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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. Interim analysis of a phase III clinical trial of HER2-positive gastric adenocarinoma shows pembrolizumab plus trastuzumab and chemotherapy improves response rates compared with trastuzumab and chemotherapy alone.

Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m2 of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 [95% CI 0·53–0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 [95% CI 0·28–0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 [95% CI 0·55–0·98]; log-rank p=0·038). Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Dutch Cancer Foundation (KWF Kankerbestrijding).

ObjectiveRecent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival.DesignThirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein–Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour–stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density.Results12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS).ConclusionsPD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.

Adding pertuzumab to trastuzumab and chemotherapy improves survival in HER2-positive early breast cancer and metastatic breast cancer. We assessed the efficacy and safety of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic gastric or gastro-oesophageal junction cancer. JACOB was a double-blind, placebo-controlled, randomised, multicentre, phase 3 trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of 55% or more. Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m2 every 3 weeks intravenously, oral capecitabine 1000 mg/m2 twice a day [2000 mg/m2 every 24 h] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m2 every 24 h intravenously [120 h continuous infusion] every 3 weeks). Randomisation was by a central permuted block randomisation scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with Clinicaltrials.gov, number NCT01774786 (ongoing, but closed to enrolment). Between June 10, 2013, and Jan 12, 2016, of 3287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n=388) or placebo plus trastuzumab and chemotherapy (control group, n=392). Median duration of follow-up was 24·4 months (95% CI 22·3–26·1) in the pertuzumab group and 25·0 months (22·3–28·9) in the control group. After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), overall survival was not significantly different between treatment groups (median overall survival 17·5 months [95% CI 16·2–19·3] in the pertuzumab group and 14·2 months [12·9–15·5] in the control group; hazard ratio 0·84 [95% CI 0·71–1·00]; p=0·057). Serious adverse events occurred in 175 (45%) of 385 patients in the pertuzumab group and 152 (39%) of 388 patients in the control group. Diarrhoea was the most common serious adverse event in both groups (17 [4%] patients in the pertuzumab group vs 20 [5%] patients in the control group). The most common grade 3–5 adverse events were neutropenia (116 [30%] patients in the pertuzumab group vs 108 [28%] patients in the control group), anaemia (56 [15%] vs 65 [17%]), and diarrhoea (51 [13%] vs 25 [6%]). Treatment-related deaths occurred in seven (2%) patients in the control group; no treatment-related deaths occurred in the pertuzumab group. Adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival in patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer compared with placebo. Further studies are needed to identify improved first-line treatment options in these types of cancer and to identify patients with HER2-driven tumours who might benefit from dual HER2-targeted therapy. F. Hoffmann-La Roche Ltd.

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. 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/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 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. 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. 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. Merck & Co.

To compare the utility of the distensibility index (DI) on functional lumen imaging probe (FLIP) topography to other esophagogastric junction (EGJ) metrics in assessing treatment response in achalasia in the context of esophageal anatomy. We prospectively evaluated 79 patients (at ages 17-81 years; 47% female patients) with achalasia during follow-up after pneumatic dilation, Heller myotomy, or per-oral endoscopic myotomy with timed barium esophagram, high-resolution impedance manometry, and FLIP. Anatomic deformities were identified based on consensus expert opinion. Patients were classified based on anatomy and EGJ opening to determine the association with radiographic outcome and Eckardt score (ES). Twenty-seven patients (34.1%) had an anatomic deformity-10 pseudodiverticula at myotomy, 7 epiphrenic diverticula, 5 sigmoid, and 5 sinktrap. A 5-minute column area of >5 cm was best associated with an ES of >3, with a sensitivity of 84% (P = 0.0013). Area under the curve for EGJ metrics in association with retention was as follows: DI, 0.90; maximal EGJ diameter, 0.76; integrated relaxation pressure, 0.64; and basal esophagogastric junction pressure, 0.53. Only FLIP metrics were associated with retention given normal anatomy (DI 2.4 vs 5.2 mm/mm Hg and maximal EGJ diameter 13.1 vs 16.6 mm in patients with and without retention, respectively; P values < 0.0001 and 0.002). Using a DI cutoff of <2.8 as abnormal, 40 of 45 patients with retention (P = 0.0001) and 23 of 25 patients with an ES of >3 (P = 0.02) had a low DI and/or anatomic deformity. With normal anatomy, 21 of 22 patients with retention had a low or borderline low DI. The FLIP DI is most useful metric for assessing the effect of achalasia treatment on EGJ opening. However, abnormal anatomy is an important mediator of outcome and treatment success will be modulated by anatomic defects that impede bolus emptying.

Background Esophagogastric junction (EGJ) carcinoma has attracted considerable attention because of the marked increase in its incidence globally. However, the optimal extent of esophagogastric resection for this tumor entity remains highly controversial. Methods This was a questionnaire-based national retrospective study undertaken in an attempt to define the optimal extent of lymph node dissection for EGJ cancer. Data from patients with EGJ carcinoma, less than 40 mm in diameter, who underwent R0 resection between January 2001 and December 2010 were reviewed. Results Clinical records of 2807 patients without preoperative therapy were included in the analysis. There are distinct disparities in terms of the nodal dissection rate according to histology and the predominant tumor location. Nodal metastases frequently involved the abdominal nodes, especially those at the right and left cardia, lesser curvature and along the left gastric artery. Nodes along the distal portion of the stomach were much less often metastatic, and their dissection seemed unlikely to be beneficial. Lower mediastinal node dissection might contribute to improving survival for patients with esophagus-predominant EGJ cancer. However, due to low dissection rates for nodes of the middle and upper mediastinum, no conclusive result was obtained regarding the optimal extent of nodal dissection in this region. Conclusions Complete nodal clearance along the distal portion of the stomach offers marginal survival benefits for patients with EGJ cancers less than 4 cm in diameter. The optimal extent of esophageal resection and the benefits of mediastinal node dissection remain issues to be addressed in managing patients with esophagus-predominant EGJ cancers.

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.Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.

Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy. To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for tumor and immune cells, that is, the combined positive score. Four previously treated tumor types in the KEYNOTE-012 and KEYNOTE-028 studies were analyzed descriptively with a version of the PD-L1 immunohistochemical 22C3 pharmDx assay labeled for investigational use only to determine the relative importance of PD-L1 expression in tumor versus immune cells as a biomarker for pembrolizumab response. A combined positive score was developed as a novel scoring method and was compared with the tumor proportion score in cohort 1 from the KEYNOTE-059 study (G/GEJ cancer). External reproducibility was assessed. Per combined positive score cutoff of 1 or more, the prevalence of PD-L1 expression in patients with G/GEJ cancer was 57.6% (148 of 257 patients), with reasonable enrichment of responses (odds ratio, 2.8). Per tumor proportion score cutoff of 1% or more, prevalence was 12.5% (32 of 257 patients), with minimal enrichment (odds ratio, 1.4). External reproducibility assessments demonstrated interpathologist overall agreement of 96.6% (591 of 612; 95% CI, 94.0%-98.7%) and intrapathologist overall agreement of 97.2% (595 of 612; 95% CI, 95.3%-98.9%). Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications.

The multicentre RESOLVE trial examined the efficacy of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in gastric or gastro-oesophageal junction cancer. Initial analyses did not encompass overall survival owing to the immature data. This paper provides an updated analysis of the survival data from the RESOLVE trial. In this randomised, open-label, phase 3 study, participants aged 18 years or older with cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma who were feasible for D2 lymphadenectomy and had a Karnofsky performance score of 70 or higher were enrolled. Participants were randomly assigned in a 1:1:1 ratio via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral capecitabine 1000 mg/m2 twice a day on days 1–14, adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40–60 mg twice a day on days 1–14), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy. The primary endpoint, assessed in the modified intention-to-treat population, was 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio [HR] non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx, and has been reported previously. This final report focuses on the secondary endpoint of 5-year overall survival, also assessed in the modified intention-to-treat population. Other secondary endpoints—R0 resection rate and safety—were not updated in this analysis. The study is registered at ClinicalTrials.gov, NCT01534546, and is complete. Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were enrolled and randomly assigned, of whom 1022 participants were included in the modified intention-to-treat population: 345 (259 male, 86 female) in the adjuvant-CapOx group, 340 (238 male, 102 female) in the adjuvant-SOX group, and 337 (271 male, 66 female) in the perioperative-SOX group. As of April 7, 2022, the median duration of follow-up was 62·8 months (IQR 52·0–75·1). The 5-year overall survival rates were 52·1% (95% CI 46·3–57·5) for the adjuvant-CapOx group, 61·0% (55·3–66·2) for the adjuvant-SOX group, and 60·0% (54·2–65·3), for the perioperative-SOX group. Overall survival was significantly prolonged with perioperative-SOX (HR 0·79; 95% CI 0·62–1·00, p=0·049) and adjuvant-SOX (HR 0·77, 0·61–0·98, p=0·033), compared with adjuvant-CapOx. Consistent with the initial analysis of 3-year disease-free survival, the extended 5-year overall survival analysis from the RESOLVE trial confirmed the survival advantage of perioperative-SOX and adjuvant-SOX compared with the standard adjuvant-CapOx regimen. The SOX regimen, given perioperatively or as an adjuvant treatment, emerges as a potential standard treatment modality for locally advanced gastric or gastro-oesophageal junction cancer management in Asian patients. The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, the Beijing Natural Science Foundation, National Natural Science Foundation of China, the Beijing Natural Science Foundation, Taiho, Hengrui Pharmaceutical and Sanofi-Aventis. For the Chinese translation of the abstract see Supplementary Materials section.