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Background: The current standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) cancers includes neoadjuvant chemoradiotherapy or perioperative chemotherapy with surgical resection; however, disease-free survival in these patients remains poor. Immune checkpoint inhibitors (ICIs) are approved for adjuvant treatment of locally advanced esophageal and GEJ cancers, but their benefit in the perioperative and neoadjuvant settings remains under investigation., Methods: We used the PubMed online database to conduct a literature search to identify studies that investigated immunotherapy for locally advanced esophageal and GEJ carcinoma. A review of ClinicalTrials.gov yielded a list of ongoing trials., Results: Adjuvant nivolumab for residual disease after neoadjuvant chemoradiotherapy and surgery is the only approved immunotherapy regimen for locally advanced esophageal cancer. Early-phase trials investigating the addition of neoadjuvant or perioperative ICIs to standard-of-care multimodality approaches have observed pathologic complete response rates as high as 60%. Response rates are highest for ICIs plus chemoradiotherapy for esophageal squamous cell carcinoma and dual checkpoint inhibition in mismatch repair-deficient adenocarcinomas. Safety profiles are acceptable, with a pooled adverse event rate of 27%. Surgical morbidity and mortality with immunotherapy are similar to historical controls with no immunotherapy, and R0 resection rates are high. When reported, disease-free survival among patients treated with perioperative immunotherapy is promising., Conclusions: Outside of clinical trials, immunotherapy for resectable esophageal carcinoma is limited to the adjuvant setting. Phase III trials investigating neoadjuvant and perioperative immunotherapy are now underway and will provide much-needed data on survival that may ultimately lead to practice-changing recommendations., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The clinical application of PD-L1 immunohistochemistry (IHC) testing is complicated by the availability of multiple IHC assays, scoring algorithms, and cutoffs. This study assessed the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer (GC) samples., Methods: Serial sections of 100 resected GC samples, with PD-L1 expression levels across the dynamic range, were stained with three in vitro diagnostic-grade PD-L1 assays (28-8, 22C3, and SP263). Three trained pathologists blindly and independently scored slides using combined positive score (CPS) and tumor area positivity (TAP) algorithms. Comprehensive statistical analyses were performed to evaluate analytical concordance. Digital image analysis (DIA) was used to objectively compare the technical performance of each assay by simulating CPS and TAP., Results: Comparable staining patterns were observed with these three PD-L1 assays. Despite discernible variation in staining intensity, reproducible evaluations of PD-L1 positivity were observed. Inter- and intra-assay assessments of all three assays, using either CPS or TAP and the same PD-L1 cutoffs, demonstrated moderate to almost-perfect (interassay Cohen's kappa [κ] range, 0.47-0.83) and substantial to almost-perfect (intra-assay κ range, 0.77-1.00) agreement. Interpathologist assessment exhibited a significant level of concordance (intraclass correlation coefficient ≥0.92). No difference in technical performance was observed using DIA., Conclusion: This study highlights analytical concordance in PD-L1 testing between three major PD-L1 assays when TAP and CPS are applied. Comparability of the technical assay performance was further supported by independent DIA. These observations support cross-application flexibility of the different PD-L1 assays and scoring algorithms to characterize PD-L1 expression in GC.

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: 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.)

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.