Gastric Cancer (2021) 24:1330–1340 https://doi.org/10.1007/s10120-021-01200-w ORIGINAL ARTICLE Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with second‑line pembrolizumab in KEYNOTE‑061 Eric Van Cutsem1 · Mayur Amonkar2 · Charles S. Fuchs3 · Maria Alsina4 · Mustafa Özgüroğlu5 · Yung‑Jue Bang6 · Hyun Cheol Chung7 · Kei Muro8 · Eray Goekkurt9 · Al B. Benson III10 · Weijing Sun11 · Zev A. Wainberg12 · Josephine M. Norquist2 · Xinqun Chen13 · Chie‑Schin Shih13 · Kohei Shitara14 Received: 9 November 2020 / Accepted: 18 May 2021 / Published online: 7 August 2021 © The Author(s) 2021, corrected publication 2021 Abstract Background In the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEY- NOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses. Methods HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimen- sion, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales. Results The HRQoL population included 371 patients (pembrolizumab, n = 188; paclitaxel, n = 183). Compliance and com- pletion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (– 3.54; 95% CI – 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/ QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups. Conclusions In this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel. Clinical trial registry and number ClinicalTrials.gov, NCT02370498. Keywords Pembrolizumab · Chemotherapy · Gastric cancer · HRQoL Introduction Patients with advanced-stage gastric and/or gastroesopha- geal junction (GEJ) cancer experience diminished health- Gastric cancer is the fifth most common cancer worldwide; related quality of life (HRQoL)—overall health status and in 2018 alone, more than 1 million new cases were diag- functioning decrease while the burden of cancer-related nosed globally and nearly 800,000 deaths occurred [1]. symptoms increases [2, 3]. The type of symptom burden also changes; weight loss, abdominal pain, vomiting, gastric obstruction, and gastric bleeding are more commonly asso- Previously presented as an abstract and a poster at the European Society of Medical Oncology annual meeting on September 29, 2019 ciated with advanced-stage gastric/GEJ [2]. In addition to disease-related symptoms, those related to chemotherapy in The original online version of this article was revised to add patients with advanced gastric/GEJ cancer include abdomi- missing information in declarations section. nal pain, fatigue, nausea/vomiting, and diarrhea [2]. Treat- ments for gastric/GEJ cancer should, therefore, be evalu- * Eric Van Cutsem eric.vancutsem@uzleuven.be ated for their effects on patients’ already diminished HRQoL associated with the disease. Extended author information available on the last page of the article 13 Vol:.(1234567890) Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with… 1331 The current recommended systemic treatment options HRQoL outcomes for gastric/GEJ cancer include first-line treatment with platinum plus fluoropyrimidine (in combination with The prespecified HRQoL-based exploratory objectives trastuzumab in HER2–positive tumors) and second-line were to evaluate mean score changes from baseline to or subsequent treatment with docetaxel, paclitaxel, irinote- week 12 in HRQoL using the European Organisation for can, fluorouracil and irinotecan, or paclitaxel and ramu- Research and Treatment of Cancer (EORTC) Quality of cirumab or with pembrolizumab in patients with high Life Questionnaire Core 30 (QLQ-C30) [10–13] and the microsatellite instability or mismatch protein repair–defi- EORTC QLQ gastric cancer questionnaire (QLQ-STO22) cient tumors [4]. Regimens preferred in the third-line or [14, 15] from baseline to week 12 and to characterize utili- later setting include trifluridine plus tipiracil and pem- ties using the EuroQol 5-dimension, 3-level questionnaire brolizumab as described below [4]. Modest improvements (EQ-5D-3L) [16, 17] among patients treated with pem- in HRQoL were observed for a minority of treatment regi- brolizumab versus paclitaxel. mens in the first-line setting—single-agent chemotherapy Other measures included completion and compliance led to clinically significant improvement in overall, func- with EORTC QLQ-C30, EORTC QLQ-STO22, and the tion, and symptom scores over approximately 4 months. In EQ-5D-3L; mean score change from baseline to week 12 the second-line or later setting, overall HRQoL remained in the EORTC QLQ-C30 global health status/quality of stable for nearly all treatments, whereas role functioning, life (GHS/QoL) scale; mean score change from baseline fatigue, appetite loss, and distress from hair loss scores to week 12 for subscales and items with EORTC QLQ- worsened over time [5]. C30 (5 functional dimensions: physical, role, emotional, Pembrolizumab, an anti–programmed death 1 (PD-1) cognitive, and social; 3 symptom scales: fatigue, nausea/ monoclonal antibody, has demonstrated antitumor activ- vomiting, and pain; 6 single-item measures: dyspnea, sleep ity, greater durability of response, and manageable safety disturbance, appetite loss, constipation, diarrhea, and in patients with advanced gastric/GEJ cancer [6, 7]. Pem- financial difficulties) and EORTC QLQ-STO22 (22 items; brolizumab is approved by the US Food and Drug Admin- 5-multi-items scales [dysphagia, pain, reflux symptoms istration as third-line or later therapy for gastric/GEJ cancer eating restrictions anxiety] and 4 single items [dry mouth, that is PD-1 ligand 1 (PD-L1)–positive (combined positive taste, body image, and hair loss]; mean score change from score [CPS] ≥ 1) [8]. In KEYNOTE-061 (NCT02370498), baseline to week 12 for EQ-5D-3L visual analog scale pembrolizumab did not prolong overall survival (OS) or pro- (VAS) and utility score; and time to deterioration (TTD) gression-free survival as second-line therapy for advanced in the GHS/QoL score from baseline with EORTC QLQ- gastric/GEJ cancer in the primary analysis population (PD- C30 and EORTC QLQ-STO22. Changes in the EORTC L1 CPS ≥ 1); however, the antitumor activity of pembroli- QLQ-C30 and EORTC QLQ-STO22 subscales and items zumab (objective response rate [ORR], 16%) was more were defined as follows: improved, ≥ 10-point increase; durable (median duration of response [DOR], 18.0 months) remained stable, no change, or change of < 10 points; dete- than paclitaxel (ORR, 14%; median DOR, 5.2 months) [9]. riorated, ≤ 10-point decrease. Pembrolizumab also had a better safety profile than pacli- The HRQoL questionnaires were administered electron- taxel. We report the results of prespecified exploratory end ically by trained personnel and were completed by patients points for HRQoL from KEYNOTE-061. in the following order: EQ-5D-3L, EORTC QLQ-C30, and EORTC QLQ-STO22. Each questionnaire was adminis- tered at baseline and at cycles 1, 2, 3, 4, 5, 7, and 9; every 6 weeks after week 24 through 1 year or end of treatment; Methods and at the 30-day posttreatment discontinuation follow- up visit. Study sites were instructed to make every effort Study design and patients to ensure that administration of HRQoL questionnaires occurred before all other study procedures. The methods and primary results of the KEYNOTE-061 study have been described in detail elsewhere [9]. Brief details are provided in the Online Resource Methods. Statistical analysis The study protocol and all amendments were approved by the institutional review board or ethics committee at each In this exploratory analysis with no formal hypothesis test- institution. The study was conducted in accordance with the ing, data were analyzed for all patients in the primary anal- protocol and its amendments and with Good Clinical Prac- ysis population who received ≥ 1 dose of study treatment tice guidelines. All patients provided written informed con- and who completed ≥ 1 HRQoL questionnaire. Compliance sent before enrollment. 13 1332 E. Van Cutsem et al. and completion were summarized by treatment group pembrolizumab group and 11 in the paclitaxel group and visit. Compliance was defined by the proportion of had not received study medication and 6 and 5 patients, patients who completed ≥ 1 HRQoL assessment among respectively, had not completed an HRQoL questionnaire. those expected to complete the questionnaires at each The HRQoL analysis population therefore included 188 visit (excluding patients missing by design because they patients in the pembrolizumab group and 183 patients in discontinued study treatment). Completion was defined the paclitaxel group. by the proportion of patients who completed ≥ 1 HRQoL assessment among the total HRQoL analysis population at each visit. The protocol-specified primary HRQoL end HRQoL compliance and completion point was least-squares mean (LSM) change from baseline to week 12, which was assessed using a constrained lon- EORTC QLQ-C30 compliance rates were 92.0% and gitudinal data analysis model, with HRQoL score as the 92.9%, respectively, at baseline in the pembrolizumab response variable and treatment-by-time interaction and group and the paclitaxel group and remained high (86.6% trial stratification factors as covariates. and 82.1%, respectively) for patients on study at week Multiple imputations based on the missing-at-random 12 (Table 1). Completion rates decreased over time, and assumption were used in the analysis of improved, stable, 51.6% of patients in the pembrolizumab group and 55.2% and deteriorated results from baseline to week 12. TTD in of patients in the paclitaxel group completed the question- EORTC QLQ-C30 GHS/QoL score was estimated using the naire at week 12. At week 12, patients in the pembroli- Kaplan–Meier method; the hazard ratio was estimated with zumab group discontinued because of disease progression a stratified (by geographic region and time to progression on (31.4%), patient/physician decision (2.2%), adverse event first-line therapy) Cox proportional hazards model. (AE; 1.1%), or death (1.1%) and patients in the pacli- taxel group discontinued because of disease progression (22.4%), patient/physician decision (3.3%), AE (4.9%), Results or death (0.5%). EORTC QLQ-STO22 and EQ-5D-3L compliance and completion rates were similar to those Patients observed for the EORTC QLQ-C30 (Online Resource Tables 1 and 2). The primary study population comprised 395 patients with CPS ≥ 1 (pembrolizumab, n = 196; paclitaxel, n = 199) [9]. At data cutoff (October 26, 2017), 2 patients in the Table 1  Rates of compliance Treatment Visit Compliancea Completionb and completion of the EORTC QLQ-C30 Pembrolizumab Paclitaxel Pembrolizumab Paclitaxel n/N (%) n/N (%) n/N (%) n/N (%) Baseline 173/188 (92.0) 170/183 (92.9) 173/188 (92.0) 170/183 (92.9) Week 3 or 4 161/178 (90.4) 127/179 (70.9) 161/188 (85.6) 127/183 (69.4) Week 6 134/159 (84.3) 117/162 (72.2) 134/188 (71.3) 117/183 (63.9) Week 9 113/132 (85.6) 107/140 (76.4) 113/188 (60.1) 107/183 (58.5) Week 12 97/112 (86.6) 101/123 (82.1) 97/188 (51.6) 101/183 (55.2) Week 18 77/91 (84.6) 70/95 (73.7) 77/188 (41.0) 70/183 (38.3) Week 24 50/69 (73.5) 42/62 (67.7) 50/188 (26.6) 42/183 (23.0) Week 30 44/60 (73.3) 18/32 (56.3) 44/188 (23.4) 18/183 (9.8) Week 36 35/48 (72.9) 12/20 (60.0) 35/188 (18.6) 12/183 (6.6) Week 42 27/39 (69.2) 11/17 (64.7) 27/188 (14.4) 11/183 (6.0) Week 48 27/36 (75.0) 7/9 (77.8) 27/188 (14.4) 7/183 (3.8) EORTC​European Organisation for Research and Treatment of Cancer, QLQ-C30 Quality of Life Question- naire Core 30 a The proportion of patients who completed ≥ 1 HRQoL assessment among those expected to complete the instruments at each visit, excluding those missing by design b The proportion of patients who completed ≥ 1 HRQoL assessment among the total HRQoL analysis popu- lation at each visit 13 Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with… 1333 Table 2  Change from baseline Results Pembrolizumab Paclitaxel to week 12 in EORTC QLQ- n = 188 n = 183 C30 GHS/QOL scores Baseline n 173 171 Mean (SD) 63.05 (21.326) 62.57 (20.953) Week 12 na 98 106 Mean (SD) 63.27 (22.918) 63.68 (20.483) Change from baseline to week 12, LSM − 6.84 (− 10.87 to − 2.81) − 3.30 (− 7.22 to 0.61) (95% CI) Difference in LSM (95% CI) − 3.54 (− 8.92 to 1.84) p value 0.196 EORTC​European Organisation for Research and Treatment of Cancer, LSM least-squares mean, QLQ-C30 Quality of Life Questionnaire Core 30, SD standard deviation a Number of patients in each treatment group with nonmissing assessments at this time point Change from baseline in HRQoL b). Worsening in these domains was similar in magnitude between pembrolizumab and paclitaxel (Fig. 2a, b). Begin- EORTC QLQ‑C30 ning at week 18, GHS/QoL mean scores showed improve- ment for patients receiving pembrolizumab (Fig. 1). This Baseline GHS/QoL mean scores were similar between treat- trend was not observed in the paclitaxel group; however, ment groups (pembrolizumab, 63.05 [SD, 21.326]; pacli- comparison of GHS/QoL mean scores for patients receiving taxel, 62.57 [SD, 20.953]) (Table 2). GHS/QoL mean scores paclitaxel is limited because of low completion rates begin- worsened slightly from baseline to week 12 in both treat- ning at week 24. ment groups (LSM change: − 6.84 for pembrolizumab [95% CI –10.87 to –2.81], – 3.30 for paclitaxel [95% CI – 7.22 EORTC QLQ‑STO22 to 0.61]) (Fig. 1). The LSM score change from baseline to week 12 in GHS/QoL score was slightly worse in the pem- LSM score changes from baseline to week 12 showed worsen- brolizumab group versus the paclitaxel group (difference, ing of most EORTC QLQ-STO22 symptom subscales for both –3.54; 95% CI – 8.92 to 1.84; nominal p = 0.196). At week treatment groups (Fig. 2c); only mean score changes for anxi- 12, LSM score changes from baseline indicated worsening ety showed improvement in both groups. Mean score change of all EORTC QLQ-C30 functional subscale and of most for hair loss was nominally different between treatment groups; symptom subscale scores in both treatment groups (Fig. 2a, patients receiving paclitaxel experienced hair loss, whereas 100 Pembrolizumab Paclitaxel EORTC QLQ-C30 GHS/QoL 90 80 70 60 50 Week 0 Week 3/4 Week 6 Week 9 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 (N = 344) (N = 289) (N = 252) (N = 223) (N = 204) (N = 148) (N = 93) (N = 62) (N = 47) (N = 38) (N = 34) Study Visit Fig. 1  Mean (SE) EORTC QLQ-C30 GHS/QoL scores over time. EORTC​ European Organisation for Research and Treatment of Cancer, GHS global health status, Q3W every 3 weeks, QLQ-30 Quality of Life Questionnaire Core 30, QoL quality of life, SE standard error 13 1334 E. Van Cutsem et al. a Pembrolizumab Paclitaxel LSM Score Change from Baseline 20 16 12 Improvement 8 4 0 –4 –8 Worsening –12 –16 –20 GHS/QoL Physical Role Emotional Cognitive Social functioning functioning functioning functioning functioning b Pembrolizumab Paclitaxel LSM Score Change from Baseline 20 16 12 Worsening 8 4 0 –4 –8 Improvement –12 –16 –20 Fatigue Nausea Pain Dyspnea Insomnia Appetite Constipation Diarrhea Financial and vomitting loss difficulties c Pembrolizumab Paclitaxel LSM Score Change from Baseline 20 16 12 Worsening 8 4 0 –4 –8 Improvement –12 –16 –20 Dysphagia Pain Reflux Eating Anxiety Dry Taste Body Hair symptoms restrictions mouth image loss Fig. 2  LSM (95% CI) change from baseline to week 12 in a EORTC Treatment of Cancer, GHS global health status, LSM least-squares QLQ-C30 GHS/QoL and functional subscale scores, b EORTC QLQ- mean, Q3W every 3 weeks, QLQ-30 Quality of Life Questionnaire C30 symptom subscale scores, and c EORTC QLQ-STO22 symptom Core 30, QLQ-STO22 health-related QoL questionnaire in gastric subscale scores. EORTC​ European Organisation for Research and cancer, QoL quality of life 13 Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with… 1335 those receiving pembrolizumab did not. Mean score changes Discussion for dysphasia and eating restrictions were worse from baseline to week 12 for patients in the pembrolizumab group, but the In this prespecified exploratory analysis, the observed difference was minimal compared with scores for patients in effects in HRQoL were comparable for patients with the paclitaxel group. advanced gastric/GEJ cancer and PD-L1 CPS ≥ 1 regard- less of whether they received second-line pembrolizumab EQ‑5D‑3L monotherapy or paclitaxel. Compliance rates were high in both groups. Both treatment groups showed some worsen- At week 12, LSM changes from baseline in EQ-5D-3L utility ing of functional and symptom subscale scores at week scores and VAS indicated worsening in both groups (Online 12. The LSM of GHS/QoL scores worsened during the Resource Fig. 1). LSM for utility scores differed between first 12 weeks in both treatment groups, with a confidence groups (difference, − 0.07; 95% CI − 0.13 to − 0.01; nominal interval crossing zero for the difference in LSM; the LSM p = 0.029) but not for VAS (difference − 2.37; 95% CI − 7.17 improved in pembrolizumab-treated patients after week to 2.43; nominal p = 0.331). 18. TTD was also similar for both groups. Overall, HRQoL as measured by the GHS/QoL and func- Proportion of patients with deteriorated tional subscales from baseline to week 12 worsened in both or improved status at week 12 groups, with overlapping confidence intervals between the treatment groups for many of the subscale scores (Figs. 1, At week 12, 41% and 33% of patients in the pembroli- 2b). Nearly all symptoms measured by the EORTC QLQ- zumab group and the paclitaxel group, respectively, C30 and the EORTC QLQ-STO22 worsened from baseline experienced deterioration from baseline in the EORTC to week 12 in both treatment groups, with many overlapping QLQ-C30 GHS/QoL mean score change; 23% in both confidence intervals between the treatment groups (Fig. 2b, groups experienced improvement (Fig. 3). Except for c). Although fatigue and diarrhea subsided in more and grew fatigue, scores for functioning and symptom subscales in fewer pembrolizumab-treated patients than paclitaxel- showed similar degrees of worsening and improvement. treated patients, the only symptom showing an apparent dif- Fatigue symptom subscale scores improved in more and ference was hair loss, which, as expected, was worse with deteriorated in fewer pembrolizumab-treated patients than paclitaxel than with pembrolizumab. As with GHS/QoL paclitaxel-treated patients (improved, 28% pembrolizumab scores, there was no difference in TTD at week 12 between and 22% paclitaxel; deteriorated, 36% pembrolizumab and treatment groups in the EORTC QLQ-C30 subscales for 50% paclitaxel) (Fig. 3). nausea/vomiting and appetite loss or in the EORTC QLQ- STO22 scale for pain. However, these results were consistent Time to deterioration with the primary safety analysis of all patients (regardless of CPS status) from KEYNOTE-061, in which fewer patients Among the 41% pembrolizumab-treated and 33% of experienced treatment-related AEs in the pembrolizumab paclitaxel-treated patients who experienced deteriora- group (53% overall, 14% grade 3–5) than in the paclitaxel tion in GHS/QoL scores, median TTD was 10.1 months group (84% and 35%, respectively) [9]. Additionally, we in the pembrolizumab group and 6.9 months in the pacli- observed a worsening of utility scores in both treatment taxel group (HR 1.06; 95% CI 0.71–1.58) (Fig. 4a); the groups using the descriptive EQ-5D-3L questionnaire. Kaplan–Meier plot revealed a slightly lower curve in the Interpretation of the observations from this explora- first 3 months in the pembrolizumab group compared tory analysis may be limited by the open-label nature of with the paclitaxel group. Median TTD was similar for the trial and the short duration of follow-up attributed to pembrolizumab and paclitaxel for the EORTC QLQ- the high rate of discontinuation, usually because of dis- C30 subscales for nausea/vomiting (HR 0.81; 95% CI ease progression. As previously discussed in the primary 0.50–1.33; 15% of all patients in both groups experi- analysis of KEYNOTE-061, we observed crossing of the enced deterioration) and appetite loss (HR 1.22; 95% survival curves in the second-line setting, suggesting that CI 0.76–1.96; 36% of pembrolizumab-treated and 27% some pembrolizumab-treated patients experienced early of paclitaxel-treated patients experienced deterioration) disease progression and poor outcomes [9]. However, there and for EORTC QLQ-STO22 pain (HR 1.09; 95% CI was a trend toward better outcomes for pembrolizumab- 0.65–1.83; 29% of pembrolizumab-treated and 27% of treated patients who achieved disease control and could be paclitaxel-treated patients experienced deterioration) maintained on therapy, as evidenced by the latter part of (Fig. 4b–d). the survival curve [9]. These findings may be attributed to 13 1336 E. Van Cutsem et al. Fig. 3  Proportion of patients a with deteriorated or improved GHS/QoL 23% 36% 41% status in EORTC QLQ-C30 Physical functioning 11% 48% 40% scores at week 12. a Pembroli- zumab. b Paclitaxel. EORTC​ Role functioning 19% 40% 41% European Organisation for Research and Treatment of Emotional functioning 15% 54% 31% Cancer, GHS, global health Cognitive functioning 16% 49% 35% status; QLQ-30 Quality of Life Questionnaire Core 30, QLQ- Social functioning 20% 45% 36% STO22, health-related QoL questionnaire in gastric cancer; Fatigue 28% 36% 36% QoL, quality of life Nausea and vomiting 15% 52% 34% Pain (QLQ-C30) 23% 39% 38% Dyspnea 12% 57% 31% Insomnia 27% 44% 29% Appetite loss 30% 34% 36% Constipation 28% 45% 28% Diarrhea (QLQ-C30) 14% 64% 22% Financial difficulties 20% 60% 20% Pain (QLQ-STO22) 23% 47% 29% 0% 20% 40% 60% 80% 100% Improved Stable Deteriorated b GHS/QoL 23% 44% 33% Physical functioning 14% 44% 43% Role functioning 21% 42% 38% Emotional functioning 21% 50% 29% Cognitive functioning 18% 50% 32% Social functioning 22% 45% 33% Fatigue 22% 28% 50% Nausea and vomiting 15% 49% 36% Pain (QLQ-C30) 30% 33% 37% Dyspnea 14% 56% 30% Insomnia 25% 46% 28% Appetite loss 29% 44% 27% Constipation 25% 46% 28% Diarrhea (QLQ-C30) 14% 58% 27% Financial difficulties 23% 55% 22% Pain (QLQ-STO22) 23% 49% 27% 0% 20% 40% 60% 80% 100% Improved Stable Deteriorated 13 Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with… 1337 Fig. 4  TTD in the a EORTC a 100 QLQ-C30 GHS/QoL scale, b EORTC QLQ-C30 nausea/ No Deterioration, % 80 vomiting subscale, c EORTC 60 QLQ-C30 appetite loss sub- scale, and d EORTC QLQ- 40 STO22 pain subscale. GHS global health status, Q3W every 20 Pembrolizumab Paclitaxel 3 weeks, QLQ-30 Quality of 0 Life Questionnaire Core 30, 0 3 6 9 12 15 18 QLQ-STO22 health-related QoL Months questionnaire in gastric cancer, No. at risk QoL quality of life, TTD time to Pembrolizumab 173 61 32 24 11 9 8 deterioration Paclitaxel 171 62 15 9 4 1 1 b 100 No Deterioration, % 80 60 40 20 Pembrolizumab Paclitaxel 0 0 3 6 9 12 15 18 Months No. at risk Pembrolizumab 173 70 44 27 11 9 8 Paclitaxel 171 69 20 9 3 1 1 c 100 80 No Deterioration, % 60 40 20 Pembrolizumab Paclitaxel 0 0 3 6 9 12 15 18 Months No. at risk Pembrolizumab 173 65 40 26 11 9 8 Paclitaxel 171 74 20 5 2 1 1 d 100 No Deterioration, % 80 60 40 20 Pembrolizumab Paclitaxel 0 0 3 6 9 12 15 18 Months No. at risk Pembrolizumab 171 70 42 30 11 9 8 Paclitaxel 171 73 23 11 4 1 1 13 1338 E. Van Cutsem et al. the time it takes to induce an antitumor immune response matter experts; after approval of the statistical analysis plan [9]. As a result, the HRQoL data must be carefully inter- and execution of a data-sharing agreement, MSD will either preted with these findings in mind. Another limitation of perform the proposed analyses and share the results with this HRQoL analysis was the week 12 end point because the requestor or will construct biomarker covariates and add separation between the treatment groups in the GHS/QoL them to a file with clinical data that is uploaded to an analy- score appeared after that point. sis portal so that the requestor can perform the proposed analyses. Conclusions Supplementary Information The online version contains supplemen- tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 10120-0​ 21-0​ 1200-w. In the KEYNOTE-061 trial comparing pembrolizumab Acknowledgements We thank the patients and their families as well as and paclitaxel as second-line treatments for patients with the investigators and site personnel involved in the study. Medical writ- advanced gastric/GEJ cancer and PD-L1 CPS ≥ 1, the study ing and/or editorial assistance was provided by Tim Peoples, MA, ELS, groups experienced generally similar HRQoL from base- Traci Stuve, MA, and Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & line through 12 weeks. In overall scores and in specific sub- Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. scales and items, pembrolizumab did not appear to worsen HRQoL to a greater extent than paclitaxel. Even though the Author contributions Conception, design, or planning of the study: HRQoL questionnaires were not intended to evaluate AEs, EVC, M. Amonkar, CSF, JMN, and KS. Analysis of the data: EVC, these results suggest that patient-reported impacts of specific MO, HCC, KM, ZAW, and XC. Acquisition of the data: EVC, M. Alsina, MO, YJB, HCC, EG, AB, WS, ZAW, CSS, and KS. Interpre- symptoms (e.g., fatigue, hair loss, decreased appetite) were tation of the results: EVC, M. Amonkar, CSF, M. Alsina, MO, YJB, consistent with the safety results of KEYNOTE-061, which HCC, ZAW, JMN, XC, CSS, and KS. Drafting of the manuscript: MO, showed fewer AEs with pembrolizumab than paclitaxel. HCC, and KS. Critically reviewing or revising the manuscript for important intellectual content: all authors. Final approval: all authors. Funding This study was sponsored by Merck Sharp & Dohme Corp., Data sharing a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Declarations Inc., Kenilworth, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data Conflict of interest E. Van Cutsem has received research funding (to and clinical study reports from the company’s clinical trials his institution) from Amgen, Bayer, Boehringer Ingelheim, Bristol for the purpose of conducting legitimate scientific research. Myers Squibb, Celgene, Ipsen, Lilly, Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, MSD is also obligated to protect the rights and privacy of USA, Novartis, Roche, and Servier. He has also served in an advi- trial participants and, as such, has a procedure in place for sory/consultancy role for Astellas, AstraZeneca, Bayer, Bristol My- evaluating and fulfilling requests for sharing company clini- ers Squibb, Celgene, Incyte, Lilly, Merck Sharp & Dohme Corp., a cal trial data with qualified external scientific researchers. subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. M. Amonkar reports employment at The MSD data-sharing website (available at: http://​engag​ Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Ke- ezone.m ​ sd.c​ om/d​ s_d​ ocume​ ntati​ on.p​ hp) outlines the process nilworth, NJ, USA, and is stockholder of Merck & Co., Inc., Kenil- and requirements for submitting a data request. Applications worth, NJ, USA. C. S. Fuchs served in an advisory/consultancy role for will be promptly assessed for completeness and policy com- Agios, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeu- pliance. Feasible requests will be reviewed by a committee tics, Genentech, Merck, Taiho, and Unum Therapeutics. He also serves of MSD subject matter experts to assess the scientific valid- as a director for CytomX Therapeutics and owns unexercised stock op- ity of the request and the qualifications of the requestors. In tions for CytomX and Entrinsic Health. He is a cofounder of EvolveIm- line with data privacy legislation, submitters of approved mune Therapeutics and has equity in this private company. M. Alsina has received honoraria from Bristol Myers Squibb, Lilly, MSD, and requests must enter into a standard data-sharing agreement Servier and served in an advisory/consultancy role for Bristol Myers with MSD before data access is granted. Data will be made Squibb, Lilly, MSD, and Servier. M. Özgüroğlu has received hono- available for request after product approval in the US and EU raria (personal and to his institution) from Astellas, Janssen, Novartis, or after product development is discontinued. There are cir- Roche, and Sanofi; served in an advisory/consultancy role for Astel- las, Janssen, and Sanofi; and received travel/accommodations from cumstances that may prevent MSD from sharing requested AstraZeneca, Bristol Myers Squibb, and Janssen. Y.-J. Bang served in data, including country or region-specific regulations. If the an advisory/consultancy role for AstraZeneca, Novartis, Genentech/ request is declined, it will be communicated to the investiga- Roche, MSD, Merck Serono, Bayer, Bristol Myers Squibb, Eli Lilly, tor. Access to genetic or exploratory biomarker data requires Taiho, Daiichi-Sankyo, Astellas, BeiGene, GreenCross, Samyang Bi- opharm, Hanmi, and Genexine and received research grant/funding (to a detailed, hypothesis-driven statistical analysis plan that is his institution) from MSD, AstraZeneca, Novartis, Genentech/Roche, collaboratively developed by the requestor and MSD subject 13 Health‑related quality of life in advanced gastric/gastroesophageal junction cancer with… 1339 Merck Serono, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, permitted by statutory regulation or exceeds the permitted use, you will Eli Lilly, Boehringer Ingelheim, MacroGenics, Boston Biomedical, need to obtain permission directly from the copyright holder. To view a FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, Bei- copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Gene, Green Cross, CKD Pharma, and Genexine. H. C. Chung has received honoraria from Merck Serono, Lilly, Foundation Medicine; served in an advisory/consultancy role for Taiho, Celltrion, MSD, Lil- ly, Quintiles, Bristol Myers Squibb, Merck Serono, Gloria, BeiGene, References Amgen, and Zymeworks; and received research grants/funding (to his institution) from Lilly, GlaxoSmithKline, MSD, Merck Serono, Bristol 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal Myers Squibb/Ono, Taiho, Amgen, and BeiGene. K. Muro has received A. Global cancer statistics 2018: GLOBOCAN estimates of inci- honoraria for speaking from Bristol Myers Squibb, Eli Lilly, Chugai dence and mortality worldwide for 36 cancers in 185 countries. Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Ono CA: Cancer J Clin. 2018;68:394–424. Pharmaceutical Co., Ltd., and Sanofi; served in an advisory/consul- 2. Casamayor M, Morlock R, Maeda H, Ajani J. Targeted literature tancy role for AstraZeneca, Amgen, and Ono Pharmaceutical Co., Ltd; review of the global burden of gastric cancer. Ecancer Med Sci. and received research funding (to his institution) from MSD, Daiichi 2018;12:883. Sankyo, Parexel International, Sumitomo Dainippon Pharma, Pfizer, 3. McKernan M, McMillan DC, Anderson JR, Angerson WJ, Stuart Mediscience Planning, Solasia Pharma, and Sanofi. E. Goekkurt has RC. The relationship between quality of life (EORTC QLQ-C30) served in an advisory/consultancy role for Bristol Myers Squibb, Lilly, and survival in patients with gastro-oesophageal cancer. Br J Can- Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck cer. 2008;98:888–93. & Co., Inc., Kenilworth, NJ, USA, Roche, and Servier. A. Benson has 4. National Comprehensive Cancer Network. NCCN clinical practice served in an advisory/consultancy role for CN, Bristol Myers Squibb, guidelines in oncology: gastric cancer (Version 4.2020). Patient Resource (educational document review), Research to Practice, 5. van Kleef JJ, Ter Veer E, van den Boorn HG, Schokker S, Ngai AVBCC, Harborside, Therabionic, Guardant, Merck (DMC), Terumo, LL, Prins MJ, et al. Quality of life during palliative systemic Lexicon, ACCC, ECOG-ACRIN, Amgen, Imedex, Artemida Pharma, therapy for oesophagogastric cancer: systematic review and meta- Intellisphere OncLiv, American College of Radiology, China National analysis. J Natl Cancer Inst. 2020;112:12–29. Medical Association 6th Affiliated Sun Yat-Sen Hospital, Springer, 6. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Health Advances, Lexicon, Array (Pfizer), NCCN, and ACCC. W. Sun et al. Pembrolizumab for patients with PD-L1-positive advanced has received research grant/funding (personal and to his institution) gastric cancer (KEYNOTE-012): a multicentre, open-label, phase from Merck. Z. A. Wainberg has served in an advisory/consultancy 1b trial. Lancet Oncol. 2016;17:717–26. role for AstraZeneca, Bayer, Daiichi, Five Prime, Lilly, Merck, and 7. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Molecular Templates; received funding (to his institution) from As- Safety and efficacy of pembrolizumab monotherapy in patients traZeneca, Daiichi, Five Prime, Lilly, and Merck; and received travel/ with previously treated advanced gastric and gastroesophageal accommodations from Bayer, Daiichi, Lilly, Merck, and Molecular junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Templates. J. M. Norquist is an employee of Merck Sharp & Dohme Oncol. 2018;4:e180013. Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and a 8. KEYTRUDA® (pembrolizumab) for injection, for intravenous use, stockholder in Merck & Co., Inc., Kenilworth, NJ, USA. X. Chen is 03/2021. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck USA 2021. & Co., Inc., Kenilworth, NJ, USA and a stockholder in Merck & Co., 9. Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandalà M, Inc., Kenilworth, NJ, USA. C.-S. Shih is an employee of Merck Sharp Ryu M-H, et al. Pembrolizumab versus paclitaxel for previously & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, treated, advanced gastric or gastro-oesophageal junction cancer USA and a stockholder in Merck & Co., Inc., Kenilworth, NJ, USA. (KEYNOTE-061): a randomised, open-label, controlled, phase 3 K. Shitara has received honoraria from AbbVie, Novartis, and Yakult; trial. Lancet. 2018;392:123–33. served in an advisory/consultancy role for Astellas Pharma, Lilly, Bris- 10. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, tol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Duez NJ, et al. The European Organization for Research and Novartis, AbbVie, GlaxoSmithKline; and received research grants/ Treatment of Cancer QLQ-C30: a quality-of-life instrument for funding (to his institution) from Lilly, Ono Pharmaceutical, Dainip- use in international clinical trials in oncology. J Natl Cancer Inst. pon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, 1993;85:365–76. Chugai Pharmaceutical, Astellas Pharma, and Mediscience. 11. Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S. Test/retest study of the European organization for research and treatment of cancer Human rights statement and informed consent The study was con- core quality-of-life questionnaire. J Clin Oncol. 1995;13:1249–54. ducted in accordance with the protocol and its amendments and with 12. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the Good Clinical Practice guidelines. significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139–44. Informed consent All patients provided written informed consent 13. Ringdal GI, Ringdal K. Testing the EORTC Quality of Life Ques- before enrollment. tionnaire on cancer patients with heterogeneous diagnoses. Qual Life Res. 1993;2:129–40. 14. Vickery CW, Blazeby JM, Conroy T, Arraras J, Sezer O, Koller Open Access This article is licensed under a Creative Commons Attri- M, et al. Development of an EORTC disease-specific quality of bution 4.0 International License, which permits use, sharing, adapta- life module for use in patients with gastric cancer. Eur J Cancer. tion, distribution and reproduction in any medium or format, as long 2001;37:966–71. as you give appropriate credit to the original author(s) and the source, 15. Blazeby JM, Conroy T, Bottomley A, Vickery C, Arraras J, Sezer provide a link to the Creative Commons licence, and indicate if changes O, et al. Clinical and psychometric validation of a questionnaire were made. The images or other third party material in this article are module, the EORTC QLQ-STO 22, to assess quality of life in included in the article's Creative Commons licence, unless indicated patients with gastric cancer. Eur J Cancer. 2004;40:2260–8. otherwise in a credit line to the material. If material is not included in 16. The EuroQol Group. EuroQol—a new facility for the measurement the article's Creative Commons licence and your intended use is not of health-related quality of life. Health Policy. 1990;16:199–208. 13 1340 E. Van Cutsem et al. 17. The EuroQol Group. EQ-5D-3L: a measure of health-related qual- Publisher's Note Springer Nature remains neutral with regard to ity of life. https://​euroq​ol.​org/​eq-​5d-​instr​uments/​eq-​5d-​3l-​about/. jurisdictional claims in published maps and institutional affiliations. Accessed September 28, 2020. Authors and Affiliations Eric Van Cutsem1 · Mayur Amonkar2 · Charles S. Fuchs3 · Maria Alsina4 · Mustafa Özgüroğlu5 · Yung‑Jue Bang6 · Hyun Cheol Chung7 · Kei Muro8 · Eray Goekkurt9 · Al B. Benson III10 · Weijing Sun11 · Zev A. Wainberg12 · Josephine M. Norquist2 · Xinqun Chen13 · Chie‑Schin Shih13 · Kohei Shitara14 1 8 Department of Digestive Oncology, University Hospitals Department of Clinical Oncology, Aichi Cancer Center Gasthuisberg Leuven and KU Leuven, 49 Herestraat, Hospital, Nagoya, Japan Leuven, Belgium 9 North‑German Trial Center for Innovative Oncology, 2 Center for Observational and Real World Evidence, Merck & Hematology Oncology Practice Eppendorf, University Co., Inc., Kenilworth, NJ, USA Cancer Center Hamburg, Hamburg, Germany 3 10 Yale Cancer Center, Yale School of Medicine, New Haven, Robert H. Lurie Comprehensive Cancer Center, Division CT, USA of Hematology‑Oncology, Feinberg School of Medicine, 4 Northwestern University, Chicago, IL, USA Department of Medical Oncology, Vall d’Hebron University 11 Hospital and Institute of Oncology, University Autònoma de Department of Internal Medicine and Medical Oncology, Barcelona, Barcelona, Spain University of Kansas, Westwood, KS, USA 5 12 Department of Internal Medicine, Medical Oncology, Department of Medicine and Hematology and Oncology, and Clinical Trial Unit, Cerrahpaşa School of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Istanbul University–Cerrahpaşa, Istanbul, Turkey CA, USA 6 13 Department of Internal Medicine, Seoul National University Department of Medical Oncology, Merck & Co., Inc., College of Medicine, Seoul, South Korea Kenilworth, NJ, USA 7 14 Department of Medical Oncology, Yonsei Cancer Center, Department of Gastrointestinal Oncology, National Cancer Yonsei University College of Medicine, Seoul, South Korea Center Hospital, Chiba, Japan 13