ORIGINAL RESEARCH Quality of life with first-line pembrolizumab for PD-L1epositive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study E. Van Cutsem1*, A. Valderrama2, Y.-J. Bang3, C. S. Fuchs4, K. Shitara5, Y. Y. Janjigian6, S. Qin7, T. G. Larson8, V. Shankaran9, S. Stein4, J. M. Norquist2, U. Kher10, S. Shah10 & M. Alsina11,12 1 Department of Digestive Oncology, University Hospital Gasthuisberg Leuven and KU Leuven, Leuven, Belgium; 2Center for Observational and Real-World Evidence, Merck & Co., Inc., Kenilworth, USA; 3Department of Biomedical Research, Seoul National University College of Medicine, Seoul, South Korea; 4Department of Internal Medicine: Hematology, Medical Oncology, Gastro-oncology, Yale University Cancer Center, Smilow Cancer Hospital, New Haven, USA; 5Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 6Department of Gastrointestinal Oncology, Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; 7Cancer Center, PLA Cancer Centre of Nanjing Bayi Hospital, Nanjing, China; 8Department of Hematology/Oncology, Minnesota Oncology Hematology, Minneapolis; 9Department of Medical Oncology, Seattle Cancer Care Alliance, Seattle; 10Department of Medical Oncology, Merck & Co., Inc., Kenilworth, USA; 11Department of Medical Oncology, Vall d’Hebron University Hospital and Institute of Oncology, Barcelona; 12University Autònoma de Barcelona, Barcelona, Spain Available online 7 August 2021 Background: In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) 1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality- of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population. Materials and methods: HRQOL, a secondary endpoint, was measured in patients who received 1 dose of study treatment and completed 1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated. Results: The HRQOL population comprised 495 patients with CPS 1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [0.16; 95% confidence interval (CI) 5.01 to 4.69; P ¼ 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P ¼ 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P ¼ 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P ¼ 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P ¼ 0.003). Conclusions: HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1epositive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population. Key words: gastric cancer, gastroesophageal cancer, pembrolizumab, quality of life, patient-reported outcomes INTRODUCTION (sixth most common among cancer types) and almost Gastric cancer is among the most commonly diagnosed 800 000 deaths (third most leading cause of cancer deaths) cancers globally, with an incidence of >1 million new cases annually.1 The 5-year survival rate for patients with advanced stage gastric/gastroesophageal junction (GEJ) cancer is 5%-10%.2 Advanced gastric/GEJ cancer is also *Correspondence to: Prof Eric Van Cutsem, MD, PhD, Department of Digestive Oncology, University Hospital Gasthuisberg Leuven and KU Leuven, 49 Here- marked by worsening overall health-related quality of life straat, 3001 Leuven, Belgium. Tel: þ32-16-34-42-18 (HRQOL) as measured by validated questionnaires. Physical, E-mail: eric.vancutsem@uzleuven.be (E. Van Cutsem). social and emotional functioning and the disease-related 2059-7029/© 2021 Published by Elsevier Ltd on behalf of European Society symptom profile (weight loss, abdominal pain, vomiting, for Medical Oncology. This is an open access article under the CC BY-NC-ND gastric obstruction, bleeding) are more burdensome in the license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 1 ESMO Open E. Van Cutsem et al. advanced stage of gastric/GEJ cancer than in earlier stages. pembrolizumab monotherapy or pembrolizumab plus In addition, chemotherapy is known to cause drug-related chemotherapy versus chemotherapy in patients with symptoms (abdominal pain, fatigue, nausea/vomiting, advanced gastric/GEJ cancer (Supplementary Figure S1, diarrhoea) in patients with advanced gastric/GEJ cancer.2 available at https://doi.org/10.1016/j.esmoop.2021.100189). For most patients with advanced gastric/GEJ cancer, the In the primary analysis, pembrolizumab versus chemo- standard of care first-line treatment is doublet chemo- therapy met the criteria for non-inferiority, whereas therapy,3-6 which offers a modest but statistically significant pembrolizumab-chemotherapy versus chemotherapy did benefit of about 1 month in overall survival (OS) compared not meet the criteria for superiority.12 Therefore, we with single-agent chemotherapy.7 Chemotherapy regimens focused on the HRQOL outcomes for pembrolizumab used as first-line therapy, regardless of type, have been monotherapy compared with chemotherapy in this HRQOL found to maintain HRQOL over time.8 analysis. Details of this comparison in the primary study The programmed death 1 (PD-1) inhibitor pembrolizumab have been reported elsewhere and are briefly summarised has demonstrated antitumour activity and a manageable here.12 Eligible patients had locally advanced unresectable toxicity profile in patients with programmed death-ligand 1 or metastatic gastric/GEJ adenocarcinoma that was human (PD-L1)epositive [combined positive score (CPS) 1] epidermal growth factor receptor 2 (HER2)/neu-negative advanced gastric/GEJ adenocarcinoma.9,10 In cohort 1 of the and PD-L1epositive (CPS 1) and Eastern Cooperative phase II KEYNOTE-059 trial (NCT02335411), pembrolizumab Oncology Group performance status 0 or 1. PD-L1 positivity monotherapy was given to patients with gastric/GEJ was tested using PD-L1 IHC 22C3 pharmDx (Agilent Tech- adenocarcinoma in the third-line or later setting. Among nologies, Carpinteria, CA, USA) and was measured using CPS patients whose tumours express CPS 1, the objective [defined as the number of PD-L1epositive cells (tumour response rate (ORR) was 16% and the median duration of cells, lymphocytes, macrophages) as a proportion of the response (DOR) was 16 months.10 Pembrolizumab also total number of viable tumour cells  100]. Patients were demonstrated antitumour activity in patients with previously randomly assigned 1 : 1 : 1 to pembrolizumab 200 mg, untreated gastric/GEJ adenocarcinoma enrolled in cohorts 2 pembrolizumab-chemotherapy [cisplatin 80 mg/m2/day on (pembrolizumab plus chemotherapy) and 3 (pembrolizumab day 1 plus 5-fluorouracil (FU) 800 mg/m2/day on days 1 to 5 monotherapy) of the KEYNOTE-059 study; patients in cohort or capecitabine 1000 mg/m2 twice daily] or placebo- 3 were required to have CPS 1 tumours. The ORR was chemotherapy every 3 weeks for a maximum of 35 cycles 60% in cohort 2 and 26% in cohort 3, and safety was (w2 years). The chemotherapy regimen was decided by the tolerable with both regimens.11 The KEYNOTE-062 trial investigator before randomisation. (NCT02494583) was a randomised, active-controlled, phase The study protocol and all amendments were approved III study of pembrolizumab as monotherapy or in combina- by the appropriate ethics committee at each centre. The tion with chemotherapy compared with placebo plus study was conducted in accordance with the protocol, its chemotherapy as first-line treatment of patients with amendments and the standards of Good Clinical Practice. advanced gastric or GEJ cancer. At the final analysis, pem- All patients provided written informed consent. brolizumab monotherapy was non-inferior to chemotherapy for OS among patients with CPS 1 tumours [median OS, 10.6 versus 11.1 months; hazard ratio (HR), 0.91; 99.2% HRQOL outcomes and assessments confidence interval (CI), 0.69-1.18 (prespecified non- HRQOL outcomes reported here were prespecified sec- inferiority margin ¼ 1.2)].12 Although not formally tested, ondary and exploratory endpoints from KEYNOTE-062. there was a clinically meaningful improvement in OS in pa- Secondary endpoints included mean change from baseline tients with CPS 10 tumours (median OS, 17.4 versus 10.8 to week 18 in the global health status/quality-of-life (GHS/ months; HR, 0.69; 95% CI, 0.49-0.97). Pembrolizumab mon- QOL), functioning and symptom scores of the European otherapy offered an improved safety profile with a lower Organisation for the Research and Treatment of Cancer incidence of any-grade (54% versus 92%) and grade 3-4 (EORTC) core 30 quality-of-life questionnaire (QLQ-C30) and (16% versus 68%) treatment-related adverse events (AEs) the EORTC QLQ 22-question quality-of-life gastric cancer- compared with chemotherapy.12 specific module (QLQ-STO22) as well as time to deteriora- Here we present findings from the prespecified second- tion (TTD) in the GHS/QOL, nausea/vomiting and appetite ary and exploratory HRQOL analyses in patients with CPS loss scores of the EORTC QLQ-C30 and the abdominal pain/ 1 gastric/GEJ cancer who received pembrolizumab mon- discomfort scores of the EORTC QLQ-STO22. Week 18 was otherapy versus chemotherapy in the KEYNOTE-062 trial. selected based on a blinded review of compliance/ completion rates where rates were 60%-80%. Health status MATERIALS AND METHODS from the EuroQol five-dimension, three-level (EQ-5D-3L) questionnaire was an exploratory endpoint. Study design and patients HRQOL questionnaires were administered by qualified KEYNOTE-062 (ClinicalTrials.gov: NCT02494583) was a site personnel and completed electronically by the patient, global, randomised, phase III clinical trial of first-line before study drug administration or AE/disease status 2 https://doi.org/10.1016/j.esmoop.2021.100189 Volume 6 - Issue 4 - 2021 E. Van Cutsem et al. ESMO Open evaluation and in the following order: EQ-5D-3L, EORTC were summarised through week 48 to further depict trends. QLQ-C30, EORTC QLQ-STO22. The EQ-5D-3L is a stand- The KaplaneMeier method was used to estimate the TTD ardised instrument that has been translated into 170 lan- survival curve for the GHS/QOL score and subscales of the guages and provides data for use in economic models and EORTC QLQ-C30 and EORTC QLQ-STO22.17 The TTD analysis analyses of health utility or quality-adjusted life-years and was censored at death. Cox proportional hazards model addresses five health state dimensions: mobility, self-care, with treatment as a covariate was used to assess the usual activities, pain/discomfort and anxiety/depression.13 magnitude of treatment differences. The median TTD HR The EORTC QLQ-C30 is a widely used and well-validated and 95% CI were reported. cancer-specific HRQOL instrument that has been trans- Analyses were conducted using the final analysis data lated to and validated in 81 languages and comprises a cut-off date of 26 March 2019 [median follow-up, 11.3 GHS/QOL scale, five functional dimensions (physical, role, months (range, 0.2-41.2 months)]. emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting and pain) and six single-item RESULTS measures (dyspnoea, sleep disturbance, appetite loss, constipation, diarrhoea and financial difficulties).14 The Patients EORTC QLQ-STO22, designed for use in clinical trials in A total of 763 patients were randomly assigned in KEYNOTE- addition to the EORTC QLQ-C30 to assess disease-specific 062 (pembrolizumab monotherapy, n ¼ 256; pem- treatment measures and translated into 60 languages, brolizumab plus chemotherapy, n ¼ 257; chemotherapy, consists of 22 items: symptoms of dysphagia (three items), n ¼ 250).12 The HRQOL population in the current analysis of pain (four items), reflux symptoms (three items), eating pembrolizumab monotherapy versus chemotherapy restrictions (five items), anxiety (three items), dry mouth, comprised 495 patients who received treatment and taste, body image and hair loss.15 Questionnaires were completed 1 HRQOL questionnaire by the final analysis administered at baseline; at weeks 3, 6, 9 and 12; every 6 (26 March 2019): 252 in the pembrolizumab arm and 243 in weeks thereafter up to 1 year or end of treatment the chemotherapy arm. (whichever came first); and at the 30-day post-treatment discontinuation follow-up visit. As previously defined for the EORTC QLQ-C30, a mean HRQOL compliance and completion change of 5 to 10 points in EORTC QLQ-C30 scores repre- Among patients in the HRQOL analysis population, compli- sents a small change (‘little’ change as reported by pa- ance rates at week 18 were similar in the pembrolizumab tients), 10 to 20 points represents a moderate change and arm and the chemotherapy arm for EORTC QLQ-C30 (87.9% >20 points represents a large change (‘very much’ as re- and 81.9%), EORTC QLQ-STO22 (87.9% and 81.3%) and EQ- ported by patients); a decline from baseline of 10 points 5D-3L (87.9% and 82.5%) questionnaires, respectively. on the functional or global health and QOL scales was Completion rates of all three questionnaires decreased from considered a clinically meaningful deterioration.16 There- baseline because of treatment discontinuation attributed fore, deterioration was defined as a 10-point decline from to disease progression, death or AEs (Supplementary baseline when measuring TTD. Tables S1-S3, available at https://doi.org/10.1016/j.esmoop. 2021.100189). Statistical analysis The HRQOL analysis population comprised all patients who Change in HRQOL from baseline to week 18 received 1 dose of study treatment and completed 1 EORTC QLQ-C30 and EORTC QLQ-STO22. Baseline GHS/QOL HRQOL questionnaire. Compliance and completion rates scores of the EORTC QLQ-C30 were well balanced between were summarised by treatment arm and visit and were the pembrolizumab and chemotherapy arms (Table 1). reported for all three HRQOL questionnaires. Compliance At week 18, mean GHS/QOL scores were 66.4 [standard rate was defined as the proportion of patients who deviation (SD) 20.2] with pembrolizumab and 63.6 (SD completed 1 HRQOL questionnaire among those expected 20.2) with chemotherapy. No clinically meaningful to complete the questionnaires at each visit (excluding between-arm differences in LSM score were observed (LSM patients missing by design because they discontinued study difference, 0.16; 95% CI, 5.0 to 4.7; nominal P ¼ 0.948). treatment). Completion rate was defined as the proportion Results were similar for the EORTC QLQ-C30 symptom of patients who completed 1 HRQOL questionnaire subscales of nausea/vomiting and appetite loss and the among the total HRQOL analysis population at each visit. EORTC QLQ-STO22 symptom subscale of pain (Table 1). Change in least squares mean (LSM) score from baseline to The LSM score change from baseline to week 18 for most of week 18 was assessed using a constrained longitudinal data the EORTC QLQ-C30 and EORTC QLQ-STO22 function and analysis model based on the missing-at-random assump- symptom subscales showed comparable worsening in both tion. Descriptive analyses of mean score and mean score treatment arms (Figure 1). The largest between-arm dif- changes from baseline [standard error (SE)] in the GHS/ ference in LSM score was for the taste subscale of the QOL and subscale scores of the EORTC QLQ-C30 and EORTC QLQ-STO22, whereas patients in the chemotherapy nausea/vomiting subscale scores for the EORTC QLQ-STO22 arm reported greater worsening. Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 3 ESMO Open E. Van Cutsem et al. Table 1. Change from baseline in EORTC QLQ-C30 GHS/QOL symptom scores and EORTC QLQ-STO22 symptom subscale scores at week 18 Treatment Baseline score, Week 18 score, Change from baseline at Difference in LSM (95% CI) mean (SD) mean (SD) week 18, LSM (95% CI)a EORTC QLQ-C30 GHS/QOL Pembrolizumab n ¼ 239 n ¼ 102 n ¼ 251 62.7 (21.8) 66.4 (20.2) 1.9 (5.8 to 2.0) 0.16 (5.0 to 4.7) Chemotherapy n ¼ 234 n ¼ 140 n ¼ 243 P ¼ 0.948 62.4 (21.1) 63.6 (20.2) 1.8 (5.2 to 1.7) EORTC QLQ-C30 nausea/vomiting Pembrolizumab n ¼ 239 n ¼ 102 n ¼ 251 16.1 (21.9) 15.9 (23.3) 5.8 (1.3-10.3) 2.1 (7.8 to 3.7) Chemotherapy n ¼ 234 n ¼ 140 n ¼ 243 P ¼ 0.477 16.8 (21.9) 21.2 (25.2) 7.9 (4.0-11.8) EORTC QLQ-C30 appetite loss Pembrolizumab n ¼ 239 n ¼ 102 n ¼ 251 33.9 (33.9) 21.9 (29.1) 3.5 (9.4 to 2.3) 4.6 (11.9 to 2.7) Chemotherapy n ¼ 234 n ¼ 140 n ¼ 243 P ¼ 0.217 36.6 (33.3) 32.9 (30.7) 1.0 (4.1 to 6.2) EORTC QLQ-STO22 pain Pembrolizumab n ¼ 239 n ¼ 102 n ¼ 251 30.4 (22.1) 22.0 (20.2) 1.1 (4.7 to 2.4) 2.4 (2.2 to 6.9) Chemotherapy n ¼ 233 n ¼ 139 n ¼ 243 P ¼ 0.308 28.8 (21.3) 22.3 (20.4) 3.5 (6.6 to 0.4) CI, confidence interval; GHS, global health status; LSM, least squares mean; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer core 30 quality-of- life questionnaire; EORTC QLQ-STO22, European Organisation for the Research and Treatment of Cancer 22-question quality-of-life gastric cancer-specific module; QOL, quality of life; SD, standard deviation. Descriptive analyses of mean change from baseline 0.83; 95% CI, 0.58-1.20; nominal P ¼ 0.314), and EORTC revealed that GHS/QOL scores remained relatively stable for QLQ-STO22 pain subscale (HR, 1.22; 95% CI, 0.78-1.91; both arms (Figure 2A). A slight improvement was observed nominal P ¼ 0.381) were similar between arms (Figure 4A, in the pembrolizumab arm between weeks 18 and 42. C, D). Longer TTD was observed for pembrolizumab than for Descriptive analyses of mean score change from baseline chemotherapy for the EORTC QLQ-C30 nausea/vomiting through week 48 of follow-up demonstrated a general trend subscale (HR, 0.61; 95% CI, 0.44-0.85; nominal P ¼ 0.003) in improvement for the EORTC QLQ-C30 nausea/vomiting (Figure 4B). and appetite loss subscales and the EORTC QLQ-STO22 pain subscale (Figure 2B-D). However, these changes from baseline were not clinically meaningful. DISCUSSION This analysis showed that HRQOL was similar in patients EQ-5D-3L visual analogue scale. The EQ-5D-3L visual with PD-L1positive (CPS 1) advanced gastric/GEJ tu- analogue scale (VAS) score decreased from baseline to week mours who received first-line pembrolizumab and those 18 in the pembrolizumab arm (LSM score change, 5.98; who received chemotherapy. Compliance rates of the three 95% CI, 9.28 to 2.69) and the chemotherapy arm (LSM HRQOL questionnaires were high (81%) and generally score change, 4.78; 95% CI, 7.70 to 1.87), indicating equivalent between treatment arms at week 18, the pri- worsening. There was no difference in LSM between mary analysis time point for HRQOL. General HRQOL as arms (LSM difference, 1.20; 95% CI, 5.41 to 3.00; nominal measured by EORTC QLQ-C30 GHS/QOL scores were com- P ¼ 0.574) (Supplementary Figure S2, available at https:// parable between treatment arms from baseline to week doi.org/10.1016/j.esmoop.2021.100189). 18. The EQ-5D-3L VAS, which measures general HRQOL regardless of disease status, was also equivalent between arms from baseline to week 18. Time to deterioration at week 18 All five functional subscales and nearly all symptom The proportion of patients with deterioration at week 18 subscales of the EORTC QLQ-C30 showed comparable (defined as a 10-point worsening from baseline) was scores between arms. The same was true of the EORTC similar between the pembrolizumab and chemotherapy QLQ-STO22 symptom subscales with the exception of taste, arms for the GHS/QOL score, the EORTC QLQ-C30 appe- which showed a worsening trend for patients treated with tite loss subscale and the EORTC QLQ-STO22 pain sub- chemotherapy than for patients treated with pem- scale. In the EORTC QLQ-C30 nausea/vomiting subscale, brolizumab. TTD for the EORTC QLQ-C30 nausea/vomiting substantially fewer patients experienced deterioration at subscale was longer for pembrolizumab-treated patients week 18 with pembrolizumab (23.4%) than with chemo- than for chemotherapy-treated patients. The primary therapy (39.7%) (Figure 3). analysis of the KEYNOTE-062 trial demonstrated a favour- TTD in GHS/QOL (HR, 0.96; 95% CI, 0.67-1.38; nominal able safety profile for pembrolizumab monotherapy P ¼ 0.826), EORTC QLQ-C30 appetite loss subscale (HR, compared with chemotherapy. The incidence of treatment- 4 https://doi.org/10.1016/j.esmoop.2021.100189 Volume 6 - Issue 4 - 2021 E. Van Cutsem et al. ESMO Open A 20 LSM score change from baseline 18 Improvement 16 14 12 10 8 6 4 2 0 –2 –4 Worsening –6 –8 –10 –12 –14 –16 –18 –20 GHS/QOL Physical Role Emotional Cognitive Social functioning functioning functioning functioning functioning Parameter B 20 LSM score change from baseline 18 16 Worsening 14 12 10 8 6 4 2 0 Pembrolizumab –2 Improvement –4 Chemotherapy –6 –8 –10 –12 –14 –16 –18 –20 Fatigue Nausea and Pain Dyspnea Insomnia Appetite Constipation Diarrhea Financial vomiting loss difficulties Parameter C 26 LSM score change from baseline 24 22 Worsening 20 18 16 14 12 10 8 6 4 2 Improvement 0 –2 –4 –6 –8 –10 –12 –14 –16 –18 –20 Dysphagia Pain Reflux Eating Anxiety Dry Taste Body Hair symptoms restrictions mouth image loss Parameter Figure 1. LSM (95% CI) change from baseline to week 18 in (A) EORTC QLQ-C30 GHS/QOL and functional subscale scores, (B) EORTC QLQ-C30 symptom subscale scores and (C) EORTC QLQ-STO22 symptom subscale scores. CI, confidence interval; GHS, global health status; LSM, least squares mean; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer core 30 quality-of-life questionnaire; EORTC QLQ-STO22, European Organisation for the Research and Treatment of Cancer 22-question quality-of-life gastric cancer-specific module; QOL, quality of life. related AEs associated with symptom and single-item sub- patients than for chemotherapy-treated patients.12 Not all scales (fatigue, nausea, vomiting, decreased appetite, con- symptoms that occurred more frequently among stipation, diarrhoea) was lower for pembrolizumab-treated chemotherapy-treated patients resulted in an observable Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 5 ESMO Open E. Van Cutsem et al. A 20 EORTC QLQ-C30 GHS/QOL scores 18 Improvement 16 Change from baseline, 14 12 10 8 mean (± SE) 6 4 2 0 -2 -4 Worsening -6 -8 -10 -12 -14 -16 -18 -20 Week Week Week Week Week Week Week Week Week Week Week 0 3 6 9 12 18 24 30 36 42 48 Pembrolizumab 239 210 182 144 134 98 63 58 48 43 45 Chemo 234 214 175 161 174 134 108 80 65 46 42 B 20 EORTC QLQ-C30 nausea/vomiting 18 16 Worsening 14 Change from baseline, 12 10 8 mean (± SE) 6 4 2 0 -2 Improvement -4 -6 -8 -10 -12 -14 -16 -18 -20 Week Week Week Week Week Week Week Week Week Week Week 0 3 6 9 12 18 24 30 36 42 48 239 210 182 144 134 98 63 58 48 43 45 234 214 175 161 174 134 108 80 65 46 42 Figure 2. Mean (±SE) change from baseline by study visit in (A) EORTC QLQ-C30 GHS/QOL scores, (B) EORTC QLQ-C30 symptom subscale nausea/vomiting scores, (C) EORTC QLQ-C30 subscale appetite loss scores and (D) EORTC QLQ-STO22 symptom pain subscale scores. Parts C and D are continued on next page. GHS, global health status; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer core 30 quality-of-life questionnaire; EORTC QLQ-STO22, European Organisation for the Research and Treatment of Cancer 22-question quality-of-life gastric cancer-specific module; QOL, quality of life; SE, standard error. change in HRQOL; no clinically meaningful differences in with solid tumours.18,19 In a systematic review of HRQOL LSM score from baseline to week 18 were observed in outcomes, there was a consistent prolongation of the time appetite loss, constipation and diarrhoea scales or in TTD to symptom deterioration and better symptom control at for appetite loss. Taken together, pembrolizumab offers different follow-up points with nivolumab, pembrolizumab favourable safety compared with chemotherapy and and atezolizumab in patients with lung cancer, melanoma, maintains HRQOL. head and neck cancer and urothelial cancer.18 Findings Intensification of chemotherapy for gastric/GEJ cancer from the present analysis of KEYNOTE-062 demonstrate can provide modest gains in OS,7 and first-line chemo- the ability of pembrolizumab monotherapy to maintain therapy regimens in gastric/GEJ cancer tend to maintain HRQOL in the first-line setting in patients with gastric/GEJ HRQOL as measured by GHS/QOL.8 Evidence from immu- cancer. notherapy trials has demonstrated that monotherapy with One limitation of these HRQOL analyses is the partially PD-1 inhibitors can provide efficacy benefits and tolerable blinded design of the study. Patients were not fully blinded safety while maintaining or improving HRQOL in patients to pembrolizumab monotherapy because only one type of 6 https://doi.org/10.1016/j.esmoop.2021.100189 Volume 6 - Issue 4 - 2021 E. Van Cutsem et al. ESMO Open C 20 EORTC QLQ-C30 appetite loss 18 Worsening 16 14 Change from baseline, 12 10 8 mean (± SE) 6 4 2 0 Improvement -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 Week Week Week Week Week Week Week Week Week Week Week 0 3 6 9 12 18 24 30 36 42 48 Pembrolizumab 239 210 182 144 134 98 63 58 48 43 45 Chemo 234 214 175 161 174 134 108 80 65 46 42 D 20 EORTC QLQ-STO22 pain 18 Worsening 16 14 Change from baseline, 12 10 8 mean (± SE) 6 4 2 0 Improvement -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 Week Week Week Week Week Week Week Week Week Week Week 0 3 6 9 12 18 24 30 36 42 48 239 210 182 144 134 98 63 58 48 43 45 233 214 175 161 174 134 108 80 65 46 42 Figure 2. Continued. study treatment was administered in that arm of the trial. treatment-related AEs from chemotherapy in the primary Conversely, administration of pembrolizumab or placebo was safety analysis. Overall, HRQOL was similar in patients with blinded in the combination chemotherapy arms. Future data PD-L1-positive advanced gastric/GEJ adenocarcinoma, releases will elucidate the HRQOL profile of double-blinded whether they received pembrolizumab or chemotherapy as pembrolizumab or placebo compared with chemotherapy. first-line treatment. Conclusion ACKNOWLEDGEMENTS In this study in patients who had advanced gastric/GEJ We thank the patients and their families, as well as the adenocarcinoma with PD-L1 CPS 1 tumours, HRQOL was investigators and site personnel involved in the study. similar between the pembrolizumab and the chemotherapy Medical writing and/or editorial assistance was provided by arms in the first-line setting. Longer TTD was observed for Tim Peoples, MA, ELS, Traci Stuve, MA, and Holly C. Cappelli pembrolizumab than for chemotherapy for the nausea/ PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assis- vomiting subscale in EORTC QLQ-C30, which aligned tance was funded by Merck Sharp & Dohme Corp., a sub- with the increased incidence of nausea and vomiting sidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 7 ESMO Open E. Van Cutsem et al. Patients with deteriorated scores at week 18, % 45% 39.7% 40% 35% 29.5% 27.8% 30% 24.7% 23.0% 23.4% Pembrolizumab 25% 17.6% 16.7% Chemotherapy 20% 10% 5% 0 EORTC QLQ-C30 EORTC QLQ-C30 EORTC QLQ-C30 EORTC QLQ-STO22 pain GHS/QOL appetite loss nausea/vomiting Figure 3. Proportion of patients with deteriorated EORTC QLQ-C30 and EORTC QLQ-STO22 scores at week 18. GHS, global health status; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer core 30 quality-of-life questionnaire; EORTC QLQ-STO22, European Organisation for the Research and Treatment of Cancer 22-question quality-of-life gastric cancer-specific module; QOL, quality of life. FUNDING Kenilworth, NJ, USA, Taiho and Unum Therapeutics. He also This work was supported by Merck Sharp & Dohme Corp. serves as a director for CytomX Therapeutics and owns un- (no grant number), a subsidiary of Merck & Co., Inc. (no exercised stock options for CytomX and Entrinsic Health. He grant number), Kenilworth, NJ, USA. is a co-founder of EvolveImmune Therapeutics and has eq- uity in this private company. KS reports grants and personal fees from Astellas Pharma, Eli Lilly and Company, Merck DISCLOSURE Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., EVC reports advisory/consultancy fees from Array, AstraZe- Kenilworth, NJ, USA, Ono Pharmaceutical and Taiho Phar- neca, Bayer, BioPharma, Bristol Myers Squibb, Celgene, maceutical; personal fees from AbbVie, Bristol Myers Squibb, Halozyme, Lilly, Merck KGaA, Merck Sharp & Dohme Corp., a GlaxoSmithKline, Novartis, Pfizer Inc., Takeda Pharmaceuti- subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, cals and Yakult; and grants from Chugai Pharma, Daiichi Novartis, Roche and Servier; and researching grant/funding Sankyo, Dainippon Sumitomo Pharma and Medi Science. YYJ (institution) from Amgen, Bayer, Bristol Myers Squibb, reports advisory fees from Bristol Myers Squibb, Lilly, Merck Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, Kenilworth, NJ, USA, Merck Serono and Pfizer; and research NJ, USA., Merck KGaA, Novartis, Roche and Servier. AV is an expenses from Amgen, Bayer, Boehringer Ingelheim, Gen- employee of Merck Sharp & Dohme Corp., a subsidiary of entech, Lilly and Roche. VS reports research funding from Merck & Co., Inc., Kenilworth, NJ, USA. Y-JB reports consul- Bristol Myers Squibb, EMD-Serono and Merck Sharp & ting/advisory role for Astellas, AstraZeneca, Bayer, BeiGene, Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, Bristol Myers Squibb, Daichii-Sankyo, Eli Lilly, Genentech/ NJ, USA. SSt reports advisory/consultancy role for Bayer, Roche, Genexine, Green Cross, Hanmi, Merck Sharp & Bristol Myers Squibb, Exelixis, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Samyang Bio- NJ, USA, and QED. JMN is an employee of Merck Sharp & pharmaceuticals and Taiho; and grants (to the institution for Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, NJ, USA. UK is an employee of Merck Sharp & Dohme Corp., Bristol Myers Squibb, Boehringer Ingelheim, Boston a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. SSh is Biomedical, CKD Pharma, Curis, Daiichi Sankyo, Eli Lilly, Five an employee and a stockholder of Merck Sharp & Dohme Prime, Genentech/Roche, Genexine, Green Cross, GSK, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MacroGenics, Merck Sharp & Dohme Corp., a subsidiary of MA reports scientific consultancy role for Bristol Myers Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Novartis, Ono, Pfizer, Taiho and Takeda. CSF reports consul- Merck & Co., Inc., Kenilworth, NJ, USA, and Servier; and ting role for Agios, Amylin Pharmaceuticals, Bain Capital, honoraria for speaking for Bristol Myers Squibb, Lilly, Merck CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Health, EvolveImmune Therapeutics, Genentech, Merck Kenilworth, NJ, USA, and Servier. All other authors have Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., declared no conflicts of interest. 8 https://doi.org/10.1016/j.esmoop.2021.100189 Volume 6 - Issue 4 - 2021 E. Van Cutsem et al. ESMO Open A 100 90 80 No deterioration, % 70 60 50 40 Deterioration Median TTD, Hazard ratiob 30 events (%) months (95% CI) (95% CI) P valuec 20 59 (24.7) NR (10.2, -) 0.96 10 (0.67-1.38) P = 0.8264 65 (27.8) NR (11.5, -) 0 0 3 6 9 12 15 18 Months Pembrolizumab 239 99 50 37 27 19 13 Chemotherapy 234 128 59 30 19 11 5 B 100 90 80 No deterioration, % 70 60 50 40 Deterioration Median TTD, Hazard ratiob 30 events (%) months (95% CI) (95% CI) P valuec 20 56 (23.4) NR (18.2, -) 0.61 10 (0.44-0.85) P = 0.0029 93 (39.7) 11.3 (4.3, -) 0 0 3 6 9 12 15 18 Months Pembrolizumab 239 91 46 36 29 19 13 Chemotherapy 234 96 52 26 16 10 5 Figure 4. TTD in (A) EORTC QLQ-C30 GHS/QOL, (B) EORTC QLQ-C30 nausea/vomiting subscale, (C) EORTC QLQ-C30 appetite loss subscale and (D) EORTC QLQ-STO22 pain subscale. Parts C and D are continued on next page. CI, confidence interval; GHS, global health status; NR, not reached; EORTC QLQ-C30, European Organisation for the Research and Treatment of Cancer core 30 quality-of- life questionnaire; EORTC QLQ-STO22, European Organisation for the Research and Treatment of Cancer 22-question quality-of-life gastric cancer-specific module; QOL, quality of life; TTD, time to deterioration; -, the median was not reached. a From product-limit (KaplaneMeier) method for censored data. b Based on stratified Cox regression model with treatment as a covariate. c Two-sided P value based on stratified log-rank test. DATA SHARING MSD is also obligated to protect the rights and privacy of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., trial participants and, as such, has a procedure in place for Inc., Kenilworth, NJ, USA (MSD) is committed to providing evaluating and fulfilling requests for sharing company qualified scientific researchers access to anonymised data clinical trial data with qualified external scientific re- and clinical study reports from the company’s clinical trials searchers. The MSD data-sharing website (available for the purpose of conducting legitimate scientific research. at: http://engagezone.msd.com/ds_documentation.php) Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 9 ESMO Open E. Van Cutsem et al. C 100 90 80 No deterioration, % 70 60 50 40 Deterioration Median TTD, Hazard ratiob 30 events (%) months (95% CI) (95% CI) P valuec 20 55 (23.0) NR (23.5, -) 0.83 10 (0.58-1.20) P = 0.3143 69 (29.5) NR (-, -) 0 0 3 6 9 12 15 18 Months Pembrolizumab 239 94 50 34 27 18 12 Chemotherapy 234 120 53 30 17 11 5 D 100 90 80 No deterioration, % 70 60 50 40 Deterioration Median TTD, Hazard ratiob 30 events (%) months (95% CI) (95% CI) P valuec 20 42 (17.6) NR (22.1, -) 1.22 10 (0.78-1.91) P = 0.3806 39 (16.7) NR (-, -) 0 0 3 6 9 12 15 18 Months Pembrolizumab 239 102 53 40 32 21 14 Chemotherapy 233 139 74 42 25 14 7 Figure 4. Continued. outlines the process and requirements for submitting a data, including country or region-specific regulations. If the data request. Applications will be promptly assessed for request is declined, it will be communicated to the inves- completeness and policy compliance. Feasible requests will tigator. Access to genetic or exploratory biomarker data be reviewed by a committee of MSD subject matter experts requires a detailed, hypothesis-driven statistical analysis to assess the scientific validity of the request and the plan that is collaboratively developed by the requestor and qualifications of the requestors. In line with data privacy MSD subject matter experts; after approval of the statistical legislation, submitters of approved requests must enter analysis plan and execution of a data-sharing agreement, into a standard data-sharing agreement with MSD before MSD will either perform the proposed analyses and share data access is granted. Data will be made available for the results with the requestor or will construct biomarker request after product approval in the US and EU or after covariates and add them to a file with clinical data that is product development is discontinued. There are circum- uploaded to an analysis portal so that the requestor can stances that may prevent MSD from sharing requested perform the proposed analyses. 10 https://doi.org/10.1016/j.esmoop.2021.100189 Volume 6 - Issue 4 - 2021 E. Van Cutsem et al. ESMO Open REFERENCES 11. Bang YJ, Kang YK, Catenacci DV, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global advanced gastric or gastroesophageal junction adenocarcinoma: re- cancer statistics 2018: GLOBOCAN estimates of incidence and mor- sults from the phase II nonrandomized KEYNOTE-059 study. Gastric tality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Cancer. 2019;22:828-837. 2018;68:394-424. 12. Shitara K, van Cutsem E, Bang YJ, et al. Efficacy and safety of pem- 2. Casamayor M, Morlock R, Maeda H, Ajani J. 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Health-related quality of life in centre, open-label, phase 1b trial. Lancet Oncol. 2016;17:717-726. cancer patients treated with PD-(L)1 inhibitors: a systematic review. 10. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab Expert Rev Anticancer Ther. 2018;18:1231-1239. monotherapy in patients with previously treated advanced gastric and 19. Nishijima TF, Shachar SS, Muss HB, Tamura K. Patient-reported out- gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. comes with PD-1/PD-L1 inhibitors for advanced cancer: a meta-anal- JAMA Oncol. 2018;4:e180013. ysis. Oncologist. 2019;24:e565-e573. Volume 6 - Issue 4 - 2021 https://doi.org/10.1016/j.esmoop.2021.100189 11