Prior to the DESTINY-Gastric01 study of T-DXd, there were no other globally recognized HER2-targeted agents for gastric cancer (GC) that progressed after trastuzumab. T-DM1 (trastuzumab emtansine, kadcyla) was the first ADC drug to explore the efficacy of treatment for advanced gastric cancer, and phase II/III clinical studies GATSBY included 415 patients with HER2-positive advanced gastric cancer or adenocarcinoma of the gastroesophageal junction treated with T-DM1 or paclitaxel in second line. Median overall survival was 7.9 and 8.6 months (P = 0.86), median progression-free survival was 2.7 and 2.9 months (P = 0.31) in the T-DM1 and paclitaxel treatment groups, respectively. The GATSBY study showed that T-DM1 was not superior to paclitaxel in the second-line treatment of HER2-positive advanced gastric cancer [12] . The reason for its failure to succeed in the treatment of advanced gastric cancer is that the linker is not cleavable, resulting in the inability of the carrier drug to cross the cell membrane, which does not have a bystander effect and therefore cannot overcome tumor heterogeneity. T-DXd has received much attention in recent years and has been beneficial in several gastroesophageal adenocarcinoma (GEA) studies. The DESTINY-Gastric01 [13] results showed an ORR of 51.3% vs 14.3% for the T-DXd group and the physician’s choice chemotherapy group, respectively. The DCR was 86% and 62% for the two groups, and the median DoR was 11.3 and 3.9 months, respectively. The median PFS was 5.6 and 3.5 months in both groups, and the PFS rates at 6 and 12 months were 43% vs. 21% and 30% vs. 0%, respectively. And, median OS was significantly longer in the T-DXd group compared to the physician’s choice chemotherapy group, 12.5 and 8.4 months in both groups, with 6- and 12-month OS rates of 80% vs 66% and 52% vs 29%, respectively. Of the 119 patients treated with T-DXd, 10 patients achieved complete remission (CR), while no patients in the physician’s choice chemotherapy group achieved CR. more than 80% and approximately 50% of patients in the T-DXd and physician’s choice chemotherapy groups, respectively, had tumor shrinkage. Similar benefits were shown in most subgroup analyses. t-DXd demonstrated antitumor activity in patients with HER2-positive advanced gastric cancer (AGC). Moreover, it can penetrate neighboring tumor cells that do not necessarily express HER2 or have low expression (bystander antitumor effect), allowing T-DXd to be a potential treatment for patients with low HER2 tumors, as explored in the DESTINY-Gastric02 anti-HER2-treated patients with HER1 low (IHC 2+/ISH- or IHC 01+) gastric/GEJ adenocarcinoma cohort has been demonstrated [14] . T-Dxd can also be applied in patients with advanced HER2 mutation expressing solid tumors [11] , and it is expected that more evidence will be generated for T-Dxd against HER2 mutated gastric cancer as well, which will be a boon for patients with advanced solid tumor mutations. T-DXd is currently evaluated for the treatment of HER2-positive and low HER2-expressing breast cancer, HER2-overexpressing colorectal cancer, HER2-positive gastric cancer, and non-small cell lung cancer expressing HER2 or mutations, with a particular focus here on possible combination strategies of T-DXd with other agents (e.g., immunotherapy, chemotherapy, and targeted therapies) to increase T-DXd activity and ultimately overcome future impending drug resistance mechanisms [15] . The DESTINY-Gastric03 study evaluating T-DXd for first-line therapy, the DESTINY-Gastric04 study evaluating head-to-head the efficacy of T-DXd for second-line therapy, the DESTINY-Gastric06 study with a sample of our patients, and the use in neoadjuvant phase therapy (NCT05034887) are currently We are looking forward to the publication of the results.

RC48, which consists of Hertuzumab (humanized anti-HER2 monoclonal antibody) coupled to monomethyl auristatin E (MMAE) via a cleavable linker, is an ADC drug developed in China. With a DAR of approximately 4, the drug carrier is membrane-permeable and therefore also possesses bystander effects. The safety and tolerability of RC-48 in HER-2-positive solid tumors have been evaluated in clinical trials [16] . The phase II study C008 trial suggested that RC48 resulted in an ORR of 24.8% and a median OS of 7.9 months in patients with HER2-positive GEA who had previously received ≥ 2 lines of therapy [17] , has been approved for the backline treatment of HER2 overexpressing gastric cancer and gastroesophageal junction cancer [18] . The results of the RC48 phase I study for the treatment of HER2 low-expressing GC showed that the antitumor response in HER2 IHC2+/FISH- patients was similar to that in IHC2+/FISH+ and IHC3+ patients, with significant cancer shrinkage achieved in 72.7%, 60.0% and 52.6% of patients, respectively [19] . For the present study, it can be concluded that RC48 has an anticancer effect in patients with HER2 low-expressing GC. The antitumor activity of RC48 in her2 gastric cancer has been confirmed, and further exploration of its indication population, combination extension protocols is needed. The combination of RC48 with immune checkpoint inhibitors in a human homozygous breast cancer model expressing HER2 resulted in immune marker activation and massive T cell infiltration enhanced tumor suppression and anti-tumor immunity [20] . This combination therapy may exhibit better antitumor activity in HER2-positive gastric cancer, but more clinical trials are needed to validate it.

ZW25 (Zanidatamab) is a novel bispecific antibody that binds to two unlinked epitopes of HER2. This antibody effectively inhibits HER2 activity and doubly blocks HER2 signaling within the cell, thus acting as an anti-cancer agent [21] . Earlier the FDA has granted ZW25 as fast-track therapy for first-line gastroesophageal adenocarcinoma and as an orphan drug for the treatment of gastric and ovarian cancers. In clinical phase I, 69 HER2+ solid tumors received ZW25 (20 mg/kg, Q2W or 10 mg/kg, Q1W) in a median of 3 lines of therapy, and the included cancer types included biliary tract cancer, gastric/gastroesophageal cancer, and CRC, 59% of patients had received HER2-targeted therapy (up to 93% in gastric/gastroesophageal cancer), with an overall patient ORR of 44% (25/69) and DCR 70%, safely tolerated, and major adverse effects were G1-2, manifested as nausea, diarrhea, and infusion reactions [19] (NCT02892123) (https://beta.clinicaltrials.gov/). In patients with gastric/gastroesophageal cancer who had received median 3 lines of therapy in clinical phase II (75% treated with trastuzumab), the single-agent ORR was 33% and mDOR 6 months; it further improved patient response after combination chemotherapy, with an ORR of 54% and mDOR 8.9 months. Phase II study of ZW25 in HER2 amplified biliary tract cancer is in enrollment trial and results are pending [22] (NCT04466891) (https://beta.clinicaltrials.gov/).

ZW49 (Zanidatamab Zovodotin) another novel bispecific antibody-drug coupling (ADC), composed by adding the toxin MMAE to Zanidatamab, uses the former’s enhanced antibody internalization to deliver the toxin to tumor cells and induce tumor cell death. The first human dose escalation (DE) and dose extension (DX) studies for the treatment of patients with locally advanced or metastatic HER2-positive cancers are ongoing, with an ORR of 31% and a disease control rate (DCR) of 72% for multiple cancer types identified in 29 patients with assessable efficacy treated with ZW49 2.5 mg/kg Q3W [23] . The ZW49 1.75 mg/kg QW dose level in the DE cohort continues to be recruited and the 1.5 mg/kg QW dose in the DX cohort continues to be recruited [24] .

Our self-developed bispecific antibody KN026 (anti-HER2 bispecific antibody) in combination with KN046 (PD-L1/CTLA-4 bispecific single-domain antibody) for HER2-positive solid tumors was announced at SITC with a disease control rate of 92.9% (13/14) and an objective remission rate of 64.3% (9/14), based on which the US Food Drug Administration (FDA) granted it as an orphan drug for the treatment of HER2-positive or HER2-low-expressing gastric cancer and gastroesophageal junction cancer (GC/GEJ) [24] . Several clinical trials are currently underway in China and the United States in various stages for indications including breast cancer, gastric/gastroesophageal junction cancer, etc. Two registration clinical studies are underway for KN026 in combination with chemotherapy and KN026 in combination with KN046 without chemotherapy for gastric cancer.

Other innovative developments of HER2 dual antibodies such as MBS301, SCTB72, JSKN003, KM501, TQB2102, etc. have entered the development study. In addition, the development of CD3 and PD-1 and Her2 bispecific antibodies has become a hot spot. In China, CD3/Her2, PD-1/Her2 bispecific antibodies, such as MQ0127, M802, IBI-315, have been developed respectively.

ARX788 is a novel antibody-coupled drug. ARX788 recognizes and enters HER2-positive tumor cells and releases the microtubule protein inhibitor pAF-AS269, which induces tumor cell growth arrest and death to achieve antitumor effects. The ACE-Gastric-01 study is a phase I dose extension trial in China of trastuzumab in patients with HER2-positive advanced gastric cancer. A phase I dose-expansion trial in patients was conducted in China to evaluate the safety, tolerability, PK profile and antitumor activity of ARX788. A total of 30 patients were enrolled in the study, nine treated with ARX788 at 1.3 mg/kg, 14 at 1.5 mg/kg, and seven at 1.7 mg/kg. Four patients (13.3%) experienced grade ≥ 3 drug-related adverse events (TRAE), including ocular adverse events, interstitial lung disease (ILD), anemia, and elevated glutamyl transferase levels. The duration of remission in the total population was 8.4 months, with an objective remission rate of 37.9%, progression-free survival of 4.1 months, and overall survival of 10.7 months [9] .

SYD985 is a novel HER2-targeted antibody-coupled drug, which is a combination of trastuzumab and a drug containing duocarmycin (betacamycin). Clinical trials for SYD985 for advanced breast, endometrial, gastric and other solid tumors are currently underway, and phase I results showed a remission rate of 6% for advanced gastric cancer [25] . On July 18, 2023, the European Medicines Agency (EMA) accepted trastuzumab duocarmazine (SYD985) marketing application for the treatment of patients with unresectable HER2-positive locally advanced or metastatic breast cancer. The indication of SYD985 in HER2-positive gastric cancer needs to be further explored. XMT1522 and MED14276, which are still in clinical phase in the article by Wang Na [26] , have both been declared suspended from clinical trials by the FDA due to safety reasons.

In recent years, researchers have successfully developed degradate-antibody coupling (DAC) in combination with target protein degradation (TPD) for more effective delivery of chemotherapeutic drugs, and this coupled drug not only allows selective delivery but also improves the therapeutic index of toxins [27] [28] . DAC is one of the most promising new paradigms in medicinal chemistry. DAC drugs targeting BRD4, STEAP1, Era, and BRM are in the development stage [29] [30] . In conclusion, this DAC drug paradigm greatly overcomes the various problems faced by PROTAC (protein degradation targeted chimeras) and promises to be a drug candidate for the treatment of many human diseases. We need to continue to optimize the existing degradation technology to challenge more difficult to target “hard to drug” targets, improve druggability and achieve clinical translation.