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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18 F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18 F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18 F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18 F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18 F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18 F-BMS-986229 accumulation on PET imaging also had lesions without 18 F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18 F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care., Methods: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUV mean of liver to the average SUV mean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS., Results: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009)., Conclusions: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer ., Methods: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction., Results: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78)., Conclusions: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma., Methods: The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual., Findings: Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0-54·8), pembrolizumab was superior to placebo for pathological complete response (52 [12·9%; 95% CI 9·8-16·6] of 402 vs eight [2·0%; 0·9-3·9] of 402; difference 10·9%, 95% CI 7·5 to 14·8; p<0·00001). Median event-free survival was longer with pembrolizumab versus placebo (44·4 months, 95% CI 33·0 to not reached vs 25·3 months, 20·6 to 33·9; hazard ratio [HR] 0·81, 95% CI 0·67 to 0·99; p=0·0198) but did not meet the threshold for statistical significance (p=0·0178). Median overall survival was 60·7 months (95% CI 51·5 to not reached) in the pembrolizumab group versus 58·0 months (41·5 to not reached) in the placebo group (HR 0·90, 95% CI 0·73 to 1·12; p=0·174). Grade 3 or worse adverse events of any cause occurred in 312 (78%) of 399 patients in the pembrolizumab group and 297 (74%) of 400 patients in the placebo group; the most common were nausea (240 [60%] vs 247 [62%]), anaemia (168 [42%] vs 158 [40%]), and decreased appetite (163 [41%] vs 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 (24%) patients. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each])., Interpretation: Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests KS reports research funding to their institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Merck Sharp & Dohme, Amgen, and Eisai, consulting fees from Eli Lilly, Bristol-Myers Squibb, Takeda Pharmaceutical, Novartis, Abbive, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, Merck Sharp & Dohme, Astellas, Guardant Health Japan, and Janssen, and honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, and Janssen; SYR reports research funding to their institution from Amgen, Astellas, Daiichi Sankyo, Eisai, Merck, Roche, Zymework, Indivumed, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, and AstraZeneca, consultancy fees from Amgen, Astellas, Daiichi Sankyo, Eisai, LG Biochem, Indivumed, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, and AstraZeneca, and fees for speaker bureau from Eli Lilly, Eisai, Daiichi Sankyo, Merck Sharp & Dohme, Ono Pharmaceutical, and Bristol-Myers Squibb; LSW, PY, JX, SA, MO, HYab, Y-KP, TO, and NK report research funding to their institution from Merck Sharp & Dohme; S-EA-B reports research funding to their institution from Celgene, Eli Lilly, Sanofi, German Cancer Aid, German Research Foundation, German Federal Ministry of Education and Research, Roche, Vifor Pharma, Eurozyto, Immutep, Ipsen, Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca, fees for speakers' bureau participation from Eli Lilly, AIO, Bristol-Myers Squibb, and MCI Group, fees for consulting or advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Daiichi Sankyo, and Eli Lilly Germany, and stock ownership in Institut fir Klinische Grebsforschung and Immutep; TY reports honoraria from Merck Sharp & Dohme, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, AstraZeneca, TREUMO, Otsuka, Covidien, Johnson & Johnson, Olympus, and Intuitive; HYas reports research funding to their institution from Merck Sharp & Dohme, and honoraria from Chugai Pharma; MDB reports research funding to their institution from Merck Sharp & Dohme, honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Eli Lilly, and Servier, reimbursement for travel from Daiichi, and participation on an advisory board for Novartis; SL reports research funding to their institution from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, Merck Sharp & Dohme, Pfizer, Roche, and Servier, consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daichii Sankyo, Incyte, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Servier, and Astellas, and honoraria from Amgen, Bristol-Myers Squibb, Incyte, GlaxoSmithKline, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Pierre-Fabre, Roche, Servier; JT reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F Hoffman-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspira, IQVIA, Eli Lilly, Menarini, Merck Serono, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, and Tolremo Therapeutics, honoraria from HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource, and stock options in Oniria Therapeutics; EVC reports research funding to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier, and fees for advisory board consulting for Abbvie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichi, GlaxoSmithKline, Incyte, Ipsen, Eli Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks; YYJ reports research funding to their institution from Merck Sharp & Dohme, the National Cancer Institute, the US Department of Defense, Cycle of Survival, Fred's Team, Rgenix, Bayer, Roche, Bristol-Myers Squibb, and Eli Lilly, fees for advisory board participation from Rgenix, Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck Sharp & Dohme, Daiichi Sankyo, Zymeworks, SeaGen, Basilea Pharmaceutical, Astra Zeneca, and equity in Rgenix; XF, C-SS, and PB are employees of and own stock options in Merck Sharp & Dohme; D-YO reports research funding to their institution from AstraZeneca, Novartis, Array, Eli Lilly, Servier, Beigene, Merck Sharp & Dohme, and Handok; and Y-JB reports research funding to their institution from Merck Sharp & Dohme and fees for consulting from Astellas, Amgen, Samyang Biopharm, Hanmi, and Daewoong., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: In CheckMate 649, first-line nivolumab plus chemotherapy prolonged overall survival versus chemotherapy in patients with advanced/metastatic non-human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC). We present exploratory patient-reported outcomes (PROs)., Methods: In patients (N = 1,581) concurrently randomly assigned 1:1 to nivolumab plus chemotherapy or chemotherapy and in those with tumor PD-L1 expression at a combined positive score (CPS) of ≥5, health-related quality of life (HRQoL) was assessed using the EQ-5D and Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), which included the FACT-General (FACT-G) and Gastric Cancer subscale (GaCS). The FACT-G GP5 item assessed treatment-related symptom burden. Longitudinal changes in HRQoL were assessed using mixed models for repeated measures in the PRO analysis population (randomly assigned patients with baseline and ≥1 postbaseline assessments). Time to symptom or definitive deterioration analyses were also conducted., Results: In the PRO analysis population (n = 1,360), PRO questionnaire completion rates were mostly >80% during treatment. Patient-reported symptom burden was not increased with nivolumab plus chemotherapy versus chemotherapy. Mean improved changes from baseline were greater with nivolumab plus chemotherapy versus chemotherapy for FACT-Ga total, GaCS, and EQ-5D visual analog scale in patients with a CPS of ≥5; results were similar for the overall PRO analysis population. In CPS ≥5 and all randomly assigned populations, nivolumab plus chemotherapy reduced the risk of symptom deterioration versus chemotherapy, on the basis of FACT-Ga total score and GaCS; time to definitive deterioration was longer, and the risk of definitive deterioration in HRQoL was reduced with nivolumab plus chemotherapy across EQ-5D and most FACT-Ga measures (hazard ratio [95% CI] <1)., Conclusion: Compared with chemotherapy alone, first-line nivolumab plus chemotherapy showed stable or better on-treatment HRQoL in patients with advanced/metastatic non-HER2-positive GC/GEJC/EAC and also showed decreased risk of definitive HRQoL deterioration.

Background: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma., Methods: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m 2 bolus followed by 2400 mg/m 2 over 48 h], leucovorin [400 mg/m 2 ], and oxaliplatin [85 mg/m 2 ]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete., Findings: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths., Interpretation: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned., Funding: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute., Competing Interests: Declaration of interests SLC reports stock ownership in Pfizer, Moderna, and BioNTech. RHM reports consulting with PureTech Health, advisory board with IDEAYA Biosciences, and research funding from Nimbus Therapeutics. JFC reports an investigator role on a research study sponsored by Paige.AI. GYK reports consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Pieris, and Zymeworks; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, CARsgen, Zymeworks, Daiichi Sankyo, Oncolys, Pieris, and Adaptimmune. SBM reports honoraria from Natera, Bicara, Novartis, Basilea, Elevation Oncology, Purple Oncology, Pinetree Therapeutics, and Daiichi Sankyo; research support from Epic Sciences; grant funding from the Conquer Cancer Foundation; and research travel support from AstraZeneca outside of the submitted work. MAS reports consulting for Boston Scientific and Novo Nordisk. MEL reports ownership or equity interests with Apricity Health; intellectual property rights with John Wiley & Sons, and the Taylor & Francis Group; uncompensated provision of services for Oncoderm; and provision of services for Adgero Biopharmaceuticals, the American Academy of Dermatology, the American Society of Pediatric Hematology/Oncology, Apricity Health, AstraZeneca, Atlantic Canada Oncology Group, BGB Communications, Bicara Therapeutics, Deciphera, DelMar Pharmaceuticals, EMD Serono, GCO Global, Hoth Therapeutics, Incyte, Innovaderm Research, Johnson & Johnson, La Fonderie Ressources, La Roche-Posay, Loxo Oncology, Lutris Pharma, MJH Life Sciences, the Michigan Dermatological Society, NKMax America, NanOlogy, Novartis, Novartis Pharmaceuticals Corporation, Novocure, OnQuality Pharmaceuticals, Patient Resource, QED Therapeutics, RBC Consulting, RMEI Medical Education, Society for Immunotherapy of Cancer, Takeda Millennium, The Lynx Group, Tyra Biosciences, Varsona Pharmaceuticals, WebMD, Wolters Kluwer, and eSquared Communication Consulting. JS reports consulting for Paige.AI. MFB reports consulting for Eli Lilly and AstraZeneca (not related to this work). YYJ reports research funding from Bayer, Bristol Myers Squibb, Memorial Sloan Kettering Cancer Center Cycle for Survival, the United States Department of Defense, Eli Lilly, Fred's Team, Genentech/Roche, Merck, the National Cancer Institute, and RGENIX; advisory board or consulting with AbbVie, Amerisource Bergen, Ask-Gene Pharma, Arcus Biosciences, Astellas, Astra Zeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Clinical Care Options, Daiichi-Sankyo, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, Imedex, Imugene, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Michael J Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Research to Practice, RGENIX, Seagen, Silverback Therapeutics, and Zymeworks; and stock options in RGENIX. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort., Patients and Methods: The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance., Results: 89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS., Conclusions: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objective: To evaluate the efficacy of chemotherapy in patients with microsatellite instability (MSI)-high gastric cancer., Background: Although MSI-high gastric cancer is associated with a superior prognosis, recent studies question the benefit of perioperative chemotherapy in this population., Methods: Locally advanced gastric adenocarcinoma patients who either underwent surgery alone or also received neoadjuvant, perioperative, or adjuvant chemotherapy between 2000 and 2018 were eligible. MSI status, determined by next-generation sequencing or mismatch repair protein immunohistochemistry, was determined in 535 patients. Associations among MSI status, chemotherapy administration, overall survival (OS), disease-specific survival, and disease-free survival were assessed., Results: In 535 patients, 82 (15.3%) had an MSI-high tumor and ∼20% better OS, disease-specific survival, and disease-free survival. Grade 1 (90%-100%) pathological response to neoadjuvant chemotherapy was found in 0 of 40 (0%) MSI-high tumors versus 43 of 274 (16%) MSS. In the MSI-high group, the 3-year OS rate was 79% with chemotherapy versus 88% with surgery alone ( P =0.48). In the MSS group, this was 61% versus 59%, respectively ( P =0.96). After multivariable interaction analyses, patients with MSI-high tumors had superior survival compared with patients with MSS tumors whether given chemotherapy (hazard ratio=0.53, 95% confidence interval: 0.28-0.99) or treated with surgery alone (hazard ratio=0.15, 95% confidence interval: 0.02-1.17)., Conclusions: MSI-high locally advanced gastric cancer was associated with superior survival compared with MSS overall, despite worse pathological chemotherapy response. In patients with MSI-high gastric cancer who received chemotherapy, the survival rate was ∼9% worse compared with surgery alone, but chemotherapy was not significantly associated with survival., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). 89 Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, 18 F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with 18 F-FDG PET. More lesions were identified on 18 F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on 18 F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on 18 F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered ( n  = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo ( n  = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion ( n  = 6) ( P  = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

HER2 is overexpressed in approximately 20% of esophagogastric cancer (EGC) cases. The addition of the anti-HER2 antibody, trastuzumab, to chemotherapy in 2010 was the first targeted treatment to demonstrate an improvement in survival. The aggressive nature and heterogeneous biology of EGC have posed a particular challenge and resulted in numerous negative trials without a change in standard of care for more than a decade. However, with the incorporation of dual HER2 and PD-1 blockade as well as the advent of a new, potent antibody-drug conjugate, trastuzumab deruxtecan, there have been 2 new FDA approvals for this patient population within the past 2 years. Consequently, the management and landscape of HER2-positive EGC is rapidly changing and increasingly optimistic.

Objective: The microbiome is hypothesized to have a significant impact on cancer development. In gastric cancer (GC), Helicobacter pylori is an established class I carcinogen. However, additional organisms in the intratumoral microbiome play an important role in GC pathogenesis and progression. In this study, we characterize the full spectrum of the microbes present within GC and identify distinctions among molecular subtypes., Methods: A microbiome bioinformatics pipeline that is generalizable across multiple next-generation sequencing platforms was developed. Microbial profiles for alpha diversity and enrichment were generated for 2 large, demographically distinct cohorts: (1) internal Memorial Sloan Kettering Cancer Center (MSKCC) and (2) The Cancer Genome Atlas (TCGA) cohorts. A total of 520 GC samples were compared with select tumor-adjacent nonmalignant samples. Microbiome differences among the GC molecular subtypes were identified., Results: Compared with nonmalignant samples, GC had significantly decreased microbial diversity in both MSKCC and TCGA cohorts ( P <0.05). Helicobacter , Lactobacillus , Streptococcus , Prevotella , and Bacteroides were significantly more enriched in GC samples when compared with nonmalignant tissue ( P <0.05). Microsatellite instability-high GC had distinct microbial enrichment compared with other GC molecular subtypes., Conclusion: Distinct patterns of microbial diversity and species enrichment were identified in patients with GC. Given the varied spectrum of disease progression and treatment response of GC, understanding unique microbial signatures will provide the landscape to explore key microbial targets for therapy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Memorial Sloan Kettering Cancer Center (MSK) nomogram combined both gastroesophageal junction (GEJ) and gastric cancer patients and was created in an era from patients who generally did not receive neoadjuvant chemotherapy. We sought to reevaluate the MSK nomogram in the era of multidisciplinary treatment for GEJ and gastric cancer., Study Design: Using data on patients who underwent R0 resection for GEJ or gastric cancer between 2002 and 2016, the C-index of prediction for disease-specific survival (DSS) was compared between the MSK nomogram and the American Joint Committee on Cancer (AJCC) 8th edition staging system after segregating patients by tumor location (GEJ or gastric cancer) and neoadjuvant treatment. A new nomogram was created for the group for which both systems poorly predicted prognosis., Results: During the study period, 886 patients (645 gastric and 241 GEJ cancer) underwent up-front surgery, and 999 patients (323 gastric and 676 GEJ) received neoadjuvant treatment. Compared with the AJCC staging system, the MSK nomogram demonstrated a comparable C-index in gastric cancer patients undergoing up-front surgery (0.786 vs 0.753) and a better C-index in gastric cancer patients receiving neoadjuvant treatment (0.796 vs 0.698). In GEJ cancer patients receiving neoadjuvant chemotherapy, neither the MSK nomogram nor the AJCC staging system performed well (C-indices 0.647 and 0.646). A new GEJ nomogram was created based on multivariable Cox regression analysis and was validated with a C-index of 0.718., Conclusions: The MSK gastric cancer nomogram's predictive accuracy remains high. We developed a new GEJ nomogram that can effectively predict DSS in patients receiving neoadjuvant treatment., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR- amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR- amplified GEA to date., Patients and Methods: A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB)., Results: Sixty patients with EGFR -amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR -amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR -amplified GEA received EGFRi., Conclusion: Patients with EGFR- amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Standard-of-care for resectable gastric/gastroesophageal junction cancer includes surgery and neoadjuvant-adjuvant 5-fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) chemotherapy. Early-phase clinical studies support further clinical development of the immune checkpoint inhibitor (ICI); durvalumab, an anti-PD-L1 antibody, in patients with gastric/gastroesophageal junction cancer. Accumulating evidence indicates that ICIs combined with FLOT chemotherapy improve clinical outcomes in patients with advanced or metastatic cancer. We describe the rationale for and the design of MATTERHORN, a randomized, double-blind, placebo-controlled, phase III study investigating the efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy followed by adjuvant durvalumab monotherapy in patients with resectable gastric/gastroesophageal junction cancer. The planned sample size is 900 patients, the primary end point is event-free survival and safety and tolerability will be evaluated. Clinical trial registration: NCT04592913 (ClinicalTrials.gov).

Background: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified., Methods: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided., Results: Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed., Conclusions: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk., (© The Author(s) 2022. Published by Oxford University Press.)

Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit Trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using patient samples, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging technologies we demonstrate the role of caveolin-1 (CAV1) as a complementary biomarker in GC selection for Trastuzumab therapy. In retrospective analyses of samples from patients enrolled on Trastuzumab trials, the CAV1-high profile associates with low membrane HER2 density and low patient survival. We show a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and Trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches (statins) increases antibody drug efficacy in tumors with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients associates with enhanced antibody efficacy. Together, this work provides preclinical justification and clinical evidence that require prospective investigation of antibody drugs combined with statins to delay drug resistance in tumors., (© 2022. The Author(s).)

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma 1-4 . Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial 5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries 6 . Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively 7-11 . Treatment combining 1 mg kg -1 nivolumab with 3 mg kg -1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer 12 . Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma., (© 2022. The Author(s).)

Purpose: Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab., Methods: Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m 2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD., Results: We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor., Conclusions: The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID., Clinical Trial Registration: NCT03193918. June 19, 2017., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient-derived xenografts (PDXs)., Materials and Methods: We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases. Clinicopathologic features of each PDX and the corresponding patient sample were annotated, including stage at diagnosis, treatment history, histology, and biomarker profile. To identify oncogenic DNA alterations, we analyzed and compared targeted sequencing performed on PDX and parent tumor pairs. We conducted xenotrials in genomically defined models with oncogenic drivers., Results: From April 2010 to June 2019, we implanted 276 patient tumors, of which 98 successfully engrafted (35.5%). This collection is enriched for PDXs derived from patients with human epidermal growth factor receptor 2-positive esophagogastric adenocarcinoma (62 models, 63%), the majority of which were refractory to standard therapies including trastuzumab. Factors positively correlating with engraftment included advanced stage, metastatic origin, intestinal-type histology, and human epidermal growth factor receptor 2-positivity. Mutations in TP53 and alterations in receptor tyrosine kinases ( ERBB2 and EGFR ), RAS/PI3K pathway genes, cell-cycle mediators ( CDKN2A and CCNE1 ), and CDH1 were the predominant oncogenic drivers, recapitulating clinical tumor sequencing. We observed antitumor activity with rational combination strategies in models established from treatment-refractory disease., Conclusion: The Memorial Sloan Kettering Cancer Center PDX collection recapitulates the heterogeneity of esophagogastric cancer and is a powerful resource to investigate mechanisms driving tumor progression, identify predictive biomarkers, and develop therapeutic strategies for molecularly defined subsets of esophagogastric cancer., Competing Interests: Daniela MolenaHonoraria: Bristol Myers Squibb/Pfizer, MerckConsulting or Advisory Role: Johnson & Johnson, UroGen pharma, Boston Scientific, AstraZeneca/MedImmune Steven B. MaronStock and Other Ownership Interests: Calithera BiosciencesConsulting or Advisory Role: Natera, Basilea, Daichi Sankyo, Bicara Therapeutics, NovartisResearch Funding: Roche/Genentech (Inst), Guardant Health (Inst)Travel, Accommodations, Expenses: Bayer David R. JonesConsulting or Advisory Role: Merck, AstraZeneca Jaclyn F. HechtmanEmployment: NeoGenomics LaboratoriesStock and Other Ownership Interests: NeoGenomics LaboratoriesHonoraria: WebMD, Illumina, BayerConsulting or Advisory Role: Cor2Ed, Axiom Healthcare Strategies, BayerResearch Funding: Bayer, Lilly, Boehringer Ingelheim David B. SolitThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: Scorpion Therapeutics, Vividion Therapeutics, Fore BiotherapeuticsConsulting or Advisory Role: Pfizer, Lilly, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals Yelena Y. JanjigianStock and Other Ownership Interests: RgenixConsulting or Advisory Role: Pfizer, Merck, Bristol Myers Squibb, Merck Serono, Daiichi Sankyo, Rgenix, Bayer, Imugene, AstraZeneca, Lilly, Zymeworks, Basilea Pharmaceutical, Michael J. Hennessy Associates, Paradigm, Seattle GeneticsResearch Funding: Bayer (Inst), Rgenix (Inst), Bristol Myers Squibb (Inst), Merck (Inst), Lilly (Inst), NCI (Inst), Department of Defense (Inst), Cycle for Survival (Inst), Fred's Team (Inst), Genentech/Roche (Inst)Other Relationship: Clinical Care Options, Axis Medical Education, Research to PracticeNo other potential conflicts of interest were reported.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas 1-3 . More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours 4 . Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer 5 , there are preclinical 6-19 and clinical 20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma 22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: How obesity has an impact on operative and oncologic outcomes for gastric cancer patients is unclear, and the influence of obesity on response to neoadjuvant chemotherapy (NAC) has not been evaluated., Methods: Patients who underwent curative gastrectomy for primary gastric cancer between 2000 and 2018 were retrospectively identified. After stratification for NAC, operative morbidity, mortality, overall survival (OS), and disease-specific survival (DSS) were compared among three body mass index (BMI) categories: normal BMI (< 25 kg/m 2 ), mild obesity (25-35 kg/m 2 ), and severe obesity (≥ 35 kg/m 2 )., Results: During the study period, 984 patients underwent upfront surgery, and 484 patients received NAC. Tumor stage did not differ among the BMI groups. However, the rates of pathologic response to NAC were significantly lower for the patients with severe obesity (10% vs 40%; p < 0.001). Overall complications were more frequent among the obese patients (44.3% for obese vs 24.9% for normal BMI, p < 0.001). Intraabdominal infections were also more frequent in obese patients (13.9% for obese vs 4.7% for normal BMI, p = 0.001). In the upfront surgery cohort, according to the BMI, OS and DSS did not differ, whereas in the NAC cohort, severe obesity was independently associated with worse OS [hazard ratio (HR) 1.87; 95% confidence interval (CI) 1.01-3.48; p = 0.047] and disease-specific survival (DSS) (HR 2.08; 95% CI 1.07-4.05; p = 0.031)., Conclusion: For the gastric cancer patients undergoing curative gastrectomy, obesity was associated with significantly lower rates of pathologic response to NAC and more postoperative complications, as well as shorter OS and DSS for the patients receiving NAC., (© 2021. Society of Surgical Oncology.)

Background: This study aimed to analyze timing and sites of recurrence for patients receiving neoadjuvant chemotherapy for gastric cancer. Neoadjuvant chemotherapy followed by surgical resection is the standard treatment for locally advanced gastric cancer in the West, but limited information exists as to timing and patterns of recurrence in this setting., Methods: Patients with clinical stage 2 or 3 gastric cancer treated with neoadjuvant chemotherapy followed by curative-intent resection between January 2000 and December 2015 were analyzed for 5-year recurrence-free survival (RFS) as well as timing and site of recurrence., Results: Among 312 identified patients, 121 (38.8%) experienced recurrence during a median follow-up period of 46 months. The overall 5-year RFS rate was 58.9%, with RFS rates of 95.8% for ypT0N0, 81% for ypStage 1, 77.4% for ypStage 2, and 22.9% for ypStage 3. The first site of recurrence was peritoneal for 49.6%, distant (not peritoneal) for 45.5%, and locoregional for 11.6% of the patients. The majority of the recurrences (84.3%) occurred within 2 years. Multivariate analysis showed that ypT4 status was an independent predictor for recurrence within 1 year after surgery (odds ratio, 2.58; 95% confidence interval, 1.10-6.08; p = 0.030)., Conclusions: The majority of the recurrences for patients with clinical stage 2 or 3 gastric cancer who received neoadjuvant chemotherapy and underwent curative resection occurred within 2 years. After neoadjuvant chemotherapy, pathologic T stage was a useful risk predictor for early recurrence., (© 2021. Society of Surgical Oncology.)

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions., (© 2021. Springer Nature Limited.)

Current guidelines recommend two-drug cytotoxic chemotherapy with a fluoropyrimidine (fluorouracil or capecitabine) and a platinum-based agent (oxaliplatin or cisplatin) as first-line treatment for advanced gastric cancer. Pembrolizumab monotherapy has demonstrated durable antitumor activity in patients with advanced programmed death ligand 1-positive (combined positive score ≥1) gastric/gastroesophageal junction adenocarcinoma. Accumulating evidence indicates that combining pembrolizumab with standard-of-care chemotherapy for the treatment of advanced or metastatic cancer improves clinical outcomes. We describe the rationale for and the design of the randomized, double-blind, placebo-controlled, Phase III KEYNOTE-859 study, which is investigating pembrolizumab in combination with chemotherapy as first-line treatment for patients with human epidermal growth factor receptor 2-negative advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma. The planned sample size is 1542 patients, and the primary end point is overall survival. Clinical trial registration: NCT03675737 (ClinicalTrials.gov).

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone., Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116., Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified., Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients., Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical., Competing Interests: Declaration of interests YYJ reports receiving consulting or advisory board fees from AstraZeneca, Daiichi Sankyo, Imugene, Jounce Therapeutics, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, Seattle, Genetics, and Zymeworks; receiving consulting or advisory and research funding from Eli Lilly, Bristol Myers Squibb, and Merck & Co; receiving research funding from Bayer, Boehringer Ingelheim, Genentech/Roche, MSK Cancer Center Support Grant/Core Grant (P30 CA008748), and Ono Pharmaceutical; receiving speaker's bureau fees from the American Society of Clinical Oncology; and receiving stock options from Rgenix, outside the submitted work. KS reports receiving personal fees for advisory roles from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Ono Pharmaceutical Company, Pfizer, and Takeda; receiving advisory role or research funding from Astellas Pharma, Eli Lilly, Merck Pharmaceutical, and Taiho Pharmaceutical; receiving honoraria (lecture fees) from AbbVie, Novartis, and Yakult Honsha; and receiving research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, and Medi Science, outside the submitted work. MM reports receiving research grants from AIO, Amgen, German Federal Ministry of Education and Research, Bristol Myers Squibb, European Organisation for Research and Treatment of Cancer, German Cancer Aid, Merck Serono, Merck Sharp & Dohme, and Pfizer; receiving personal fees from Bristol Myers Squibb, Falk Foundation, Lilly, MCI Group, Merck Serono, Merck Sharp & Dohme, Pfizer, and Roche; and receiving non-financial support from AIO, Amgen, Bristol Myers Squibb, German Federal Ministry of Education and Research, European Organisation for Research and Treatment of Cancer, and German Cancer Aid, outside the submitted work. MG reports receiving grants and personal fees from Bristol Myers Squibb and Novartis; and receiving personal fees from Merck Sharp & Dohme and Roche, outside the submitted work. KY reports receiving grants and personal fees from Daiichi-Sankyo, Ono Pharmaceutical Company, Taiho Pharmaceutical, and Yakult Honsha; receiving personal fees from Chugai, Lilly, and Takeda; receiving grants from Sanofi; and receiving personal fees from Bristol Myers Squibb, Merck Serono, and Takeda, outside the submitted work. MS reports receiving personal fees for clinical research from Bristol Myers Squibb, during the conduct of the study; and receiving personal fees for clinical research from Astellas, AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Roche, outside the submitted work. MT reports receiving research funding from Bristol Myers Squibb, during the conduct of the study. RK reports receiving grants from Amgen, AstraZeneca, Athenex, Eli Lilly, Nektar, and Sanofi; receiving grants and non-financial support from Roche; grants and personal fees from Astellas and Novartis; grants, personal fees, and non-financial support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; and personal fees from Gador, outside the submitted work. MVK reports serving in an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Ipsen, Roche, Sandoz, Sanofi, and Servier, outside the submitted work. RB reports serving as a medical adviser for Merck Serono and Novartis; receiving clinical research funding from Novartis; serving as a medical adviser and speaker for AstraZeneca, Bristol Myers Squibb, and Pfizer; receiving clinical research funding from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and serving as a speaker for Merck, during the conduct of the study. TZ reports receiving personal advisory board fees from AstraZeneca, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Sanofi, outside the submitted work. JMC reports personal fees and consulting and travel support from Bristol Myers Squibb; and research funding from AstraZeneca, Esperas Pharma, Merck, and Tesaro, outside the submitted work. VP, DC, MLe, HX, KK, and MLi report employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. JAA reports receiving clinical research grants and receiving personal advisory board fees from Bristol Myers Squibb, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Few Western studies have evaluated the long-term oncologic outcomes of minimally invasive surgery (MIS) approaches to gastrectomy for gastric cancer. This study aimed to compare the outcomes between minimally invasive and open gastrectomies and between laparoscopic and robotic gastrectomies at a high-volume cancer center in the United States., Methods: The study analyzed data for all patients undergoing curative gastrectomy for gastric adenocarcinoma from January 2007 to June 2017. Postoperative complications and disease-specific survival (DSS) were compared between surgical approaches., Results: The median follow-up period for the 845 patients in this study was 38.5 months. The stage-stratified 5-year DSS did not differ significantly between open surgery (n = 534) and MIS (n = 311). The MIS approach resulted in significantly fewer complications, as confirmed by adjusted comparison (odds ratio [OR], 0.70; range, 0.49-1.00; p = 0.049). After adjustment, the two groups did not differ in terms of DSS (hazard ratio [HR], 0.83; range, 0.55-1.25; p = 0.362). The robotic operations (n = 190) had fewer conversions to open procedure (p = 0.010), a shorter operative time (212 vs 240 min; p < 0.001), more dissected nodes (27 vs 22; p < 0.001), fewer Clavien-Dindo grade ≥3 complications (5.8% vs 13.2%; p = 0.023), and a shorter postoperative stay (5 vs 6 days; p = 0.045) than the laparoscopic operations (n = 121). The DSS rate did not differ between the laparoscopic and robotic groups., Conclusion: The study findings demonstrated the long-term survival and oncologic equivalency of MIS gastrectomy and the open approach in a Western cohort, supporting the use of MIS at centers that have adequate experience with appropriately selected patients.

Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov).

Background: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer., Methods: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m 2 of intravenous oxaliplatin or 80 mg/m 2 of cisplatin on day 1, 850 mg/m 2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m 2 per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment., Findings: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7-23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths., Interpretation: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway., Funding: Merck & Co., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A subset of patients with early gastric cancer demonstrate early recurrence and poor survival despite margin-negative resection. This study used an extremes-of-survivorship approach to identify an association between TP53 hotspot mutations co-occurring with loss of heterozygosity and unexpectedly poor survival in early gastric cancer. This distinct genomic profile may be a novel biomarker of poor survival in patients with completely resected early gastric cancer, and warrants large-scale validation. Promising, validation needed., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer., Materials and Methods: Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS., Results: Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy., Conclusion: Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control., Implications for Practice: Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible., (© AlphaMed Press 2019.)

Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulation of HER2 endocytosis as a strategy to improve pertuzumab uptake in HER2-positive gastric tumors and allow the use of a pretargeted imaging approach. Methods: We conducted in vitro and in vivo studies with NCI-N87 gastric cancer cells to determine how HER2 endocytosis affects pertuzumab binding to tumor cells. Lovastatin, a clinically approved cholesterol-lowering drug, was used to modulate caveolae-mediated HER2 endocytosis. Results: Administration of lovastatin to NCI-N87 cancer cells resulted in significant accumulation of non-activated HER2 dimers at the cell surface. Pretreatment of NCI-N87 cells with lovastatin increased in vitro specific accumulation of membrane-bound 89 Zr-labeled pertuzumab. Lovastatin-enhanced pertuzumab tumor uptake was also observed in NCI-N87 gastric cancer xenografts, allowing tumor detection as early as 4 h and high-contrast images at 48 h after tracer administration via PET. Temporal enhancement of HER2 membrane availability by lovastatin allowed imaging of cell surface HER2 with transcyclooctene-conjugated antibodies and 18 F-labeled tetrazine. Conclusion: Temporal pharmacological modulation of membrane HER2 may be clinically relevant and exploitable for pretargeted molecular imaging and therapy in gastric tumors., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC., Experimental Design: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features., Results: One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors ( n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed., Conclusions: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded., (©2019 American Association for Cancer Research.)

Purpose: VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib., Patients and Methods: Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response., Results: The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months-NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019)., Conclusions: Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers., (©2019 American Association for Cancer Research.)

Background: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial., Methods: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity., Results: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13 months (95% CI 6.4-20.7) and the median OS was 24.9 months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia., Conclusion: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2 . Heterogeneous 89 Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2 -amplified EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2 -amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR / ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones. See related commentary by Klempner and Catenacci, p. 166 . This article is highlighted in the In This Issue feature, p. 151 ., (©2018 American Association for Cancer Research.)

Esophagogastric (EG) cancer has a poor prognosis despite the use of standard therapies, such as chemotherapy and biologic agents. Recently, immune checkpoint inhibitors (ICIs) have been introduced as treatments for EG cancer; nivolumab and pembrolizumab have been approved in the United States and Europe to treat advanced EG cancer. Other ICIs, such as avelumab, durvalumab, ipilimumab, and tremelimumab, have been evaluated in several trials, although their roles are still not established in clinical practice. In addition, preclinical evidence suggests that combining an ICI with a tumor-targeting antibody can result in greater antitumor effects in metastatic EG cancer. There are not yet validated predictive biomarkers to identify which patients will respond best to ICI treatment. PD-L1 expression may predict intensity of response, although PD-L1-negative patients can still respond to ICIs. Despite differences in PD-L1 expression between Asian and non-Asian populations, no geographic differences in rates of treatment-related or immune-mediated/infusion-related adverse events have been reported. Also, several trials are currently evaluating combinations of ICIs, standard chemotherapy, and biologic agents as well as novel biomarkers to improve treatments and outcomes. Our review will address the current use of and evidence for ICIs for advanced EG cancer treatment and future trends in this area for clinical practice.

Background: Gastric adenocarcinoma is a heterogenous disease that results from complex interactions between environmental and genetic factors, which may contribute to the disparate outcomes observed between different patient populations. This study aimed to determine whether genomic differences exist in a diverse population of patients by evaluating tumor mutational profiles stratified by race., Methods: All patients with gastric adenocarcinoma between 2012 and 2016 who underwent targeted next-generation sequencing of cancer genes by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform were identified. Patient race was categorized as Asian, African American, Hispanic, or Caucasian. Fisher's exact test was used to examine differences in mutation rates between racial designations for the most common mutations identified. The p values in this study were adjusted using the false discovery rate method., Results: The study investigated 595 mutations in 119 patients. The DNA alterations identified included missense mutations (66%), frame-shift deletions (13%), and nonsense mutations (9%). Silent mutations were excluded. The most frequently mutated genes were ARID1A, CDH1, ERBB3, KRAS, PIK3CA, and TP53. Of these, TP53 was the most frequently mutated gene, affecting 50% of patients. The proportion of patients with TP53 mutations differed significantly between races (p = 0.012). The findings showed TP53 mutations for 89% (16/18) of the African American patients, 56% (10/18) of the Asian patients, 43% (9/21) of the Hispanic patients, and 40% (25/62) of the Caucasian patients., Conclusions: Significantly higher rates of TP53 mutations were identified among the African American patients with gastric adenocarcinoma. This is the first study to evaluate tumor genomic differences in a diverse population of patients with gastric adenocarcinoma.

There are few effective treatment options for metastatic esophagogastric adenocarcinomas after progression on second-line chemotherapy. Immune checkpoint blockade therapy is a promising treatment strategy for selected advanced esophagogastric cancer, and the PD-1 inhibitor pembrolizumab has recently been approved for metastatic or recurrent gastric or gastroesophageal junction cancer that has progressed beyond second-line systemic therapy. We review the current data supporting immune checkpoint blockade therapy in advanced esophagogastric adenocarcinoma., (© 2018 Wiley Periodicals, Inc.)

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14 See related article by Pectasides et al., p. 37 This article is highlighted in the In This Issue feature, p. 1 ., (©2017 American Association for Cancer Research.)

Trastuzumab with chemotherapy improves clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive esophagogastric adenocarcinoma (EGA). Despite the therapeutic benefit, responses are rarely complete, and most patients develop progression. To our knowledge, this is the first report evaluating 89 Zr-trastuzumab in HER2-positive EGA; here, we evaluate the safety, pharmacokinetics, biodistribution, and dosimetry 89 Zr-trastuzumab. Methods: Trastuzumab was conjugated with deferoxamine and radiolabeled with 89 Zr. A mean activity of 184 MBq was administered to 10 patients with metastatic HER2-positive EGA. PET imaging, whole-body probe counts, and blood draws were performed to assess pharmacokinetics, biodistribution, and dosimetry. Results: No clinically significant toxicities were observed. At the end of infusion, the estimated 89 Zr-trastuzumab in plasma volume was a median 102% (range, 78%-113%) of the injected dose. The median biologic half-life T 1/2β was 111 h (range, 78-193 h). The median biologic whole-body retention half-life was 370 h (range, 257-578 h). PET images showed optimal tumor visualization at 5-8 d after injection. The maximum tumor SUV ranged from no to minimal uptake in 3 patients to a median of 6.8 (range, 2.9-22.7) for 20 lesions in 7 patients. Dosimetry estimates from OLINDA showed that the organs receiving the highest absorbed doses were the liver and heart wall, with median values of 1.37 and 1.12 mGy/MBq, respectively. Conclusion: 89 Zr-trastuzumab imaging tracer is safe and provides high-quality images in patients with HER2-positive EGA, with an optimal imaging time of 5-8 d after injection., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC)., Background: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy., Methods: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected., Results: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy., Conclusion: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.

Background: Conventional cytotoxic chemotherapy has been the backbone of advanced gastric cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. A better understanding of genetic alterations and molecular signatures of gastric cancer has been reached in the last years. It will serve as a roadmap for better treatment stratification and future drug development., Materials and Methods: We reviewed preclinical and clinical studies that assessed novel treatment targets and emerging drug therapies in gastric cancer. We performed research via PubMed, and the congress webpages of the American Society of Clinical Oncology, European Society of Medical Oncology and the Japanese Society of Medical Oncology., Results: HER2-targeting with trastuzumab is effective in HER2-positive metastatic gastric cancer; combined HER2 targeting strategies are being investigated. Studies assessing the role of HER2 targeting in the perioperative setting are ongoing. Novel treatment targets include inhibition of cancer stemness-related signaling pathways like STAT3. DNA damage repair and Claudin 18.2, a tight junction protein with high expression in gastric cancers are also novel molecular drug targets. Modification of the tumor microenvironment, including activation of immune response by PD-1/PD-L1 checkpoint inhibitors and stroma modification by matrix metalloproteinase-9 inhibition, led to first promising treatment results., Conclusion: Novel treatment options for gastric cancer patients are emerging. They involve novel mechanisms of action, and are based on our constantly increasing understanding of tumor biology and better molecular stratification of gastric cancer patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gastric cancers, with gastric adenocarcinoma (GAC) as the most common histological type, impose a considerable global health burden. Although the screening strategies for early detection have been shown to be successful in Japan and South Korea, they are either not implemented or not feasible in most of the world, leading to late diagnosis in most patients. Helicobacter pylori infection contributes to the development of many endemic GACs, and pre-emptive eradication or early treatment of this bacterial infection might provide effective primary prevention. GACs are phenotypically and genotypically heterogeneous. Localized (clinical stage I) GAC is best treated either endoscopically or with limited surgical resection, but clinical stage II or stage III tumours require multidisciplinary adjunctive approaches in addition to surgery. Although GAC is highly treatable in its early stages, advanced (clinical stage IV) GAC has a median survival of just ∼9-10 months. However, detailed molecular and immune profiling of GAC is yielding promise; early studies with immune checkpoint inhibitors suggest that GAC is amenable to immune modulation. Molecular studies have yielded a vast quantity of new information for potential exploitation. Nevertheless, advances against GACs have lagged compared with other tumours of similar incidence, and more research is necessary to overcome the obstacles to prolong survival.

The characterization of oesophageal and gastric cancer into subtypes based on genotype has evolved in the past decade. Insights into the molecular landscapes of gastroesophageal cancer provide a roadmap to assist the development of new drugs and their use in combinations, for patient stratification, and for trials of targeted therapies. Trastuzumab is the only approved treatment for gastroesophageal cancers that overexpress HER2. Acquired resistance usually limits the duration of response to this treatment, although a number of new agents directed against HER2 have the potential to overcome or prolong the time until resistance occurs. Beyond that, anti-VEGFR2 therapy with ramucirumab was the first biological treatment strategy to produce a survival benefit in an unselected population of patients with chemotherapy-refractory gastroesophageal cancer. Large initiatives are starting to address the role of biomarker-driven targeted therapy in the metastatic and in the perioperative setting for patients with this disease. Immunotherapy also holds promise, and our understanding of subsets of gastroesophageal cancer based on patterns of immune response continues to evolve. Efforts are underway to identify more relevant genomic subsets through genomic screening, functional studies, and molecular characterization. Herein, we provide an overview of the key developments in the treatment of gastroesophageal cancer, and discuss potential strategies to further optimize therapy by targeting disease subtypes.