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Background Body weight loss (BWL) is a negative prognostic factor in metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). In the phase III TAGS study, trifluridine/tipiracil improved survival versus placebo in third- or later-line mGC/GEJC. These retrospective analyses examined the association of early BWL with survival outcomes in TAGS. Methods Efficacy and safety were assessed in patients who experienced Results Body weight data were available for 451 of 507 (89%) patients in TAGS. In the trifluridine/tipiracil and placebo arms, respectively, 74% (224/304) and 65% (95/147) experienced P P = 0.0003) for OS. Similar results were obtained for progression-free survival. Any-cause grade ≥ 3 adverse events were reported in 77% and 82% of trifluridine/tipiracil-treated and 45% and 67% of placebo-treated patients with Conclusions In TAGS, early BWL was a strong negative prognostic factor for OS in patients with mGC/GEJC receiving third- or later-line treatment.

PURPOSE In the phase III KEYNOTE-181 study ( NCT02564263 ) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations. PATIENTS AND 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 EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales. RESULTS The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, –1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups. CONCLUSION In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients’ allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were “high”, “low” and “very high” (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in “high” vs. “low” clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the “very highly” infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1+ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with “very high” TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts.

Background Weight loss is common in advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA); however, the prognostic implications of weight loss during the first cycle (C1) of chemotherapy remain poorly characterized. In this study, we investigated the impact of early weight loss during systemic treatment as a potential prognostic factor for overall survival (OS) in patients with advanced G/GEA. Materials and Methods We performed a post hoc analysis of three phase III studies of ramucirumab. Patients were categorized into two groups: weight loss of ≥3% and, This article analyzes the impact of early weight loss during systemic therapy as a potential prognostic factor for overall survival in patients with gastric and gastroesophageal junction adenocarcinoma.

Background In TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS. Methods Patients were randomized 2:1 to trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2. Results Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS. Conclusion QoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Background The aim of the present study was to assess the prognosis of patients with esophageal or gastroesophageal junction (E/GEJ) adenocarcinoma extending beyond the muscularis propria layer (≥ypT3) and positive circumferential resection margin (CRM), post neoadjuvant chemotherapy. Methods 177 patients were retrospectively studied. The majority (94.9%) received ECX (epirubicin, cisplatin, capecitabine), and all had clear proximal/distal resection margins. CRM was defined as positive (CRM+) when it was directly infiltrated (infiltrated CRM) or when tumor cells were detected within 1 mm from CRM (close CRM) and as negative (CRM-) when tumor cells were found in a distance > 1 mm from CRM. Results CRM+ was found in 83 patients (46.9%). Of them, infiltrated CRM was recorded in 36 (20.3%) and close CRM in 47 (26.6%). Adjuvant chemotherapy was administered to 132 patients (74.6%). Lymphovascular invasion and primary site in the lower esophagus were independently associated with higher risk of CRM+. Patients with infiltrated CRM, compared to those with close CRM and those CRM-, had the shortest median time-to-relapse (11.4 vs. 15.6 vs. 22.1 months, respectively, p = 0.005) and overall survival (18.7 vs. 23.1 vs. 38.8 months, respectively, p = 0.001). However, CRM status was not an independent predictor of poor outcome. Symptomatic isolated locoregional recurrences were rare in both CRM+ and CRM-patients (4/56 [7.1%] vs. 5/52 [9.6%], p = 0.736), as well as in infiltrated vs. non-infiltrated CRM (CRM- and close CRM) (0/26 [0%] vs. 9/82 [11.0%], p = 0.110). Conclusion Although CRM status is associated with poor outcome, it does not represent an independent prognostic factor. The status of CRM did not significantly influence the pattern of cancer relapse.

Background: In the phase 3 KEYNOTE-061 study (NCT02370498), second-line pembro did not significantly prolong OS vs pac in patients with PD-L1-positive (CPS ≥1) GC (N = 395) but did elicit a longer DOR and offered a favorable safety profile. We explored the association between tumor gene expression signatures and clinical outcomes. Methods: In patients with tumor RNA-sequencing data, we analyzed the association of the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 other signatures (angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MYC, proliferation, RAS, stroma/EMT/TGFβ, WNT) on a continuous scale with outcomes using logistic (ORR) and Cox proportional hazards (PFS; OS) regression. For TcellinfGEP, 1-sided (pembro) and 2-sided (pac) P values were calculated (prespecified significance, α = 0.05). For the 10 non-TcellinfGEP signatures, 1-sided (pembro) and 2-sided (pac) multiplicity-adjusted P values were calculated (prespecified significance, α = 0.10). Clinical data cutoff was October 26, 2017. Results: There were 274 patients with tumor RNA-sequencing data (n = 137 in each arm). Association with clinical outcomes for gene expression signatures are reported in the Table. Conclusions: In this exploratory analysis of patients with previously treated GC from KEYNOTE-061, tumor TcellinfGEP showed some association with clinical outcomes for pembro (ORR and PFS) but not pac (ORR, PFS, and OS). The TcellinfGEP-adjusted mMDSC signature was negatively associated with clinical outcomes for pembro (ORR, PFS, and OS), while the TcellinfGEP-adjusted glycolysis, MYC, and proliferation signatures were negatively associated with OS for pac. This exploratory biomarker analysis suggests that myeloid-driven suppression may play a role in resistance to PD-1 inhibition and supports a strategy of considering immunotherapy combinations intended to target this myeloid axis. Association between clinical outcomes and TcellinfGEP and non-TcellinfGEP signatures adjusted for TcellinfGEP Pembrolizumabn = 137 Paclitaxeln = 137 ORR PFS OS ORR PFS OS TcellinfGEPa 0.041 0.026 0.178 0.822 0.207 0.644 Angiogenesisb 0.077 0.298 0.623 0.220 0.462 0.263 Glycolysisb 0.934 0.861 0.956 0.223 0.097 0.018 gMDSCb 0.626 0.573 0.623 0.694 0.352 0.263 Hypoxiab 0.934 0.861 0.956 0.223 0.220 0.440 mMDSCb 0.077 0.057 0.033 0.694 0.932 0.263 MYCb 0.934 0.861 0.956 0.223 0.327 0.057 Proliferationb 0.934 0.861 0.956 0.223 0.071 0.002 RASb 0.934 0.861 0.956 0.223 0.327 0.440 Stroma/EMT/TGFβb 0.306 0.366 0.522 0.694 0.462 0.263 WNTb 0.934 0.861 0.956 0.097 0.327 0.440 aBolded P values (1-sided for pembrolizumab with hypothesized positive association and 2-sided for paclitaxel with no hypothesized association) indicate nominal statistical significance (α = 0.05); model includes additional covariates of ECOG PS. bBolded P values (1-sided for pembrolizumab with hypothesized negative association except for proliferation and 2-sided for paclitaxel with no hypothesized association) indicate multiplicity-adjusted statistical significance (α = 0.10); model includes additional covariates of ECOG PS and TcellinfGEP. Citation Format: Kohei Shitara, Maria Di Bartolomeo, Mario Mandala, Min-Hee Ryu, Christian Caglevic, Tomasz Olesinski, Hyun C. Chung, Kei Muro, Eray Goekkurt, Raymond S. McDermott, Wasat Mansoor, Zev A. Wainberg, Chie-Schin Shih, Julie Kobie, Michael Nebozhyn, Razvan Cristescu, Z. Alexander Cao, Andrey Loboda, Mustafa Özgüroğlu. Association between gene expression signatures and outcomes of pembrolizumab (pembro) and paclitaxel (pac) in advanced gastric cancer (GC): Exploratory analysis from KEYNOTE-061 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2140.

BACKGROUND The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy AIM To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63–76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs. Chiramel J, Almond R, Slagter A, Khan A, Wang X, Lim KHJ, Frizziero M, Chakrabarty B, Minicozzi A, Lamarca A, Mansoor W, Hubner RA, Valle JW, McNamara MG. Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours. World J Clin Oncol 2020; 11(4): 205-216 [PMID: 32355642 DOI: 10.5306/wjco.v11.i4.205]

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

IMPORTANCE: Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. OBJECTIVE: To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. DESIGN, SETTING, AND PARTICIPANTS: This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. INTERVENTIONS: Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. RESULTS: Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. CONCLUSIONS AND RELEVANCE: The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02500043. ispartof: JAMA ONCOLOGY vol:6 issue:1 ispartof: location:United States status: published

243 Background: KEYNOTE-062 (NCT02494583) is a global phase 3 study of pembrolizumab (pembro) as monotherapy and in combination with chemotherapy (chemo) versus chemo as first-line therapy for PD-L1–positive (combined positive score [CPS] ≥1) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. At the time of the protocol-specified final analysis, pembro was noninferior to chemo, with fewer adverse events (AEs) observed. Pembro or pembro + chemo was not superior to chemo for the overall survival (OS) and progression-free survival (PFS) end points tested. We present the results of KEYNOTE-062 after ̃25 additional months of follow-up (cutoff: April 19, 2021). Methods: Patients with previously untreated gastric or GEJ cancer were randomly assigned 1:1:1 to pembro 200 mg Q3W, pembro + chemo (cisplatin 80 mg/m2/day on day 1 + 5-FU 800 mg/m2/day on days 1-5 Q3W [or capecitabine 1000 mg/m2 twice daily on days 1-14 Q3W per local guidelines]), or placebo Q3W + chemo. Primary end points were OS in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo and pembro versus chemo and PFS (RECIST v1.1; central review) in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo. Safety was also evaluated. Results: At the time of data cutoff, 689 of 763 patients (90.3%) had died. Median follow-up (defined as time from randomization to data cutoff) was 54.3 months (range, 46.8-66.1). Pembro was noninferior to chemo for OS in the CPS ≥1 population (median, 10.6 vs 11.1 months; HR, 0.90; 95% CI, 0.75-1.08) but had a clinically meaningful OS benefit in the CPS ≥10 population (median, 17.4 vs 10.8 months; HR, 0.62; 95% CI, 0.45-0.86). 24-month OS rates (pembro vs chemo) were 26.6% versus 18.8% in the CPS ≥1 population and 39.1% versus 21.1% in the CPS ≥10 population. Pembro + chemo was not superior to chemo for OS in the CPS ≥1 (median, 12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.71-1.02) or the CPS ≥10 (median, 12.3 vs 10.8 months; HR, 0.76; 95% CI, 0.56-1.03) population. 24-month OS rates (pembro + chemo vs chemo) were 24.5% versus 18.8% in the CPS ≥1 population and 28.3% versus 21.1% in the CPS ≥10 population. Pembro + chemo did not significantly prolong PFS versus chemo in the CPS ≥1 (median, 6.9 vs 6.5 months; HR, 0.84; 95% CI, 0.70-1.01) or the CPS ≥10 (median, 5.8 vs 6.2 months; HR, 0.71; 95% CI, 0.52-0.96) population. Grade 3-5 treatment-related AEs rates were 17.3% (pembro), 73.2% (pembro + chemo), and 69.3% (chemo). Conclusions: After ̃25 additional months of follow-up, efficacy and safety outcomes with first-line pembro or pembro + chemo versus chemo in patients with gastric or GEJ adenocarcinoma enrolled in KEYNOTE-062 were consistent with the final analysis data. Clinical trial information: NCT02494583.

241 Background: At interim analysis of the phase 3, randomized, double-blind KEYNOTE-590 (NCT03189719) study, 1L pembrolizumab (pembro) + chemotherapy (chemo) vs chemo alone provided superior OS, PFS, and ORR with a manageable safety profile in patients (pts) with untreated, advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). We report efficacy, safety, and health-related quality of life (HRQoL) results with an additional 12 months (mo) of follow-up. Methods: 749 eligible pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2 yr + chemo. Randomization was stratified by geographic region, histology, and performance status. Treatment continued until progression, unacceptable toxicity, or withdrawal, or 2 yr. No crossover was permitted. Primary endpoints were OS in pts with ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and OS and PFS (RECIST v1.1; by INV) in ESCC, PD-L1 CPS ≥10, and all pts. Secondary endpoints included ORR, DOR, safety, and HRQoL. HRQol was assessed in 711 treated pts with ≥1 HRQoL assessment (356 pembro + chemo; 355 chemo). Data cutoff was July 9, 2021. Results: At data cutoff, median follow-up (randomization to data cutoff) was 34.8 mo. Median OS was longer with pembro + chemo vs chemo in pts with ESCC CPS ≥10 (HR 0.59; 95% CI, 0.45-0.76), ESCC (HR 0.73; 95% CI, 0.61-0.88), CPS ≥10 (HR 0.64; 95% CI, 0.51-0.80), and all pts (HR 0.73, 95% CI, 0.63-0.86). In pts with adenocarcinoma OS HR was 0.73 (95% CI, 0.55-0.99). The 24-mo OS rate in all pts was 26.3% vs 16.1%. Median PFS was longer with pembro + chemo vs chemo in ESCC (HR 0.65; 95% CI, 0.54-0.78), CPS ≥10 (HR 0.51; 95% CI, 0.41-0.65), and all pts (HR 0.64; 95% CI, 0.55-0.75). The 24-mo PFS rate in all pts was 11.6% vs 3.3%. Confirmed ORR was 45.0% (25 CR [6.7%]) vs 29.3% (9 CR [2.4%]), with median DOR of 8.3 vs 6.0 mo. Approximately 20% vs 6% of pts had response duration ≥24 months. Grade 3-5 drug-related AE rates were 72% vs 68%. Discontinuation rates from drug-related AEs were 21% vs 12%. There was no significant difference in least square mean (LSM) change from baseline to wk 18 between arms in EORTC QLQ-C30 global health status/quality-of-life (LSM difference -0.10; 95% CI, -3.40-3.20). LSM change from baseline to wk 18 was better with pembro + chemo vs chemo for QLQ-OES 18 pain (-2.94; 95% CI, -5.86 to -0.02) and dysphagia (-5.54; 95% CI, -10.92 to -0.16). Conclusions: With an additional 12 months of follow-up, pembro + chemo continued to provide significant and clinically meaningful improvement in OS, PFS, and ORR vs chemo with a manageable safety profile, and stable quality-of-life for pts with untreated, advanced esophageal and EGJ cancer. These data continue to support 1L pembro + chemo as a new standard of care in these patients. Clinical trial information: NCT03189719.

// Elizabeth C. Smyth 1, 2, * , Catherine Cafferkey 1, * , Andrea Loehr 3 , Tom Waddell 1, 4 , Ruwaida Begum 1 , Clare Peckitt 5 , Thomas C. Harding 3 , Minh Nguyen 3 , Alicia F. Okines 1 , Mitch Raponi 3 , Sheela Rao 1 , David Watkins 1 , Naureen Starling 1 , Gary W. Middleton 6 , Jonathan Wadsley 7 , Wasat Mansoor 4 , Tom Crosby 8 , Andrew Wotherspoon 9 , Ian Chau 1 and David Cunningham 1 1 Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London & Sutton, United Kingdom 2 Current affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom 3 Clovis Oncology, San Francisco, CA, United States of America 4 Current affiliation: Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom 5 Department of Clinical Research & Development, Royal Marsden Hospital, London & Sutton, United Kingdom 6 Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom 7 Department of Medical Oncology, Weston Park Hospital, Sheffield, United Kingdom 8 Department of Clinical Oncology, Velindre Hospital, Cardiff, Wales, United Kingdom 9 Department of Histopathology, Royal Marsden Hospital, London & Surrey, United Kingdom * These authors have contributed equally to this work Correspondence to: David Cunningham, email: david.cunningham@rmh.nhs.uk Keywords: gastric cancer; oesophageal cancer; chemotherapy; homologous recombination deficiency; loss of heterozygosity Received: August 01, 2018 Accepted: October 06, 2018 Published: November 30, 2018 ABSTRACT Background: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 – 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature’s predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.

Summary Background Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. Methods TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT02500043 . The trial, including follow-up of all participants, has been completed. Findings Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group). Interpretation Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need. Funding Taiho Oncology and Taiho Pharmaceutical.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

The new American Joint Committee on Cancer eighth edition (AJCC8) staging is the first to describe separate clinical and pathology staging systems, but still has low performance to predict prognosis in patients with oesophageal/gastroesophageal junction (O/GOJ) adenocarcinoma, who are candidates for surgery. Recent studies have demonstrated that O/GOJ cancer patients with 18F-fluorodeoxyglucose (FDG) avid regional lymph nodes (RLNs) may have poor prognosis. The aim of our study was to examine whether the baseline assessment of the FDG uptake of RLN improves the prognostic accuracy of the new AJCC8 staging.This single-centre retrospective study included patients with operable FDG avid O/GOJ adenocarcinoma treated with perioperative chemotherapy. All patients were reclassified according to the new AJCC8 clinical staging. Prognostic factors for time-to-progression (TTP) and overall survival (OS) were explored.Of 430 patients included in the study, 180 (41.9%) had FDG avid RLN at baseline PET/CT scan before starting perioperative chemotherapy. The presence of FDG avid RLN was significantly and independently associated with shorter TTP and OS, especially in clinical stage III patients (p .001 in both cases). Stage III patients with FDG avid RLN had similar TTP and OS to those with stage IVA. Classifying stage III patients with FDG avid RLN into stage IVA led to a significant improvement of the prognostic accuracy of the new AJCC8 clinical staging system (Harrell's concordance index improved from 0.555 to 0.588, p .001). Of 430 patients starting perioperative chemotherapy, 332 underwent radical tumour resection. The presence of FDG avid RLN before starting perioperative chemotherapy could additionally predict a significantly shorter postoperative time-to-relapse and OS (p .001 in both cases).We propose that the incorporation of RLN status (by FDG PET/CT scan) into the AJCC8 staging system of O/GOJ adenocarcinoma improves its prognostic accuracy and may also improve treatment stratification.

Summary Background Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). Methods This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m 2 every 3 weeks or intravenous paclitaxel 80 mg/m 2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. Findings Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. Interpretation Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. Funding F Hoffmann-La Roche.

Cancer cachexia is common in patients with oesophagogastric cancer (OG) and is linked to overall survival (OS). One of the key components of cachexia is anorexia; it is not known whether anorexia impacts on OS and there is no method of routine screening in current practice. Diagnosis relies on patients describing the symptoms, clinicians diagnosing anorexia and acting upon it. Patients with oesophageal/gastroesophageal junction or gastric cancer were assessed using the Functional Assessment of Anorexia Cachexia Therapy Anorexia/Cachexia Subscale (FAACT A/CS). FAACT A/CS includes 12 questions validated previously to diagnose anorexia in patients with cancer. Of the 182 patients included, 69% scored ≤37/48 and were considered to be anorexic; FAACT A/CS was a better predictor of OS in metastatic patients than body mass index or weight loss in the six months prior to cancer diagnosis. The median OS of patients with FAACT A/CS scores of >37 was longer than patients with scores of ≤37 (19.3 months vs 6.7 months, Hazard Ratio [HR] 2.9, 95% Confidence Interval [CI] 1.4–6.0, p37 had substantially longer OS than those with PS 0–2 and FAACT A/CS ≤37 (18.7 months vs 7.9 months, HR 2.5 (95% CI 1.2–5.1, P

8574 Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI 50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]

4039 Background: Despite potentially curative surgery, long-term survival from OGC remains poor due to high relapse rate. Neoadjuvant (naFLOT) and adjuvant (aFLOT) FLOT is currently standard treatment for resectable OGC based on data from the FLOT-4 trial. We explored whether TRG was associated with FLOT-outcome using RWD. Methods: Pts with OGC treated with naFLOT +/- aFLOT at a tertiary UK centre were identified following institutional board approval. Clinical and laboratory data were extracted from the patient record. TRG was evaluated by a histopathologist. Median overall survival (OS) and median progression-free survival (PFS) were evaluated using Kaplan-Meier and Log-rank tests; time taken from start of naFLOT, and associations between factors with Fisher’s exact (FE) test. Results: 171 pts were identified, median FU 30 mths. 144 (84%) male; median age 66 (32-84); oesophagus 66 (38%), junctional (GOJ) 73 (43%), gastric 32 (19%); stage IB 3 (2%), stage IIB 26 (15%), stage III 91 (53%), stage IVA 47 (28%) and unknown 4 (2%). Pts had median of 2 comorbidities (range 0-6); performance status (PS) 0: 95 (56%), PS 1: 71 (41%), PS 2: 3 (2%) and PS unknown 2 (1%). 132/171 pts completed 4 cycles of naFLOT and this was significantly associated with undergoing surgery (p = 0.02). Those who had surgery (140/171) had significantly improved PFS (not reached (NR) vs. 6 mths; 95% CI 2-10; p < 0.001) and OS (NR vs. 12 mths; 95% CI 6-18; p < 0.001). TRG was reported for 126/140 patients who underwent surgery. TRG 1/2 (42/126) vs. TRG ≥3 was significantly associated with improved PFS (NR vs. 35 mths; 95% CI NR; p < 0.001) and OS (median NR either group; p < 0.001). Pts with TRG 1/2 who commenced aFLOT (≥1 cycle; n = 31/42) or completed 4 cycles of aFLOT (17/31) did not have improved PFS or OS vs. those who did not. Those with TRG ≥3 who commenced aFLOT (≥1 cycle; n = 62/85) had improved PFS (median NR vs. 22 mths; 95% CI 13-31 p = 0.006) and OS (median NR vs. 25 mths; 95% CI 18-32 p = 0.019). Those with TRG ≥3 who completed 4 cycles of aFLOT (n = 38/62) had significantly improved PFS (median NR vs. 25 mths; 95% CI 14-36 p = 0.016) and OS (median NR vs. 36 mths; 95% CI 16-55 p = 0.012). There was no difference in PFS or OS in pts with TRG ≥3 who had a dose reduction at any time during aFLOT. Conclusions: TRG is a predictor of outcome following naFLOT + surgery with superior outcomes in those with TRG 1/2. Our analyses suggest that only pts with TRG >3 following naFLOT + surgery benefit from adjuvant FLOT. Prospective randomised studies are required to confirm whether pts with TRG 1/2 require treatment with aFLOT.

168 Background: In the randomized, international, double-blind, placebo-controlled KEYNOTE-590 (NCT03189719) study, pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs placebo + chemo as first-line therapy for patients (pts) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). Here we report HRQoL outcomes in KEYNOTE-590. Methods: 749 pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2y + chemo (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-5 Q3W). EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L questionnaires were administered at baseline, every 3 weeks (Q3W) up to week 24, and then Q9W up to 1 year or end of treatment, and at the 30-d safety follow-up visit. HRQoL was assessed in all treated patients who completed ≥1 HRQoL assessment (N = 711: 356 for pembro + chemo; 355 for chemo). Change from baseline to week 18 in EORTC-QLQ-C30 global health status (GHS)/QoL and physical functioning, and in QLQ-OES18 scores were prespecified secondary endpoints. Change from baseline to week 18 in EQ-5D scores was an exploratory endpoint. Time to deterioration (TTD) was evaluated for all endpoints. Least square mean (LSM) change from baseline (95% CI) was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log rank test and Cox proportional hazards model. P-values are nominal and two-sided. Results: QLQ-C30, QLQ-OES18 and EQ-5D-5L compliance was ≥90% in both arms at baseline and at week 18. There was no significant difference in least squares mean (LSM) change from baseline to week 18 in GHS/QoL status between arms (LSM difference [95% CI] -0.10 [-3.40-3.20]; P = 0.9530). Median TTD in GHS/QoL was similar between arms (HR, 0.86 [95% CI, 0.66-1.13]; P = 0.2864). Outcomes were similar in ESCC PD-L1 CPS ≥10, ESCC, and PD-L1 CPS ≥10 patient populations. LSM change from baseline to week 18 for QLQ-OES18 pain subscale was better for pembro + chemo (-4.78) vs chemo (-1.85 ) (-2.94, -5.86 to -0.02; P = 0.0487). There was no significant difference in LSM change from baseline to week 18 between arms for reflux (-1.19; -4.49-2.10; P = 0.4781) or dysphagia (-2.35; -7.78-3.07; P = 0.3945). VAS LSM change from baseline to week 18 was similar between arms (1.20, -1.61-4.01; P = 0.4016). Conclusions: HRQoL was stable and similar over 18 weeks in the pembro + chemo and chemo arms. Together with superior OS, PFS, and ORR and a manageable safety profile with pembro + chemo, these results support the clinically meaningful benefit of pembro + chemo in patients with advanced esophageal cancer including EGJ adenocarcinoma. Clinical trial information: NCT03189719.

476 Background: Nutritional status is closely linked to cancer mortality, and BWL has been shown to be prognostic for survival in curative, first-, and second-line settings in mGC/GEJC. In the phase III TAGS trial, trifluridine/tipiracil (FTD/TPI) showed clinical benefit versus placebo (PBO) and manageable safety in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. The association of early BWL with survival outcomes in TAGS was examined in retrospective analyses. Methods: The TAGS intent-to-treat (ITT) population was categorized into pts who experienced

Neuroendocrine tumors (NETs) are a rare diverse group of malignancies occurring most commonly in the gastroenteropancreatic system and the lungs. The incidence of NETs is increasing worldwide; median survival for patients with metastatic NETs is 5–65 months. A growing body of evidence shows survival benefit in patients with advanced NETs (gastroenteropancreatic and lung) treated with mTOR inhibitor everolimus, with improvement in survival being demonstrated in the clinical trial and real-world setting. Everolimus has been shown to have a manageable safety profile, with the most common adverse events being stomatitis, rash, diarrhea, fatigue and infections. Due to the rarity of the condition, there are challenges in conducting clinical trials in these patients. Further research is required to clarify the role of adjuvant therapy, treatment sequencing and the use of multimodality treatments.

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m2 followed by oxaliplatin 130 mg/m2 (maximum 8 cycles) and then S-1 [20 mg/m2 (cohort 1) or 25 mg/m2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2–14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naive advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naive advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583

The financial impact of cancer on patients in the UK is poorly understood. We assessed financial burden (FB), defined as financial impact on patient at diagnosis and financial toxicity (FT), defined as financial impact throughout treatment, in patients with upper gastrointestinal UGI), pancreatobiliary (PB) and lower GI (LGI) cancers. Patients enrolled in 5 clinical trials (REAL-3, RAINFALL, ESPAC-4, QoL BIL and CAPITAL) at the Christie, Manchester, were identified. FB at baseline and FT throughout treatment were defined according to answers to the EORTC QLQ-C30 questionnaire (EQ) Q28 to which patients score financial difficulty relating to disease/treatment from 1 (not at all) to 4 (very much). 141 patients were identified, 68.1 % were male; median age was 62 years (range 39–94). 15 (10.6 %) patients had LGI, 85 (60.3 %) PB and 41 (29.1 %) UGI cancer. 62 % had no FB, 25 % ‘a little’, 9% ‘quite a bit’ and 5% ‘very much’. 63.5 % experienced no FT, 19.8 % worse FT and 16.7 % improved FT. Multiple regression analysis showed that younger age, lower index of multiple deprivation (IMD) and tumour type were independent predictors of FB. Significant covariates included escalating IMD (OR 0.78, 95 %CI 0.68−0.92, p = 0.002), age above vs. below median (OR 0.10, 95 %CI 0.04−0.24, p We report the first study of FB and FT in cancer patients in the UK, identifying independent baseline parameters predicting FB and the prognostic role of IMD.

e16545 Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.

// Angela Lamarca 1 , Daisuke Nonaka 2, 3 , Wolfgang Breitwieser 4 , Garry Ashton 5 , Jorge Barriuso 1, 3 , Mairead G. McNamara 1, 3 , Sharzad Moghadam 5 , Jane Rogan 5 , Wasat Mansoor 1 , Richard A. Hubner 1 , Christopher Clark 4 , Bipasha Chakrabarty 2 and Juan W. Valle 1, 3 1 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK 2 Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK 3 Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK 4 Molecular Biology Core Facility, Cancer Research UK Manchester Institute, Manchester, UK 5 Manchester Cancer Research Centre (MCRC) BioBank, University of Manchester, Manchester, UK Correspondence to: Juan W. Valle, email: juan.valle@manchester.ac.uk , juan.valle@christie.nhs.uk Keywords: PD-L1; tumour infiltrating lymphocytes; neuroendocrine; immunotherapy; treatment Received: November 22, 2017 Accepted: February 03, 2018 Epub: February 12, 2018 Published: March 13, 2018 ABSTRACT Background: The extent of resistance to immune surveillance in patients with well-differentiated (Wd) (grade 1/2) small-intestinal neuroendocrine tumours (Si-NETs) is unknown. Methods: Patients diagnosed with Wd Si-NETs (excluding appendix, which are considered to have a different biology to other midgut NETs) were eligible. Tumoural programmed death (PD)-ligand(L) 1 (PD-L1)/PD-L2/PD-1 and tumour infiltrating lymphocytes (TILs) [presence and phenotype] were analysed in archival tissue by immunohistochemistry (IHC); reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for confirmation of IHC results. Results: Of 109 patients screened, 62 were eligible: 54.8% were male; median age was 63.7 years (95%-CI 59.7-67.2); disease stage II: 4.8%, III: 40.3% and IV: 54.8%; 41.9% were functional. Analysed samples (67.1% from primary tumours, 32.9% from metastases) were of grade 1 (67.1%) or 2 (32.86%) with a median Ki-67 of 2%. From the total of 62 eligible patients, 70 and 63 samples were suitable for IHC and RT-qPCR analysis, respectively. PD-L1 expression within tumour cells and TILs were identified in 12.8% and 24.3% of samples respectively; 30% of samples showed PD-L1 expression within tumour cells and/or TILs. PD-1 was present in TILs in 22.8% of samples. Majority of samples showed significant presence of CD4 + (focal 42.86%; moderate 2.86%) and CD8 + (focal 92.86%; moderate 4.29%) TILs. IHC findings were confirmed with RT-qPCR; which showed higher expression levels of PD-L1 (p-value 0.007) and PD-1 (p-value 0.001) in samples positive for IHC compared to negative-IHC. Conclusions: Thirty-percent of patients express PD-L1 within tumour cells and/or TILs. Identification of presence of TILs was also significant and warrant the investigation of immunotherapy in this setting.

Thromboembolic events (TEEs) represent a significant treatment and disease complication for cancer patients. In the present study we assessed the incidence of TEEs in patients receiving preoperative chemotherapy for esophagogastric adenocarcinoma. The risk factors for TEE development and their impact on prognosis were further analyzed.Data from 590 patients with esophagogastric adenocarcinoma, who received preoperative epirubicin-cisplatin with capecitabine (ECX) or 5-fluorouracil (ECF) between 2009 and 2016 in three UK hospitals were retrospectively collected.Twenty-one percent had stomach primary and 98% received ECX chemotherapy. In total, 52 patients (9%) had a venous and 22 (4%) an arterial event. Of those patients with venous TEEs (vTTEs), 39 had pulmonary embolism and 13 deep vein thrombosis, whereas in patients with arterial TEEs (arTTEs), 7 developed a myocardial infarct, 8 developed limb ischemia, 4 developed cerebrovascular accidents and 3 developed superior mesenteric artery thrombosis. ArTEEs were associated with a much higher inoperability rate compared to cases without TEE or with vTEE (77% vs. 20% vs. 31%, respectively, p .001). Independent risk factors of vTEEs were primary site being the stomach (Odds ratio [OR] 3.24, 95%CI 1.72-6.12, p .001), being overweight (OR 3.11, 95%CI 1.33-7.26, p = .009) or obese (OR 4.52, 95%CI 1.85-11.09, p = .001) and the presence of central venous access device (OR 3.40, 95%CI 1.00-11.55, p = .050). In contrast, anticoagulant treatment was independently associated with a lower risk of vTEE (OR 0.22, 95%CI 0.06-0.83, p = .026). Khorana score of 4-5 was an independent risk factor of arTEE (OR 6.38, 95%CI 1.85-22.04, p = .003). Finally, arTEEs were an independent poor prognostic factor for OS, when adjusted for baseline patient, tumor and treatment characteristics (Hazard ratio 3.02, 95%CI 1.85-4.95, p .001).Preoperative ECX/ECF chemotherapy for patients with resectable esophagogastric adenocarcinoma was associated with relatively high incidence of TEEs. However, only arTEEs affected patient survival outcomes.

Background KEYNOTE-062 (NCT02494583) was a randomized, study of 1L pembrolizumab (P) or pembro + chemo (P+C) vs chemo (C) in patients (pts) with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods Eligible pts were randomized 1:1:1 to P 200mg Q3W for up to 2 y, P+C (cisplatin 80mg/m2 + 5-FU 800mg/m2/d on d1-d5 Q3W [or capecitabine 1000mg/m2 BID on d1-d14 Q3W per local guideline]) or placebo Q3W + C. Primary endpoints were OS in CPS ≥1 and CPS ≥10 for P+C vs C and P vs C and PFS (RECIST v1.1; central review) in CPS ≥1 for P+C vs C. ORR (RECIST v1.1; central review) in CPS ≥1 for P+C vs C was the secondary endpoint. The final analysis cutoff date was 26 Mar 2019. Results 763 pts (281 with CPS ≥10) were randomized to P+C (257), P (256), or C (250) (Table). Median follow-up was 11.3mo. P was noninferior to C for OS in CPS ≥1 per prespecified margins. P vs C prolonged OS in CPS ≥10 (median 17.4 vs 10.8mo; HR 0.69; 95% CI 0.49-0.97) but wasn't tested per analysis plan. P+C vs C was not superior for OS in CPS ≥1 or CPS ≥10, with a favorable trend for P+C. In an exploratory analysis of pts with MSI-H tumors with CPS ≥1 (N=50), median OS was not reached vs 8.5mo for both P vs C (HR 0.29; 95% CI 0.11-0.81) and P+C vs C (HR 0.37; 95% CI 0.14-0.97). PFS was longer with P vs C (HR 0.72; 95% CI 0.31-1.68) and P+C vs C (HR 0.45; 95% CI 0.18-1.11). ORR was higher with P (57%) and P + C (65%) vs C (37%). Median DOR was 21.2mo with P, not reached (P + C) vs 7.0mo (C). Grade 3-5 drug-related AE rates were 17% (P), 73% (P+C), and 69% (C). Conclusions As 1L therapy for advanced GC, P was noninferior to C for OS in CPS ≥1 with clinically meaningful improvement for OS in CPS ≥10. P+C did not show superior OS and PFS in CPS ≥1 and OS in CPS ≥10. Clinical benefit was substantially enhanced in a small subset of pts with MSI-H tumors. The safety profile was more favorable for P vs C.TableLBA44TableCPS ≥1P+CCPCaMedian, mo (95% CI)N=257N=250N=256N=250OSa12.5 (10.8-13.9)/ 11.1 (9.2-12.8)10.6 (7.7-13.8)/11.1 (9.2-12.8)HR (95% CI)/ b99.2% CI0.85 (0.70-1.03)0.91 (0.74-1.10)P=0.0460.91b (0.69-1.18); NI margin=1.2PFSa6.9 (5.7-7.3)/ 6.4 (5.7-7.0)2.0 (1.5-2.8)/6.4 (5.7-7.0)HR (95% CI)0.84 (0.70-1.02); P=0.0391.66 (1.37-2.01)MSI-HN=17/N=19N=14/N=19OSaNot reached (3.6-NR)/8.5 (5.3-20.8)Not reached (10.7-NR)/8.5 (5.3-20.8)ORR, %64.7/36.857.1/36.8PFSaNot reached (3.6-NR)/6.6 (4.4-8.3)11.2 (1.5-NR)/6.6 (4.4-8.3)DOR, median, mo (range)NR (1.6+ to 34.5+)/7.0 (2.0-30.4+)21.2 (1.4+ to 33.6+)/7.0 (2.0-30.4+) Clinical trial identification NCT02494583. Editorial acknowledgement Medical writing assistance was provided by Luana Atherly-Henderson, an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA. Legal entity responsible for the study Merck & Co., Inc. Funding Merck & Co., Inc. Disclosure K. Shitara: Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Yakult; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical ; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma. E. Van Cutsem: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: Samyang Biopharma . C.S. Fuchs: Leadership role: CytomX Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Unum Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho. L. Wyrwicz: Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): BMS; Licensing / Royalties: Cervico. K.W. Lee: Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Pfizer. M. Garrido: Advisory / Consultancy: MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Roche. H. Cheol Chung: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (institution): Foundation medicine; Advisory / Consultancy: Taiho; Advisory / Consultancy: Celltrione; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): BMS-Ono; Research grant / Funding (institution): Taiho. H.R. Castro: Research grant / Funding (institution): Merck. W. Mansoor: Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: BMS. M.I.F.M. Braghiroli: Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Merck; Research grant / Funding (institution): AstraZeneca. E. Goekkurt: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. J. Chao: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: FivePrime Therapeutics; Research grant / Funding (institution): Novonco Therapeutics. Z.A. Wainberg: Advisory / Consultancy: Aduro Bio; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Five Prime Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sirtex Medical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon. U. Kher: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. S..P. Kang: Shareholder / Stockholder / Stock options, Full / Part-time employment, Non-remunerated activity/ies, Patent: Merck & Co., Inc.. J. Tabernero: Advisory / Consultancy: Array Bio; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background TAGS, a randomised, double-blind, phase III study, showed that FTD/TPI significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo in heavily pretreated mGC patients (pts) receiving best supportive care. The aim of this analysis was to evaluate the effects of FTP/TPI in the European subpopulation of TAGS. Methods TAGS enrolled pts with histologically confirmed, non-resectable mGC, Eastern Cooperative Oncology Group (ECOG) performance status 0/1, and ≥2 prior chemotherapy regimens. Pts were randomised 2:1 to FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 every 28 days) or placebo. Primary endpoint was OS. Secondary endpoints included PFS, time to deterioration (TTD) of ECOG and safety; 507 pts were randomised to FTD/TPI (n = 337) or placebo (n = 170). Median follow-up was 10.7 months. Results 277 pts (mean age 63.0 years; 75% male) were enrolled from 64 sites in Europe. Baseline characteristics were balanced between groups; 120 (67%) and 63 (65%) of pts in FTD/TPI and placebo groups had received ≥3 regimens of prior systemic therapy. FTP/TPI significantly prolonged OS (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.78), PFS (HR 0.46, 95% CI 0.35–0.61) and TTD to ECOG (HR 0.59, 95% CI 0.45–0.78; Table) compared with placebo. FTD/TPI had a predictable and manageable safety profile. Treatment-emergent adverse events (TEAEs) were reported in 172/180 (96%) FTD/TPI-treated and 92/97 (96%) placebo-treated pts. Efficacy and safety in European population of TAGS. Table . 801P FTD/TPI Placebo HR (95% CI) P-value (2-sided) (n = 180) (n = 97) Efficacy outcomes, median (95% CI) OS 5.45 (4.34– 6.21) 3.15 (2.43– 3.58) 0.59 (0.44– 0.78) 0.0002 PFS 1.94 (1.91– 2.50) 1.77 (1.74– 1.87) 0.46 (0.35– 0.61) TTD of ECOG 3.84 (2.89– 4.50) 2.10 (1.87– 2.53) 0.59 (0.45– 0.78) 0.0001 TEAEs, n (%) Any 172 (96.1) 92 (95.8) Serious 79 (44.1) 49 (51.0) Grade ≥3 143 (79.9) 62 (64.6) Treatment-related 140 (78.2) 55 (57.3) Leading to dose modification 107 (59.8) 26 (27.1) Leading to treatment discontinuation 24 (13.4) 19 (19.8) Leading to death 19 (10.6) 14 (14.6) Conclusions FTD/TPI was effective and well tolerated in European patients, consistent with the overall population of TAGS. Clinical trial identification NCT02500043. Editorial acknowledgement Simone Tait of Springer Healthcare Communications, funded by Institut de Recherches Internationales Servier. Legal entity responsible for the study Taiho Oncology and Taiho Pharmaceutical. Funding Taiho Oncology and Taiho Pharmaceutical. Disclosure M. Alsina: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Laboratoire Servier; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Merck. J. Tabernero: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Celgene; Advisory / Consultancy: Chugai Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Taiho pharmaceutical; Advisory / Consultancy: Takeda; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Servier. M. Squadroni: Research grant / Funding (self): Taiho Pharmaceutical; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen. T. Doi: Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Kyowa Hakko Kirin; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sumitomo Dainippon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Novartis; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Janssen; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Takeda; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Lilly; Research grant / Funding (self): Celgene; Research grant / Funding (self): BMS; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Quintiles. C. Faustino: Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self): Astellas; Honoraria (self), Advisory / Consultancy: Servier. K. Shitara: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self): Yakult; Honoraria (institution): Dainippon Sumitomo Pharma; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Taiho Pharmaceutical; Honoraria (institution): Chugai Pharma; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): Medi Science. E. Van Cutsem: Research grant / Funding (self): Amgen; Research grant / Funding (self): Bayer; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Celgene; Research grant / Funding (self): Ipsen; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck; Research grant / Funding (self): Merck KgA; Research grant / Funding (self): Novartis; Research grant / Funding (self): Roche; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Servier. N. Causse-Amellal: Full / Part-time employment: Laboratoire Servier. C. LEGER: Full / Part-time employment: Laboratoire Servier. D. Skanji: Full / Part-time employment: Laboratoire Servier. All other authors have declared no conflicts of interest.

BACKGROUND: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.METHODS: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.FINDINGS: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.INTERPRETATION: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.FUNDING: Novartis Pharma AG.

Introduction: MANEC is a rare diagnosis and little is known on its epidemiology/prognosis/management. Methods: Demographic/clinical-pathological/survival data of patients with a diagnosis of MANEC (2010 WHO criteria) from five European centres were retrospectively reviewed. Results: Sixty-six patients were identified (09/80–07/17); median age: 62.5 years (range 34–89); male: 66.7%; ECOG-PS 0-1: 59%; primary tumours from: small/large bowel 62.1%, oesophagus/stomach 22.7%, pancreas/biliary tract 13.6%, unknown 1.5%; adult-comorbidity-evaluation (ACE)-27 score 0: 36.4%. The NE component (predominant histology in 58.1% of 43 cases where this information was available) was poorly-differentiated (PD) in 80.3%, with a median Ki-67 value of 70% (95%-Confidence-Interval (CI): 60–73.6). Most frequently expressed IHC markers were: synaptophysin (87.9%), chromogranin-A (CgA) (54.5%) and CDX2 (48.5%). Histology from recurrent/metastatic sites (14 patients) was PD-NE in 71.4%. Median follow-up time was 11.5 months (mo). Of 34 (51.5%) patients with localised-stage (LA) disease, 91.2% had curative surgery (22.5% had neoadjuvant chemo-radiotherapy (CT-RT), 29% had adjuvant or peri-operative CT), 5.9% had definitive CT-RT and 2.9% had unknown management; 77.4% recurred. Fifty-four (81.8%) patients were treated for advanced-stage (adv) disease: 50% had platinum-based CT, 5.5% irinotecan-based CT, 1.8% gemcitabine, 1.8% 5-fluorouracil/leucovorin, 3.7% unknown CT regimen, 1.8% CT-RT, 1.8% RT, 24% best-supportive-care (BSC), and 9.25% unknown management. Median overall-survival (OS) for all patients was 16.2 mo (95%-CI 12.1–21). Median recurrence-free-survival and OS in patients with LA disease were 12.9 mo (95%-CI 6.7–21) and 21 mo (95%-CI 14.57–35). Median progression-free-survival (PFS) and OS in patients with adv disease were 4.9 mo (95%CI 3.5–7.2) and 14.6 mo (95%CI 9.6–19.4). On univariable analysis, age

AIM:To characterise venous thromboembolism (VTE) in gastrointestinal cancer and assess the clinical utility of risk stratification scoring.METHODS:We performed a retrospective analysis using electronic patient records of 910 gastro-oesophageal (GO) cancer and 1299 colorectal cancer (CRC) patients referred to a tertiary cancer centre to identify the incidence of VTE, its relationship to chemotherapy and impact on survival. VTE risk scores were calculated using the Khorana index. Patients were classified as low risk (0 points), intermediate risk (1 to 2 points) or high risk (3 points). Data was analysed to determine the sensitivity of the Khorana score to predict VTE.RESULTS:The incidence of VTE was 8.9% for CRC patients and 9.7% for GO cancer patients. Pulmonary emboli (PE) were more common in advanced than in localised CRC (50% vs 21% of events respectively) and lower limb deep vein thrombosis (DVT) were more common in localised than in advanced CRC (62% vs 39% of events respectively). The median time to VTE from cancer diagnosis was 8.3 mo for CRC patients compared to 6.7 mo in GO cancer. In localised CRC median time to VTE was 7.1 mo compared with 10.1 mo in advanced CRC. In contrast in GO cancer, the median time to VTE was 12.5 mo in localised disease and 6.8 mo in advanced disease. No survival difference was seen between patients with and without VTE in this cohort. The majority of patients with CRC in whom VTE was diagnosed had low or intermediate Khorana risk score (94% for localised and 97% in advanced CRC). In GO cancer, all patients scored either intermediate or high risk due to the primary site demonstrating a limitation of the risk assessment score in discriminating high and low risk patients with GO cancers. Additional risk factors were identified in this cohort including surgery, chemotherapy or hospital admission. Overall, 81% of patients with CRC and 77% of patients with GO cancer had one or more of these factors within 4 wk prior to diagnosis VTE. These should be factored into clinical risk assessment scores.CONCLUSION:The Khorana score has low sensitivity for thrombotic events in CRC and cannot discriminate low risk patients in high risk cancer sites such as GO cancer.

Background: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. Patients and methods: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week offschedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. Results: Of 71 patients randomized (AZD4547 n1/441, paclitaxel n1/430), 67 received study treatment (AZD4547 n1/440, paclitaxel n1/427). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P1/40.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. Conclusions: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

Introduction: Platinum-etoposide is considered standard-of-care first-line treatment for patients diagnosed with advanced EP-PD-NECs. The optimal platinum-etoposide schedule remains undefined; carboplatin is often substituted for cisplatin, although quality data is lacking. Methods: Electronic records of patients with advanced EP-PD-NEC treated with carboplatin-etoposide (06/09-02/17) were reviewed retrospectively, with aim to provide real-life efficacy/safety data on carboplatin-etoposide in this setting. Chi-square test, Kaplan-Meier and univariate/multivariable Cox-regression analyses were performed, as appropriate. Results: Seventy-three patients were screened, 57 eligible; median follow-up 8.57 months (m); median age 70.4 years (range 36.2–88.4). Most patients were male (68.4%), had Eastern-Cooperative-Oncology-Group performance-status (ECOG-PS) 0–1 (79%) and none-mild comorbidities (72%). Site of primary tumour: foregut 35.1%, hindgut 24.6%, unknown 21%, pancreas 8.8%, others 10.5%. Most had stage IV disease (87.7%); median number of metastatic sites: 2 (range 1–6), liver (68%) being the most common. Histopathology: median Ki-67 75% (95%-Confidence-Interval (95%-CI) 60–80%); morphology included small-cell (33.3%), large-cell (22.8%), others (3.5%), not-specified (40.4%). The 57 patients received a total of 64 courses of carboplatin-etoposide: 54 (84.4%) first-line, 9 (14%) second-line and 1 (1.6%) third-line. Etoposide was administered orally (81.2%) or intravenously (18.8%); median number of cycles: 4 (range 1–7). In the first- and second-line settings, median progression-free-survival (PFS) was 5.4 m (95%-CI 3.6–6.9) and 3.4 m (95%-CI 1.6–11.0) and median overall-survival was 7.5 m (95%-CI 6.2–11.5) and 5.8 m (95%-CI 1.6–15.4), respectively. Most common grade 3–4 adverse events in first/second-line were myelotoxicity (29.6%/44.4%), infections (13%/11.1%), venous thromboembolism (11.1%/22.2%); no differences between first-/second-line were identified (all P-values >0.05). Median carboplatin-etoposide dose-intensity was 94.8 and 94.4% in first-/second-line, respectively. Line of chemotherapy did not impact PFS (P-value >0.3). Liver metastases and age were significant in the univariate analysis for PFS and included in the multivariable Cox-regression: presence of liver metastases was the only independent factor related to worse PFS (Hazard-Ratio 1.9 (95%-CI 1.1–3.3); P-value 0.03). Conclusion: Carboplatin-etoposide is associated with survival outcomes in real-life comparable to those reported in current literature. It is an active combination for patients with advanced EP-PD-NECs, with a manageable toxicity profile which allows adequate dose-intensity.

LBA4007 Background: KEYNOTE062 (NCT02494583) was a randomized, active controlled study of 1L P or P+C vs C in pts with PD-L1 combined positive score ≥1 (CPS ≥1), HER2-negative, advanced GC. Methods: Eligible pts were randomized 1:1:1 to P 200 mg Q3W for up to 2 y, P+C (cisplatin 80 mg/m2 + 5-FU 800 mg/m2/d on d1-d5 Q3W [or capecitabine 1000 mg/m2 BID on d1-d14 Q3W per local guideline]) or placebo Q3W + C. Randomization was stratified by region, disease status, and fluoropyrimidine treatment. Primary endpoints were OS in CPS ≥1 and CPS ≥10 for P+C vs C and P vs C and PFS (RECIST v1.1; central review) in CPS ≥1 for P+C vs C. ORR (RECIST v1.1; central review) in CPS ≥1 for P+C vs C was the secondary endpoint. Final analysis cutoff date was 26 Mar 2019. Results: 763 pts (281 with CPS ≥10) were randomized to P+C (257), P (256), or C (250) (Table). Median follow-up was 11.3 mo. P was noninferior to C for OS in CPS ≥1 per prespecified margins. P vs C prolonged OS in CPS ≥10 (median 17.4 vs 10.8 mo; HR 0.69; 95% CI 0.49-0.97) but wasn’t tested per analysis plan. P+C vs C was not superior for OS in CPS ≥1 or CPS ≥10, with a favorable trend for P+C. P+C did not significantly prolong PFS in CPS ≥1. ORR was higher for P+C vs C. Grade 3-5 drug-related AE rates were 17% (P), 73% (P+C), and 69% (C). Conclusions: As 1L therapy for advanced GC, P was noninferior to C for OS in CPS ≥1 with clinically meaningful improvement for OS in CPS ≥10. P+C did not show superior OS and PFS in CPS ≥1 and OS in CPS ≥10. The safety profile was more favorable for P vs C. Clinical trial information: NCT02494583. [Table: see text]

4038 Background: The incidence of GEJC is increasing in North America and Europe, especially among white men. Many pts present with metastatic disease or relapse locally or systemically after resection of early-stage disease. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with metastatic gastric cancer (mGC)/mGEJC. Here we report results in the mGEJC subgroup from TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy and safety analysis was performed in pts with mGEJC. Results: Of 507 randomized pts, 145 (29%) had GEJC as the sole primary disease site (FTD/TPI, 98/337; placebo, 47/170). Of pts with mGEJC, 85% were male and 83% were white (overall population, 73% and 70%). Baseline characteristics were generally balanced for pts with mGEJC across treatment groups, except for fewer pts having prior gastrectomy (40% vs 55%) and more pts having received ≥3 prior regimens (74% vs 66%) in the FTD/TPI group than in the placebo group. FTD/TPI had an efficacy benefit in pts with mGEJC, and the FTD/TPI safety profile was similar in this subgroup and the overall population (table). Conclusions: FTD/TPI showed a manageable safety profile and efficacy benefit in pts with mGEJC in the TAGS trial, despite heavier pretreatment of the FTD/TPI than the placebo group. Clinical trial information: NCT02500043. [Table: see text]

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts

4043 Background: The phase 3, randomized, double-blind, placebo-controlled study (TAGS) evaluated the efficacy and safety of FTD/TPI (35 mg/m² given orally twice a day on days 1–5 and 8–12 of a 28-day cycle) in mGC patients who had previously received≥2 prior regimens for advanced disease and demonstrated a clinically relevant and statistically significant benefit in OS and PFS with a predictable and manageable safety profile. HRQoL data and association between QoL and time to ECOG status deterioration (2 or more) are reported here. Methods: HRQoL was evaluated using EORTC QLQ-C30 and the gastric-specific module (QLQ-STO22) questionnaires at baseline and at every 4 weeks thereafter until treatment discontinuation. Prespecified key HRQoL were changes from baseline and time to deterioration. Changes ≥10 points were deemed clinically relevant. A time-dependent Cox-regression analysis was performed to evaluate the association of 10-point Global Health Status deterioration with worsening ECOG status. Results: Of 507 patients randomized, 332/337 (98.5%) of FTD/TPI and 164/170 (96.5%) of placebo had baseline QoL data. Overall compliance was 84% for both questionnaires. Demographic and disease were generally balanced between the two groups; QoL scores were also similar between groups. HRQoL was largely maintained during treatment in both arms for most items; mean changes from baseline remained under the 10-point threshold. Clinically relevant changes from baseline were observed only for pain relief at cycle 2 (favouring FTD/TPI); and improved role functioning at cycle 3 (favouring placebo). In a sensitivity analysis including death or progression as an event, FTD/TPI was associated with a positive trend suggesting a reduced risk of QoL deterioration across all scales compared to placebo (HRs ranged from 0.57 to 0.74. A 10-point Global Health Status deterioration was associated with a worsening ECOG status (HR, 95% CI, 1.5, 1.2 to 1.86). Conclusions: During the treatment period, HRQoL remained stable for most functional and symptom scales in both arms, suggesting that HRQoL is largely maintained with FTD/TPI. Treatment with FTD/TPI was associated with a positive trend toward a lower risk of QoL deterioration than placebo across all scales. Changes in QoL were informative for patients ‘expected ECOG status. Clinical trial information: NCT02500043.

4048 Background: KEYNOTE-181 (NCT02564263) is an open-label, randomized, phase 3 trial in ACC and SCC of the esophagus that evaluated IV pembro 200 mg Q3W for up to 2 years vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (control). Pembro was superior to control for OS in patients with PD-L1 CPS ≥10 (N = 222; median 9.3 vs 6.7 months; P= 0.0074). Here we present results of prespecified HRQoL analyses in this population. Methods: The EORTC QLQ-C30 and EORTC QLQ-OES18 were administered at baseline; weeks 2, 3, 4, 6, 9, 12, 18; every 9 weeks up to 1 year/end of treatment; and 30-day safety follow-up visit. Data from patients receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were analyzed. Least squares mean (LSM) score change from baseline to week 9, 95% CI, and nominal P values were calculated. Time to deterioration (TTD) (≥10-point decline from baseline) was assessed by Kaplan-Meier method and Cox regression model. HRs, 95% CIs, and nominal P values are provided. Results: The HRQoL population included 218 PD-L1 CPS ≥10 patients (107 pembro, 111 control). QLQ-C30 compliance at week 9 was 88.9% for pembro and 83.9% for control. There was no significant difference in LSM between arms (3.68; 95% CI –2.28, 9.64; P= 0.2248) in global health status (GHS)/QoL score. Week 9 QLQ-OES18 compliance was 88.4% for pembro and 83.3% for control. QLQ-OES18 scores were not significantly different between arms. TTD for pain (HR 1.02; 95% CI 0.58, 1.81; P= 0.5282), reflux (HR 1.69; 95% CI 0.83, 3.47; P= 0.9254), and dysphagia (HR 1.81; 95% CI 0.97, 3.37; P= 0.9693) subscales were not significantly different between arms. Conclusions: Over 9 weeks, patients treated with pembro had stable GHS/QoL scores similar to those of patients treated with single-agent docetaxel/paclitaxel/irinotecan. Combined with the superior OS and lower rate of treatment-related AEs seen with pembro, these data support clinically meaningful benefit of pembro in esophageal cancer patients with PD-L1 CPS ≥10. Clinical trial information: NCT02564263.