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Background: Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe., Methods: DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing., Findings: Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis., Interpretation: These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests EVC has received research grants paid to his institution from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Novartis, Roche, and Servier and has participated in advisory boards for AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck, Mirati, Novartis, Pierre Fabre, Roche, Seagen, Servier, Sirtex, Terumo, Taiho, TRIGR, and Zymeworks. ES has received consulting fees from Amal Therapeutics, AstraZeneca, Bristol Myers Squibb, Beigene, Daiichi Sankyo, Merck, Novartis, Pfizer, Roche, Servier, Turning Point Therapeutics, and Zymeworks; speaker payments or honoraria from Amgen, Bristol Myers Squibb, Novartis, and Servier; support for meeting attendance or travel from Amgen, Bristol Myers Squibb, and Servier; and participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, and Beigene; and held a leadership role (co-chair) of the EORTC GI Trials Group Gastric Cancer Task Force. IC has received research funding from Eli Lilly and Janssen-Cilag, has participated in advisory boards for Eli Lilly, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Merck Serono, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas, GlaxoSmithKline, Sotio, Eisai, Daiichi Sankyo, Taiho, Servier, Seagen, and Turning Point Therapeutics; speaker payments or honoraria from Eli Lilly, Eisai, and Servier; and has received support for meeting attendance or travel from Bristol Myers Squibb. HP has received grants or contracts from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics, Array BioPharma, Bayer, BeiGene, BJ Bioscience, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Millennium, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, RePare Therapeutics, Seagen, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor, and participated on a data safety monitoring board or advisory board for Jacobio. SS has participated in advisory boards for Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, Guardant Health, Menarini, Merck, Novartis, Pierre Fabre, Roche-Genentech, and Seagen. SL has received research funding paid to her institution from Daiichi Sankyo, Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb; consulting fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and Merck Sharp & Dohme; and speaker payments or honoraria from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen. ZAW has received consulting fees from Merck, Ibsen, Lilly, Five Prime, QED, Molecular Templates, Daiichi Sankyo, AstraZeneca, Bayer, and Novartis; support for meeting attendance or travel from Lilly, Merck, Novartis, and Daiichi Sankyo; and participated on a data safety monitoring board or advisory board for Array. JC has received research funding paid to his institution from Daiichi Sankyo, Merck, and Brooklyn Immunotherapeutics; consulting fees from Lilly, Merck, AstraZeneca, Foundation Medicine, Daiichi Sankyo, Macrogenics, Amgen, Ono Pharmaceutical, Bristol Myers Squibb, Astellas, Turning Point Therapeutics, Silverback Therapeutics, Novartis, Coherus Biosciences, Geneos, and Roche; speaker payments or honoraria from Merck and Bristol Myers Squibb; and participated on a data safety monitoring board for Yiviva. YJ has received grants or contracts from Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred's Team, Genentech Roche, Merck, NCI, and RGENIX; speaker payments or honoraria from Amerisource Bergen, Arcus Biosciences, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Imedex, Imugene, Lynx Health, Merck, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Research to Practice, RGENIX, Seagen, Silverback Therapeutics, and Zymeworks; and stock options from RGENIX. FB was an employee at the time of this study and held stocks or stock options in Daiichi Sankyo. YK, AQ, and JS are employees of Daiichi Sankyo. GK has received research funding paid to his institution from Arog, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Merck, Oncolys, Pieris, and Zymeworks; consulting fees from Apexigen, AstraZeneca, Bristol Myers Squibb, Merck, Pieris, and Zymeworks; support for meeting attendance or travel from Bristol Myers Squibb, Merck, and Pieris; and participated on a data safety monitoring board or advisory board for Zymeworks. MdB and JA declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer., Methods: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice., Results: Eighteen randomized controlled trials met the inclusion criteria for the systematic review., Recommendations: For human epidermal growth factor receptor 2 (HER2)-negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Background: More than one-half of patients treated with esophagectomy for esophageal cancer experience recurrence. Oligometastasis, a proposed intermediate state of isolated local or solid organ recurrence that occurs before widespread systemic disease, is a potential target for aggressive local intervention. This study investigated presentation and prognosis among solid organ recurrence sites., Methods: Patients with isolated solid organ recurrence at the liver, lung, or brain who underwent R0 esophagectomy from 1995 to 2016 were identified. Clinicopathologic characteristics and outcomes were compared among sites of recurrence. Overall survival was quantified using the Kaplan-Meier approach and Cox proportional hazards models., Results: In total, 104 patients were included (site: brain, 37; lung, 27; liver, 40). Eighty percent of liver, 51% of brain, and 44% of lung oligometastases occurred in the first 12 months after esophagectomy. Despite the limited use of aggressive therapy, patients with lung oligometastasis had significantly longer median overall survival (2.41 years; 95% confidence interval [CI], 1.58 to 3.31) than did patients with brain (0.95 years; 95% CI, 0.62 to 1.49) or liver (0.95 years; 95% CI, 0.82 to 1.41) oligometastasis (P < .001). This difference remained after patient and tumor characteristics were adjusted for (brain: hazard ratio, 4.48; 95% CI, 2.24 to 8.99; liver: hazard ratio, 2.94; 95% CI, 1.48 to 5.82)., Conclusions: Presentations and prognoses differ by site of esophageal cancer recurrence. Lung oligometastases are associated with a more indolent course, and patients with these lesions may benefit from more aggressive treatment to improve their more favorable outcomes further. These differences by site of recurrence advocate for moving beyond a standardized palliative approach to all esophageal cancer recurrences., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively., Methods: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test., Results: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy., Conclusion: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors., Patients and Methods: In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression., Results: There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes ( CD274, CD8A, LAG3 , and STAT1 ), showed associations with response to NIVO ± IPI., Conclusions: This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation. See related commentary by Moutafi and Rimm, p. 3812 ., (©2021 American Association for Cancer Research.)

Background: Recurrence of esophageal cancer in the brain is rare but associated with a poor prognosis. Identification of risk factors for isolated brain metastasis of esophageal cancer (iBMEC) after surgical treatment may guide surveillance recommendations to enable early identification and intervention before widespread metastasis., Methods: Patients with iBMEC (n = 38) were identified from a prospective database of patients with esophageal cancer who underwent esophagectomy. Risk factors for iBMEC were identified using competing risk regression analysis., Results: In a cohort of 1760 patients, 39% recurred and iBMEC developed in 2% by the end of the study. Survival in patients with iBMEC was similar to survival in patients with distant recurrence (median overall survival, 0.95 years; 95% confidence interval, 0.6-1.5 years). More than half of patients with iBMEC were diagnosed within 1 year postoperatively. All 38 patients with iBMEC had received neoadjuvant therapy before surgery. Pathologic complete response (PCR) to neoadjuvant therapy was associated with improved survival after brain recurrence (median overall survival, 1.56 vs 0.66 years; P = .019)., Conclusions: In patients with PCR, iBMEC may represent true isolated recurrence, whereas in those with residual nodal disease, iBMEC may actually be the first observed site of widespread metastasis. Patients who receive neoadjuvant therapy, especially with PCR, may benefit from brain imaging, both preoperatively and with routine surveillance., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease., (© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Background: To determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma., Patients and Methods: Formalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan-Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive., Results: Seventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44-1.14; P = 0.194)., Conclusions: Approximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.