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Approximately 15 to 20% of gastric adenocarcinomas express HER2. Trastuzumab deruxtecan is an antibody-drug conjugate composed of trastuzumab and the topoisomerase I inhibitor deruxtecan. In a randomized trial, the antibody-drug conjugate led to higher response and longer overall survival than physician’s choice of therapy among patients with relapsed disease.

The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer. We did a randomised, multicentre, double-blind, placebo-controlled, phase 2–3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 [SOX] or oral capecitabine 1000 mg/m2 [CAPOX], twice daily on days 1–14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing. Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7–14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44–14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97–9·40) in the placebo plus chemotherapy group (hazard ratio [HR] 0·68; 98·51% CI 0·51–0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1–29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67–20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18–19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75–1·08; p=0·26). The most common treatment-related grade 3–4 adverse events were neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapy group vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 [5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease). Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients. Ono Pharmaceutical and Bristol-Myers Squibb.

Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed. In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. Ono Pharmaceutical and Bristol-Myers Squibb.

Standard adjuvant treatment for locally advanced gastric cancer (LAGC) is regionally different. Whereas perioperative chemotherapy is the standard in Western populations, D2 gastrectomy followed by adjuvant chemotherapy has been the standard in East Asia. Recently, the pivotal phase 3 PRODIGY and RESOLVE studies have demonstrated survival benefits of adding neoadjuvant chemotherapy to surgery followed by adjuvant chemotherapy over up-front surgery followed by adjuvant chemotherapy in Asian patients. Based on these results, neoadjuvant chemotherapy is considered one of the viable options for patients with LAGC. In this review, various aspects of neoadjuvant chemotherapy will be discussed for its optimal application in Asia. Candidates for neoadjuvant chemotherapy should be carefully chosen in consideration of the inaccurate aspects of radiological clinical staging and its potential benefit over up-front surgery followed by a decision on adjuvant chemotherapy according to the pathological stage. Efforts should continuously be made to optimally apply neoadjuvant chemotherapy to patients with LAGC, considering various factors, including a more accurate radiological assessment of the tumor burden and the optimization of post-operative chemotherapy. Future neoadjuvant trials involving novel agents for Asian patients should be designed based on proven Asian regimens rather than adopting Western regimens.

Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer (GC), but little is known about the heterogeneity of its expression in GC. This study investigated the heterogeneity of claudin 18.2 expression in 166 patients with metastatic GC whose surgical or paired primary–metastatic specimens were available. The prevalence of claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was 47.0%. Claudin 18.2-positive tumors exhibited more frequent peritoneal metastasis and a lower incidence of hepatic and distant lymph node involvement. Survival outcomes were comparable between patients with claudin 18.2-positive and -negative tumors. Intratumoral heterogeneity was noted in 38.5% of surgical specimens. Paired primary-metastatic site analysis revealed that 25.2% of patients had discordant results for claudin 18.2 positivity. Across different metastatic organ categories, peritoneal lesions showed the highest positivity rate (44.3%) and positive concordance rate (31.4%), whereas liver lesions had the lowest positivity rate (17.9%) and concordance rate (12.8%). In conclusion, claudin 18.2 expression exhibits intratumoral and intrapatient spatial heterogeneity in metastatic GC. Claudin 18.2 positivity is associated with more frequent peritoneal metastasis, and peritoneal lesions are more likely to have positively concordant claudin 18.2 results with the primary site than other metastatic sites.

BackgroundAlthough discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy.MethodsWe enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression.ResultsAt baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH−. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4–36.8) months.ConclusionA substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.

S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40–60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40–60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0–32·8), median overall survival was 16·0 months (95% CI 13·8–18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6–16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69–0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. Taiho Pharmaceutical and Yakult Honsha.

Claudin 18.2 has emerged as a promising therapeutic target in gastric cancer based on phase 3 studies. However, clinicopathologic features associated with claudin 18.2 overexpression have not been comprehensively studied specifically for patients with resectable gastric cancer. This retrospective study included 299 patients with stage I–III resectable gastric cancer who underwent curative surgical resection. Possible associations between claudin 18.2 overexpression (moderate-to-strong expression in ≥ 75% by the 43-14A clone) and clinicopathologic features and survival outcomes were analyzed. There were 90 (30.1%), 96 (32.1%), and 113 (37.8%) patients with stage I, II, and III disease, respectively. Claudin 18.2 overexpression was noted in 139 out of 299 patients (46.5%). Claudin 18.2 overexpression was associated with a younger age, a lower invasion depth limited to the mucosa/submucosa, and less frequent lymphovascular invasion. Claudin 18.2 overexpression was also associated with Borrmann type 4 among patients with advanced gastric cancer and the diffuse histological type. Claudin 18.2 overexpression was not an independent factor for survival outcomes. In conclusion, claudin 18.2 was overexpressed in almost half of resectable gastric cancer patients. Claudin 18.2 overexpression was associated with some clinicopathological characteristics, but was not an independent prognostic factor in a localized setting.

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4 . We herein report six cases of SMARCA4 -deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities.

Background Loss of PTEN function leads to increased PI3Kβ signaling. AZD8186, a selective PI3Kβ/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. This phase 1b/2 study was conducted to determine the safety and efficacy of AZD8186 and paclitaxel combination in patients with metastatic or recurrent gastric cancer (MRGC). Methods In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. Results In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. Conclusion Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed. ClinicalTrials.gov Identifier: NCT04001569. This phase Ib/II study was conducted to determine the safety and efficacy of AZD8186 and paclitaxel combination in patients with metastatic or recurrent gastric cancer.