Gastric cancer is one of the most common malignant tumors in my country. Relying solely on cytotoxic drugs, survival is not optimistic. On December 11, 2022, the "Innovation leads to victory, stomach love is born" column hosted by Chuangsheng Group launched an online discussion m

Figure 1 Dr. Qi Chuan of Chuangsheng Group

Then West China Hospital Sichuan University Professor Gou Hongfeng talked about the progress of treatment of advanced gastric cancer. In recent years, the development of diagnosis and treatment of advanced gastric cancer has entered the "fast lane". A variety of targeted and immune drugs have gradually emerged and have made their mark in the field of advanced gastric cancer.

Figure 2 Professor Gou Hongfeng of West China Hospital of Sichuan University

Anti-HER2 treatment is the earliest successful targeted treatment for gastric cancer. ToGA research has opened the precedent for targeted treatment of HER2-positive gastric cancer ^[1]. Antibody-conjugated drugs (ADC) can significantly improve the survival time after HER2-positive advanced gastric cancer ^[2], pembrolizumab combined with trastuzumab , chemotherapy drugs first-line treatment of HER2-positive advanced gastric cancer can significantly improve the objective response rate (ORR) ^[3], HER2 dual anti-KN026 combined with PD-L1/CTLA-4 Dual anti-KN046 showed clinical benefit in untreated HER2-positive gastric cancer ^[4].

In the first-line treatment of HER2-negative gastric cancer, anti-PD-1 antibodies such as nivolumab, sindilizumab, pembolizumab, and anti-CLDN8.2 antibodies Zolbetuximab also obtained positive results in the first-line treatment of advanced gastric cancer ^[8,9]. Remoxizumab combined with paclitaxel has become the new standard for the second-line treatment of advanced gastric cancer ^[5]. Nivolumab and apatinib have been approved for the third-line treatment of gastric cancer ^[10].

As we all know, gastric cancer is a malignant tumor with strong heterogeneity. According to the molecular type, it can be divided into four types: EBV virus-positive gastric cancer, microsatellite unstable (MSI) gastric cancer, genomic stable gastric cancer, and chromosomally unstable gastric cancer.Clinical studies have confirmed that immunotherapy has shown clinically valuable efficacy improvements in patients with highly unstable microsatellites (MSI-H) and patients with high tumor mutation burden (TMB-H) tumors. More new targets such as FGFR2b, cMET, MUC17 may become "novels" that will change the clinical practice of advanced gastric cancer in the future. Gastric cancer diagnosis and treatment are gradually moving towards a new era of precise treatment guided by multiple targets.

Hubei Provincial Cancer Hospital Professor Xu Huiting explained in detail the research progress of emerging targets for advanced gastric cancer. At present, advanced gastric cancer only targets for drugs that target HER2+, VEGFR, and PD-1 have been approved. Clinical research on emerging targets for gastric cancer is in full swing.

Figure 3 Professor Xu Huiting from Hubei Cancer Hospital

• FGFR2b: 30.2% of advanced gastric cancers showed FGFR2b positive ^[14], and positive results were obtained in the Phase II FIGHT study. Compared with the chemotherapy group, the progression-free survival (PFS), OS and ORR of patients in the Bemarituzumab combined with chemotherapy group were significantly improved ^[15].

• CLDN18.2: 36% of advanced gastric cancer CLDN18.2 highly expressed ^[16], Zolbetuximab first-line treatment FAST study obtained positive results ^[17], and TST001 showed favorable efficacy in the first-line treatment of advanced gastric cancer ^[18].

• MET: 50% of gastric cancers are manifested as MET overexpression, 3%-4% of gastric cancers are gene amplified ^[19], and targeted treatment shows certain efficacy in different treatment lines ^[20].

• DKK1:DisTinGuish study, DKK high expression accounted for 57% ^[21]. DKN-01 is a neutralizing antibody against DKK1. The efficacy of DKN01 combined with PD-1 monoclonal antibody in the treatment of advanced gastric cancer is ^[21].

• FAK: The high expression of FAK is related to the poor prognosis of gastric cancer ^[22]. The initial efficacy of FAK inhibitors was observed in patients with advanced gastric cancer ^[23] in the second-line and above.

• TROP-2: TROP2 is a therapeutic target for pan-cancer species and has shown efficacy in multiple cancer cohorts, including 5 gastric cancer and 4 cases of stable disease (SD) ^[24].

• MUC17: MUC17 overexpresses ^[25] in 23.3%-52.2% of patients with gastric cancer. A phase I trial targeting MUC17-positive and CD3-positive is underway.

In recent years, domestic and foreign research on molecular targeted treatment and immunotherapy for advanced gastric cancer has made great progress. More and more new target drugs have entered clinical trials, which is expected to bring new hope to patients with advanced gastric cancer. Under the auspices of First Affiliated Hospital of Xiamen University, Professor Li Jiayi, Professor , Professor Chen Ye of West China Hospital of Sichuan University, Professor Second Affiliated Hospital of Zhejiang University School of Medicine, Professor Dong Caixia and Professor and Professor Yuan Yuan of Xuzhou Central Hospital combined with their own clinical experience, they shared their respective views on the first-line treatment of advanced gastric cancer in the era of precision treatment:

• Advanced gastric cancer adopts comprehensive treatment based on systemic anti-tumor drug treatment, and anti-tumor drugs include: chemical drugs, molecular targeted drugs, and immune checkpoint inhibitors.

• Before first-line therapy, tests for specific molecules should be carried out (such as tests for HER2, PD-L1, MSI) to determine whether patients can benefit from HER2 targeted therapy, immunotherapy and other therapies.

• How to screen clinical patients, improve the accuracy of immunotherapy, and explore the combination drug regimen of immunotherapy will be the direction of further research in the future.

Figure 4 Discussion guest

interprets the star target CLDN18.2, which is expected to achieve a new breakthrough in gastric cancer treatment

Second Affiliated Hospital of Nanchang University Professor Wang Hua brings the theme report "CLDN18.2: Biomarker with the potential of advanced gastric cancer". Gastric cancer is the fourth leading cause of cancer-related death in the world and seriously threatens human life and health ^[26]. More than 65% of newly diagnosed gastric cancer patients in my country are in the middle and late stages, with a low 5-year survival rate of ^[27].Gastric cancer has complex classification and strong heterogeneity. Currently, only the subtype of MSI-H or EBV virus-positive gastric cancer has strong prognosis and therapeutic efficacy. The identification of biomarker and clinical drug development promote the development of the entire gastric cancer research forward, and biomarker-guided treatment can bring survival improvements to patients with advanced gastric cancer.

Figure 5 Professor Wang Hua, Second Affiliated Hospital of Nanchang University,

Claudin protein is a cell-cell adhesion molecule located on the tight junction (TJs) between cells of epithelial cells, tablets. CLDN18.2 is specifically expressed in human normal gastric mucosal epithelial cells. Globally, the high expression rate of CLDN18.2 in patients with gastric cancer and gastroesophageal junction cancer is 24%-34% ^[28]. Studies have shown that CLDN18.2 positive is related to higher diagnostic stage and EBV virus infection ^[29], CLDN18-ARHGAP26 fusion is related to patient clinical characteristics and chemotherapy efficacy ^[30,31], CLDN18.2 positive gastric cancer shows higher CD8-positive T cell infiltration ^[32], and CLDN18.2 positive has become an ideal target for gastric cancer drug development. Drug development based on targeting CLDN18.2 targets is in full swing, and standardized CLDN18.2 detection is an important direction in the future.

Professor Xue Junli of Oriental Hospital Affiliated to Tongji University summarizes the research progress of CLDN18.2 in advanced gastric cancer. The characteristics of CLDN18.2 support it as an ideal antibody target. Except for the monoclonal antibody Zolbetuximab, the other types of drugs have been tested in clinical studies:

Figure 6 Professor Xue Junli of Oriental Hospital Affiliated to Tongji University

• Zolbetuximab is a mouse chimeric monoclonal antibody. FAST study showed that ^[34]. Among patients with CLDN18.2 expression ratio ≥70%, the median OS of Zolbetuximab combined with chemotherapy group and chemotherapy alone group was 16.5 vs 8.9 months respectively; among patients with CLDN18.2 expression ratio ≥40%, the median OS of Zolbetuximab combined with chemotherapy group and chemotherapy group were 13.0 vs. 8.3 months, recently, Astel announced that its first-line phase 3 registration study on gastric cancer had positive results.

• TST001 is a humanized antibody that specifically binds to CLDN18.2 and has a strong killing activity against CLDN18.2 positive cell lines. The TST001 combined regimen showed favorable efficacy in early-stage early studies of advanced gastric cancer, with an ORR of 73.3%, a disease control rate (DCR) of 100%, and treatment-related adverse events (TRAEs) in the dose-expansion stage are mostly grade 1-2 ^[35].

• CAR-T therapy CT041 showed excellent therapeutic effect in patients with posterior gastric cancer, with an ORR of 57.1%, a DCR of 78.6%, a median PFS of 5.6 months, and a median OS of 10.8 months ^[36].

• bispecific antibody targeting CLDN18.2 and ADC have no clinical data disclosed yet.

Currently, CLDN18.2 targets lack standardized detection methods. Establishing standard detection methods and accurately screening populations is the key to the clinical success of CLDN18.2 drugs.

Subsequently, Professor Liu Qing from Zhongshan Hospital Affiliated to Fudan University shared the diagnosis and treatment process of a phase IV (pT3N3M1) gastric cancer patient CLDN18.2 (CLDN18.2 expression is 1+30%, 2+30%, 3+10%).

Figure 7 Professor Liu Qing, Zhongshan Hospital Affiliated to Fudan University,

patient received first-line treatment of TST001 combined with CAPOX, showing good efficacy, and is still receiving long-term treatment and has good tolerability. The specific expression of

CLDN18.2 in gastric tissue makes it an ideal target for gastric cancer drug development. A variety of drugs targeting CLDN18.2 are in the clinical development stage and are expected to provide more choices for patients with CLDN18.2 positive gastric cancer. Under the auspices of Professor Mou Haibo of of Shulan (Hangzhou) Hospital, Professor Yu Yiyi of Zhongshan Hospital Affiliated to Fudan University, Professor Mao Chenyu of the First Affiliated Hospital of Zhejiang University School of Medicine, and Professor Zhou Xiang of Sichuan Cancer Hospital expressed their respective views on the application of targeted CLDN18.2 in the first-line treatment of gastric cancer. The main views are as follows:

• CLDN18.2 is highly expressed in gastric cancer, and drugs targeting CLDN18.2 have achieved good efficacy in the first-line treatment of gastric cancer. For example, this year, it was reported in ESMO that TST001 showed controllable safety and encouraging anti-tumor activity in patients with untreated gastric cancer expressing CLDN18.2.

• With the in-depth research on the target of CLDN18.2, I believe that more and more CLDN18.2 targeted drugs will be approved for marketing. The detection of CLDN18.2 will be more important. It is recommended to use unified detection methods to identify CLDN18.2. It is necessary to confirm the optimal limit value for CLDN18.2 expression. Whether different detection reagents and patient populations need unique limit values ​​need further exploration, which can provide support for the accurate identification of potential beneficiaries.

Figure 8 Discussion guests

Conference summary

Conference 0 is coming to an end, and Professor Xu Nong and Professor Liu Tianshu summarized the content of this conference. Research on new targets and new drugs for advanced gastric cancer has been underway. CLDN18.2 is a very promising target among HER2-negative gastric cancer patients. Exciting research results have been observed in many clinical studies. The targeted drug of CLDN18.2 is promising in the future. I hope that related drugs can be launched as soon as possible so that patients can benefit as soon as possible.

References:

[1] Bang YJ, et al. Lancet. 2010;376(9742):687–697.

[2] Peng Z, et al. Cancer Commun (Lond). 2021;41(11):1173-1182.

[3] Janjigian YY, et al. Nature. 2021;600(7890):727-730.

[4] Gong J, et al. ESMO 2022 1210P.

[5] Wilke H, et al. Lancet Oncol. 2014;15(11):1224-1235.

[6] Shitara K, et al. Lancet Oncol. 2018;19(11):1437-1448.

[7] Ann Oncol. 2022;33(suppl 4):S370.

[8] Shitara K, et al. Nature. 2022;603(7903):942-948.

[9] Xu. ESMO 2021. Abstr LBA53.

[10] Kang YK, et al. Lancet. 2017;390(10111):2461-2471.

[11] The Cancer Genome Atlas Network. Nature. 2014; 513:202-209.

[12] Chao J, et al. JAMA Oncol. 2021;7(6):895-902.

[13] Ann Oncol. 2019; 30(suppl_5):v475-v532.

[14] Ooki A, et al. Gastric Cancer 2021;24(6):1169-83.

[15] Catenacci DV et. 2021 ASCO, No.4010.

[16] Pellino A,et al. J Pers Med (Epub) 10-26-2021.

[17] Sahin U, et al. Ann Oncol. 2021;32(5):609-619.

[18] Shen et al, ESMO 2022, Abstract#3520.

[19] Lee, H.E, et al. Br. J. Cancer 2012, 107, 325–333.

[20] Jeeyun Lee, et al. Cancer Discov. 2019;9(10):1388-1405.

[21] Klempner et al., 2022 ESMO Abstract 1835.

[22] Thanapprapasr D, et al. Mol Cancer Ther. 2015;14(6):1466-1475.

[23] Doi T, et al. Target Oncol. 2019;14(1):57-65.

[24] Bardia A, et al. Ann Oncol. 2021;32(6):746-756.

[25] Yang B, et al. J of Experimental Clin Cancer Research. 2019;38:138.

[26] Sung H, et al. CA Cancer J Clin. 2021;71(3):209-249.

[27] Wang H.et al. Mol Clin Oncol.2018;9(4):423-431.

[28] Annals of Oncology, 2018, 29(suppl_8).

[29] Pellino A, et al. J Pers Med. 2021;11(11):1095.

[30] Zhang WH, et al. Front Oncol. 2020;10:1214.

[31] Shu Y, et al. Nat Commun. 2018;9(1):2447.

[32] Jia K, et al. BMC Med. 2022 ;20(1):223.

[33] Sanada Y, et al. J Pathol. 2006 ;208(5):633-642.

[34] Sahin U, et al. Ann Oncol. 2021 ;32(5):609-619.

[35] ESMO 2022, Abstract#3520.

[36] Shen et al, ASCO 2022, Abstract#4017.

*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform