46.97%), while greater proportions of patients had improved or worsened scores in the zolbetuximab arm (improved, n/n = 19/66, 28.79%; worsened, n/n = 16/66, 24.24%) compared with the placebo arm (n/n = 9/51, 17.65%; n/n = 11/51, 21.57%). In SPOTLIGHT, at week 49, a greater proportion of patients had improved scores for abdominal pain and discomfort in the zolbetuximab arm (n/n = 33/66, 50.00%) compared with the placebo arm (n/n = 20/66, 39.22%). In GLOW, at week 49, a greater proportion of patients had stable scores for abdominal pain and discomfort in the placebo arm (n/n = 13/24, 54.17%) compared with the zolbetuximab arm (n/n = 16/39, 41.03%), while a greater proportion of patients had improved scores in the zolbetuximab arm (n/n = 17/39, 43.59%) compared with the placebo arm (n/n = 8/24, 33.33%).

Discussion

In SPOTLIGHT and GLOW, 1L zolbetuximab plus chemotherapy demonstrated improved PFS and OS compared with placebo plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive.27,28 Patients treated with zolbetuximab plus chemotherapy maintained measured HRQoL relative to baseline while on therapy as assessed by patient-reported overall health status and gastroesophageal-cancer-specific PRO measures.

Similar trends were seen in the zolbetuximab arms compared with the placebo arms for change from baseline in the HRQoL measures of GHS/QoL, PF, abdominal pain and discomfort, and N/V. Over 49 weeks, in the combined population of SPOTLIGHT and GLOW, there was a difference in PF and N/V between treatment arms that favored the placebo arms. Although N/V worsened during the first few cycles of zolbetuximab treatment (LSM change from baseline up to 9.13 points in the zolbetuximab arms and 2.70 points in the placebo arms), levels of N/V returned to baseline values after the first 6-8 zolbetuximab treatments (i.e. 18-24 weeks) without clinically meaningful deterioration. In SPOTLIGHT and GLOW, the difference between the proportion of patients who experienced nausea in early cycles compared with baseline was also greater than the difference between the proportion of patients who experienced vomiting in early cycles compared with baseline, suggesting that nausea contributed more than vomiting to the observed changes in N/V scores. N/V were identified as key adverse events in safety analyses in the SPOTLIGHT and GLOW studies and were previously reported as adverse events associated with zolbetuximab plus chemotherapy or zolbetuximab monotherapy.21,23,27, 28, 29, 30 The return of PRO scores for N/V toward baseline levels may reflect the previously reported decreased incidence of N/V as adverse events after the first two zolbetuximab infusions in SPOTLIGHT and GLOW. Although infusion rate modification, infusion interruptions, and prophylactic antiemetic use were advised to manage N/V in SPOTLIGHT and GLOW, additional research may be needed to further characterize the reasons for decreased N/V as adverse events following later zolbetuximab infusions.27,28 N/V are likely on-target effects resulting from the induction of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in the stomach through expression of CLDN18.2 on gastric epithelial cells.21,23,31 Despite increased N/V in the zolbetuximab arms compared with the placebo arms through the first 24 weeks of treatment, there was no difference in overall GHS/QoL between treatment arms in this or previous studies of zolbetuximab plus chemotherapy.27,28,31

Overall TTCD results were similar in the zolbetuximab arms compared to the placebo arms in the HRQoL measures of GHS/QoL, PF, and abdominal pain and discomfort as key secondary end points, and of N/V, GP, and EQ VAS as additional analyses; overall TTDD results were also similar between treatment arms. Using the primary threshold for clinically meaningful change, and treating death as a censored event, there was a trend favoring the placebo arm in TTCD for N/V in the GLOW study; however, this seemed to resolve over time as there was no significant difference between treatment arms in TTDD for N/V in either study. As discussed above, mean change from baseline results demonstrated that N/V scores worsened in early treatment cycles and later returned to baseline levels in SPOTLIGHT and GLOW. The responder analysis also showed that there were more patients with improved or stable N/V scores relative to baseline in later compared with earlier treatment cycles in the zolbetuximab arms. In addition, a significant difference in TTCD for N/V was not observed in SPOTLIGHT. Furthermore, despite N/V, there was not a negative effect on time to deterioration for overall GHS/QoL in either treatment arm. There were statistically significant differences in TTCD for PF favoring the placebo arm in the SPOTLIGHT study and in TTDD for PF favoring the zolbetuximab arm in the GLOW study, suggesting that there is not a general trend for differences in time to deterioration in PF with zolbetuximab plus chemotherapy compared to placebo plus chemotherapy. Finally, there was a statistically significant difference in TTDD for EQ VAS favoring the zolbetuximab arm in GLOW, but this was not observed in SPOTLIGHT, suggesting that overall effects on EQ VAS are similar with zolbetuximab plus chemotherapy and placebo plus chemotherapy.

The results of this study are consistent with previous PRO analyses in the phase II FAST study of zolbetuximab plus epirubicin and oxaliplatin (EOX) versus EOX alone in patients with LA unresectable, recurrent, or metastatic gastroesophageal adenocarcinoma whose tumors expressed CLDN18.2.31 In FAST, zolbetuximab plus EOX demonstrated similar HRQoL versus EOX alone. Like this study, an exception was change from baseline in N/V scores, which favored EOX alone. However, this did not negatively impact GHS/QoL scores for patients treated with zolbetuximab plus EOX.31 While in GLOW TTCD for N/V significantly favored placebo, there were no differences in time to deterioration for GHS/QoL between treatment arms in SPOTLIGHT or GLOW. In the FAST study, zolbetuximab plus EOX improved time to deterioration in GHS/QoL compared with EOX alone.31 Together, these studies suggest that zolbetuximab plus chemotherapy does not negatively impact HRQoL compared to chemotherapy alone in patients with LA unresectable or mG/GEJ adenocarcinoma.

This study had several strengths, including a double-blinded study design, which intends to reduce bias in PRO assessments compared with open-label study designs. SPOTLIGHT and GLOW were global studies, allowing the PRO results to be generalizable to different geographic populations. The PROs during zolbetuximab treatment reported here are validated by analysis of the two studies SPOTLIGHT and GLOW, which used two different chemotherapy regimens. Compliance rates were generally high and were similar between treatment arms. This study used both general health-focused and gastroesophageal-cancer-specific PRO measures to provide a comprehensive view of patient perspectives of the effect of 1L zolbetuximab plus chemotherapy on HRQoL; the comprehensive and frequent PRO assessments in SPOTLIGHT and GLOW aimed to thoroughly capture patient perspectives on their treatment experience.

A potential limitation of this study is that discontinuation of a greater number of patients in the zolbetuximab arms, mainly due to N/V in early treatment cycles, may have biased reports of N/V during zolbetuximab treatment.27,28 Another limitation of this study is the limited number of assessable patients at later timepoints in both treatment arms in SPOTLIGHT and GLOW following disease progression, death, or treatment discontinuation for other reasons as specified in the study protocols.27,28 Because of the small number of patients contributing to each of the categories of symptom improvement, stability, or worsening at later timepoints, interpretation of the responder analyses should be made with caution. The dosing schedule of the chemotherapy backbones was different between SPOTLIGHT and GLOW. In SPOTLIGHT, patients received zolbetuximab or placebo every 3 weeks and mFOLFOX6 every 2 weeks. In GLOW, patients received both zolbetuximab or placebo and CAPOX every 3 weeks. In both studies, patients completed PRO assessments every 3 weeks, before administration of study treatment, which reflected the patient’s experience over the last 7 days for the QLQ-C30 and QLQ-OG25. Because of this, in SPOTLIGHT, patients received mFOLFOX6 1 week before some PRO assessments and in GLOW, patients received CAPOX 3 weeks before PRO assessments. Therefore, the PRO assessments in SPOTLIGHT may potentially have been more reflective of the patients’ experiences related to mFOLFOX6 than to zolbetuximab. Finally, while patients treated with zolbetuximab plus chemotherapy maintained HRQoL on treatment, clinically meaningful and statistically significant improvements in HRQoL were not seen with zolbetuximab compared with placebo. This may have been due to the following: (i) the PRO assessments may not have been sufficiently sensitive to changes to HRQoL in metastatic disease because the QLQ-OG25 was developed in patients with mostly non-advanced disease, and (ii) because patients were not sufficiently followed up after disease progression, potential differences between HRQoL in patients who had received zolbetuximab or placebo that could arise in the setting of disease progression were not captured.

Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy in the phase III SPOTLIGHT and GLOW studies. This supports the use of 1L zolbetuximab plus chemotherapy as a potential new standard of care in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive.

Supplementary data

Supplementary data

Supplementary data

Supplementary data

Acknowledgements

The authors thank the patients who participated in the trials and their families and caregivers.

Funding

This work was supported by Astellas Pharma Inc. (no grant number). Authors affiliated with Astellas Pharma Inc. participated in the study design, analysis and interpretation of data, writing and review of the manuscript, and approved the final version of the manuscript for publication. Medical writing support was provided by Ann Ferguson, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was conducted in accordance with the International Committee of Medical Journal Editors and Good Publication Practice 2022 guidelines; this support was funded by Astellas Pharma Inc.

Disclosure

FL reports receiving research funding from Astellas Pharma Inc.; receiving consulting fees from Amgen, Astellas Pharma Inc., Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Novartis, and Roche; receiving payment or honoraria from Amgen, Astellas Pharma Inc., AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Elsevier, the Falk Foundation, Incyte Corporation, Medscape, MedUpdate GmbH, Merck, Merck Sharp & Dohme, Novartis, Roche, Servier Laboratories, Springer Nature, and Streamed Up; receiving support for travel and/or meeting attendance from Bristol Myers Squibb; and participating on data safety monitoring boards or advisory boards for BioNTech SE. EVC reports receiving research funding from Astellas Pharma Inc., Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier Laboratories; and receiving consulting fees from AbbVie, Array BioPharma, Astellas Pharma Inc., AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Helsinn Healthcare SA, Incyte Corporation, Ipsen, Janssen Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Mirati Therapeutics, Inc., Novartis, Laboratoires Pierre Fabre, Roche, Seagen, Servier Laboratories, Sirtex Medical, Terumo Corporation, Taiho Pharmaceutical, TRIGR, and Zymeworks. KS reports receiving research funding from Astellas Pharma Inc., Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Merck Sharp & Dohme, Amgen, Eisai, and Medi Science; receiving consulting fees from Eli Lilly and Company, Bristol Myers Squibb, Takeda Pharmaceutical Company, Pfizer, Ono Pharmaceutical, Novartis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, Merck Sharp & Dohme, Astellas Pharma Inc., Guardant Health Japan, and Janssen Pharmaceuticals; and receiving payment or honoraria from Bristol Myers Squibb, Takeda Pharmaceutical Company, and Janssen Pharmaceuticals. RHX reports receiving research funding from Astellas Pharma Inc. JAA reports receiving study funding from Astellas Pharma Inc., Turning Point Therapeutics, Inc., Bristol Myers Squibb, Merck, Taiho Pharmaceutical, Delta-Fly Pharma, Inc., Roche, ProLynx, Inc., Zymeworks, Daiichi Sankyo, Leap Therapeutics, Inc., Gilead Sciences, Inc., and Lanova Pharma; receiving consulting fees from Bristol Myers Squibb, Merck, Astellas Pharma Inc., Amgen, Taiho Pharmaceutical, Zymeworks, BeiGene, AstraZeneca, Daiichi Sankyo, Bayer, GRAIL, Novartis, Geneos, Servier Laboratories, and Gilead Sciences, Inc.; receiving support for travel and/or meeting attendance from Daiichi Sankyo, Bristol Myers Squibb, and Merck; and participating on data safety monitoring board or advisory board for BeiGene. MAS reports receiving research funding from Astellas Pharma Inc., Merck, Bristol Myers Squibb, and Oncolys BioPharma; and serving a leadership or judiciary role in board, society, committee, or advocacy groups for the American Society of Clinical Oncology Leadership Council. MO, AG, LC, PB, MM, JWP, RP, and RR are full-time employees of Astellas Pharma Inc. SR is a full-time employee of IQVIA. YKK reports research funding from Astellas Pharma; and consulting fees from Daehwa Pharma, ALX Oncology, Zymeworks, Amgen, Novartis, MacroGenics, Blueprint Medicines, Surface Oncology, Bristol Myers Squibb, and Merck.

Data sharing

Upon request, and subject to certain criteria, conditions, and exceptions, Astellas will provide access to anonymized patient-level data from completed Astellas sponsored phase I-IV interventional clinical studies conducted for its products. Where available, the following anonymized patient-level data and information is provided for each clinical study: raw dataset, analysis ready dataset, protocols with any amendments or addenda, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Additional data may be available upon request. Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas-sponsored clinical trials by submitting a query at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.
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