Trastuzumab in the Second-Line Treatment of HER2-Positive Metastatic Gastric Cancer. Experience of the Moscow Oncology Service

Gastric cancer is a common malignant tumor of the digestive system, and its morbidity and mortality rank among the top five in the world. Although significant progress has been made in cytotoxic chemotherapy, immunotherapy and targeted therapy in recent years, the long-term prognosis of patients with advanced or metastatic gastric cancer is still poor. Trastuzumab combined with chemotherapy is the first-line standard of care (SOC) for HER2-positive advanced or metastatic gastric cancer. Two ADC drugs targeting HER2, DS-8201 and RC-48, have also been approved for the treatment of gastric cancer. However, their limited clinical benefits and occurrence of adverse events still present a significant challenge. Therefore, minimizing the off-target toxicity and collateral damage while achieving significant chemotherapy efficacy has become the focus of gastric cancer treatment. DX126-262 is a novel HER2-targeting antibody-drug conjugate (ADC), generated by conjugating a Tubulysin B analogue to a recombinant humanized anti-HER2 monoclonal antibody through a linker containing branched hydrophilic polyethylene glycol, using thiol-maleimide chemistry to achieve drug antibody ratio (DAR) of 3.8. Previous studies have confirmed that DX126-262 monotherapy showed excellent efficacy in HER2-positive gastric cancer NCI-N87 cells in vitro and in vivo. And the efficacy has also been demonstrated in clinical trials (now in phase II, CTR20211871). Based on above results, we intended to further explore whether combination therapy of DX126-262 with Cisplatin and 5-FU can improve the anti-tumor efficacy compared with SOC (Herceptin plus Cisplatin and 5-FU) or DS-8201 monotherapy. The triple-drug combination therapy demonstrated much better therapeutic efficacy than single drug (DX126-262, Cisplatin, 5-FU, Herceptin, or DS-8201) or double-drug combination (Cisplatin plus 5-FU) or SOC (Herceptin plus Cisplatin and 5-FU) on human gastric cancer cells in vitro and in vivo. Meanwhile, triple-drug combination therapy did not exhibit superimposed toxicity, judging by the body weight of mice and hemal biochemistry assays. These results suggested that DX126-262 plus Cisplatin and 5-FU might be a promising strategy for treatment of HER2-positive advanced or metastatic gastric cancer in clinic. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Yongxiang Chen, Miaomiao Chen, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Mengmeng Liu, Zhongliang Fan, Hangbo Ye, Yifang Xu, Binbin Chen, Meng Dai, Robert Y. Zhao. DX126-262 combined with chemotherapy (Cisplatin and 5-Fu) demonstrates promising antitumor efficacy in HER2-positive gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6581.

SY10-4 - First-Line Treatment in HER2-Positive Advanced or Metastatic Gastric Cancer

Human epidermal growth factor receptor 2 (HER2) overexpression/amplification affects about 6.1%–23.0% of gastric cancer patients [1, 2]. All major guidelines recommend HER2 testing to guide the selection for trastuzumab treatment in metastatic gastric cancer (mGC) [3], because doublet chemotherapy with trastuzumab significantly improved overall survival (OS) in the crucial trastuzumab for gastric cancer trial (the ToGA trial) [4]. However, the unsatisfactory gain of median progression-free survival (PFS) stresses important issues of intrinsic and acquired resistance to HER2-targeted therapies [4]. Currently, the underlying molecular mechanism of trastuzumab resistance in mGC is still unclear, and the strategies to real time monitor resistance-specific aberrations are urgently needed. As circulating tumor DNA (ctDNA) carries the same genomic alterations that are present in the primary tumor [5, 6], liquid biopsy-based ctDNA profiling offers a unique opportunity for serially monitoring treatment response in a non-invasive manner, and has opened the door for identification the mechanisms of drug resistance. In a study recently published in Gut, titled “Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer”, Wang et al. [7] demonstrated for the first time that longitudinal ctDNA sequencing could promisingly predict tumor shrinkage and progression in HER2 + mGC patients under trastuzumab treatment. Based on the detected molecular alterations from the ctDNA profiling, they further dissected various mechanisms of trastuzumab resistance (Fig. 1). Longitudinal circulating tumor DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2-positive metastatic gastric cancer. HER2+: HER2-positive; mGC: metastatic gastric cancer; ctDNA: circulating tumor DNA: Copy No.: copy number In this study, the authors sequenced 416 clinically relevant genes to determine the genomic profiles of GC patients. The molecular alterations, including copy number alterations, mutations and structural variations, detected in 78 paired plasma and tissue samples (46 from HER2+ patients and 32 from HER2− patients) were used to evaluate the consistency of detection between the “liquid” and “solid” biopsies. As expected, the alterations detected in plasma provided a good representation of the status in the tumor tissues. In particular, HER2 amplification status, the major marker of HER2 + GC, detected by plasma-based ctDNA sequencing was highly consistent with that by tissue-based sequencing and fluorescence in situ hybridisation. These findings indicated that plasma-based ctDNA profiling might provide insights into HER2 amplification in HER2 + GC. Further longitudinal analysis were perform in 97 time-course plasma samples collected from 24 HER2 + mGC patients to track the resistance during trastuzumab treatment. As compared to plasma carcinoembryonic antigen, the copy number variations (CNVs) of HER2 in ctDNA were better at tracking trastuzumab treatment response. Generally, the HER2 copy number decreased during treatment compared with baseline and levels of progressive disease (PD), indicating tumor shrinkage. Additionally, most patients with intrinsic resistance-related progression presented higher HER2 copy numbers at PD than baseline, while the patients with acquired resistance often had lower HER2 copy numbers at PD. From the same ctDNA profiles, the authors found evidence for reported mechanisms of trastuzumab resistance in 76.5% patients. They found that the patients with multiple resistance mechanisms (PIK3CA/R1/C3 and ERBB2/4 mutations) displayed much shorter PFS during trastuzumab treatment. These findings suggested that liquid biopsy-based ctDNA profiling can effectively capture the heterogeneity information about acquired resistance. Furthermore, they also observe several novel resistance mechanisms. One of them is the ERBB4 S774G mutation. This novel mutation can increase the sensitivity to trastuzumab treatment, suggesting for the first time that the mutation of ERBB4 play a critical role in mediating resistance to ERBB2 inhibitors in HER2 + GC. Another novel resistance mechanism is the emergence of NF1 mutations. Using in vitro and in vivo experiments, the authors demonstrated that NF1 was a resistance-related gene and could be used as a potential resistance marker of trastuzumab. NF1 lost (mutation or deletion) contributes to driving resistance of HER2-targeted therapy via elevating pMEK/ERK activation, whereas the combination of HER2 and MEK/ERK inhibitors might overcome trastuzumab resistance. This study has some obvious limitations. First, other rare genomic or even nongenomic mechanisms of trastuzumab resistance may have been missed by the 416-gene panel. Second, the relatively small number of patient enrolled does not allow drawing definitive conclusion on the predictive value of this liquid biopsy approach. Nevertheless, the study provides helpful information to monitor the treatment response of trastuzumab and develop therapeutic strategies for the HER2 + mGC patients with trastuzumab resistance. The author read and approved the final manuscript. Not applicable. The author declares no competing interests. Not applicable. Not applicable. Not applicable. Not applicable.

Background: Recent advancements in immune checkpoint inhibitors (ICIs) have revolutionized treatment options in many solid cancers. Pembrolizumab and nivolumab, an anti-programmed death ligand 1 (anti PD-L1) agent, has approved in treatment of advanced or metastatic gastric cancer previously treated with two or more therapies. Although immunotherapy has shown durable response in selective patients, there are also growing evidences of hyperprogression (HPD) in a subset of patients treated with ICIs. Here, we report a patient who hyper-progressed after two cycles of pembrolizumab containing regimen. Methods: Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, HPD is defined as time to treatment failure (TTF) <2 months and minimum increase of measurable lesions of 10mm plus one of the following: 1) increase of >40% of target lesion compared with baseline or 2) increase of >20% and appearance of multiple new lesions. Medical records of the patient were retrieved from electronic medical record (EMR). Tumor samples were obtained from stomach and liver before and after anti-PD1 treatment. Serial blood was collected to evaluate circulating tumor cells (CTC), targeted NGS of circulating free DNA (cfDNA) and immune phenotyping to identify possible underlying mechanism. To identify the mechanisms of HPD, Next-Generation Sequencing (NSG) of tissue and cfDNA of FoundationOne Liquid was utilized to analyze genomic alterations such as copy number alterations, rearrangements somatic mutations. Results: The 57 year old female, was initially diagnosed with HER2 positive advanced gastric cancer (AGC) with multiple liver metastases. Before treatment, immunohistochemistry (IHC) from stomach revealed amplification of human epidermal growth factor receptor 2 (HER2, ERbB2) with combined positive score (CPS) of 10% using PD-L1 IHC 22C3 pharmDx. She was then enrolled in the currently ongoing, investigator-initiated PANTHERA trial (NCT02901301), a phase Ib/II study of first line pembrolizumab in combination with trastuzumab, capecitabine and cisplatin. However, rapid progression was noted after two cycles. Target lesions increased by 27.1%, and several new liver metastasis as well as non-targetable lesions such as stomach and peritoneal seeding, increased. Tumor markers including CA 72-4, CA 125 and aFP also increased. Since the patient’s condition deteriorated rapidly, she was immediately started with a different chemotherapy and response evaluation with immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) was not evaluated. IHC of re-biopsied stomach revealed that CPS was 30%. Notably, there were no differences in IHC of liver before and after treatment, which were both HER2 and CPS negative. Interestingly, baseline cfDNA analysis showed the amplification of EGFR, which were known to be related to HPD. Also, high level of TP53, APC mutations and Rb amplification were observed. CTC (EpCAM+CK+CD45) was initially 2 at baseline and increased to 7 after hyperprogression. Conclusion: Among 41 patients enrolled in ongoing PANTHERA trial, only one patient progressed after 2 cycles of treatment . To our knowledge, this is the first documented hyperprogression in advanced or metastatic gastric cancer after treatment with pembrolizumab. Although mechanisms behind HPD remain to be elucidated, the discrepancy in pre and post IHC results points out that tumor heterogeneity may play a role. NGS results and immune phenotyping results are pending. Citation Format: Jii Bum Lee, Garden Lee, Woo Sun Kwon, Jun Hyeok Heo, Seung-Hyun Jung, Yeun-Jun Chung, Beodul Kang, Hyo Song Kim, Hyun Cheol Chung, Sun Young Rha. Hyperprogressive disease after two cycles of immunotherapy in HER-2 positive metastatic gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B049. doi:10.1158/1535-7163.TARG-19-B049

Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.

Trastuzumab has recently been introduced as a treatment for HER2-positive metastatic and/or unresectable gastric cancer (MUGC); however, compared with breast cancer, some issues concerning HER2 and trastuzumab therapy for gastric cancer remain unclear. A 74-year-old woman received trastuzumab-containing chemotherapy for HER2-positive MUGC. She had a marked response to 8 months of chemotherapy, and gastrectomy and hepatic metastasectomy with curative intent were performed. The resected specimen showed complete loss of HER2 positivity in the residual tumor. For MUGC, a change in HER2 status during the course of the disease with or without chemotherapy has rarely been reported. However, in breast cancer, a significant frequency of change in HER2 status during the course of disease has been reported, and reevaluation of HER2 positivity in metastatic/recurrent sites is recommended. The choice of trastuzumab for MUGC is currently based on the HER2 status of the primary tumor at the time of initial diagnosis, without reassessment of HER2 status during the course of disease and/or in metastatic/recurrent sites, on the assumption that HER2 status is stable. However, our case casts doubt on the stability of HER2 in gastric cancer.

Fluoropyrimidine+cisplatin/oxaliplatin+trastuzumab therapy is recommended for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric adenocarcinoma. However, there is no comprehensive study on which platinum-based treatment should be preferred. This study aimed to compare the treatment response and survival characteristics of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer who received fluorouracil, oxaliplatin, and leucovorin (mFOLFOX)+trastuzumab or cisplatin and fluorouracil (CF)+trastuzumab as first-line therapy. It was a multicenter, retrospective study of the Turkish Oncology Group, which included 243 patients from 21 oncology centers. There were 113 patients in the mFOLFOX+trastuzumab arm and 130 patients in the CF+trastuzumab arm. The median age was 62 years in the mFOLFOX+trastuzumab arm and 61 years in the CF+trastuzumab arm (p = 0.495). About 81.4% of patients in the mFOLFOX+trastuzumab arm and 83.1% in the CF+trastuzumab arm had gastric tumor localization (p = 0.735). The median progression-free survival (PFS) was significantly higher in the mFOLFOX+trastuzumab arm (9.4 months vs. 7.3 months, p = 0.024). The median overall survival (OS) was similar in both groups (18.4 months vs. 15.1 months, p = 0.640). Maintenance trastuzumab was continued after chemotherapy in 101 patients. In this subgroup, the median OS was 23.3 months and the median PFS was 13.3 months. In conclusion, mFOLFOX+trastuzumab is similar to CF+trastuzumab in terms of the median OS, but it is more effective in terms of the median PFS in the first-line treatment of HER2-positive metastatic gastric and GEJ cancer. The choice of treatment should be made by considering the prominent toxicity findings of the chemotherapy regimens.

PurposeAs the first-line drug for treatment of HER2-positive metastatic gastric cancer (GC), Herceptin exhibits significant therapeutic efficacy. However, acquired resistance of Herceptin limits the therapeutic benefit of gastric cancer patients, in which the molecular mechanisms remain to be further determined.MethodsQuantitative real-time polymerase chain reaction was performed to detect the mRNA levels of ARPP-19 and CD44 in GC cells. Protein levels were determined using Western blot and IHC staining. MTT and soft agar colony formation assays were used to measure cell proliferation. Xenograft model was established to verify the functional role of ARPP-19 in Herceptin resistance in vivo. Sphere formation assay was conducted to determine cell stemness.ResultsWe observed ARPP-19 was up-regulated in Herceptin resistance gastric cancer cells NCI-N87-HR and MKN45-HR. The forced expression of ARPP-19 promoted, whereas the silencing of ARPP-19 impaired Herceptin resistance of HER2-positive gastric cancer cells both in vitro and in vivo. Moreover, ARPP-19 significantly enhanced the sphere formation capacity and CD44 expression, CD44 was also a positive factor of Herceptin resistance in HER2-positive gastric cancer cells. In addition, high level of ARPP-19 was positively associated with Herceptin resistance and poor survival rate of gastric cancer patients.ConclusionWe have demonstrated that ARPP-19 promoted Herceptin resistance of gastric cancer via up-regulation of CD44, our study suggested that ARPP-19 could be a potential diagnostic and therapeutic candidate for HER2-positive gastric cancer.

642P - Trastuzumab in Combination with Different First-Line Chemotherapies for Treatment of Her2-Positive Metastatic Gastric Cancer: Updated Findings from the German Non-Interventional Study Hermes

Trastuzumab (Herceptin®, F. Hoffman-La Roche) is now approved for the treatment of metastatic HER2-positive gastric cancer based on the improved survival observed on the phase III Trastuzumab for Gastric Adenocarcinoma (ToGA) study. Standard dosing of trastuzumab is currently extrapolated from breast cancer data: a 3-week schedule (8 mg/kg load, 6 mg/kg q 3 weeks) or a weekly schedule (4 mg/kg load, 2 mg/kg q week). Our case study examines an HER2-positive metastatic gastric cancer patient that required a higher than currently recommended standard dose of trastuzumab to achieve treatment response. Several mechanisms may explain these findings and include higher clearance of trastuzumab, higher tumor burden, and pharmacologic resistance in metastatic gastric cancer versus breast cancer. The question of trastuzumab dosing in gastric cancer is currently being evaluated in a phase III clinical trial.

151 Background: Some phase II and III studies of second-line chemotherapy for metastatic or advanced gastric cancer have been reported in recent years. Irinotecan is one of the standard regimen for second-line therapy. On the other hand, the efficacy of continuing trastuzumab (Tmab) beyond progression in patients (pts) who had previously been treated with Tmab plus standard first line chemotherapy has not been reported. We conducted this study to assess the efficacy and safety of Tmab with irinotecan in HER2-positive gastric cancer pts previously treated with Tmab (UMIN ID: 000007636). Methods: Patients with HER2-positive metastatic or advanced gastric cancer who were previously treated with Tmab and failed were included. Pts received Tmab every 3 weeks and irinotecan every 2 weeks. Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), six-month survival rate, safety, sub-group analysis by HER2 status (IHC 3+ group, IHC 2+/FISH positive group), and so on. Results: Only 16 pts were enrolled from 9 institutions in three years during a pre-planned registration period. We stopped this study on the way, unfortunately. In a total of 16 pts, one patient was excluded and 15 were analyzed. Median age was 65, male/female; 9/6, ECOG PS 0/1; 8/7, and IHC 3+/IHC 2+ and FISH positive; 10/5, respectively. Response rate was 7% and disease control rate was 53%. Median PFS and overall survival (OS) were 2.4 (95%C.I.; 0.0-5.2 months) and 9.7 months (95%C.I.; 8.2-11.2 months), respectively. Six-month PFS rate was 13%. In sub-group analysis by HER2 status, median PFS of IHC 3+ and IHC 2+/FISH positive were 2.2 and 2.4 months, respectively. Median OS of each groups were 8.8 and 10.8 months. The most frequently reported grade 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%). Conclusions: This study was closed prematurely due to poor accrual. It seemed that continued use of Tmab and irinotecan beyond disease progression has not significant clinical benefit in HER2-positive metastatic or advanced gastric cancer pts previously treated with Tmab. Clinical trial information: UMIN000007636.

We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1-3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. UMIN000005603.

Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.

Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target