Next stage of collaboration in East Asia gastric cancer treatment

East Asia has the highest incidence of gastric cancer (GC). Considering the large population base, the burden of GC is particularly heavy. According to the latest report of cancer epidemiology published from GLOBOCAN, the age-standardized incidence of GC is 45.7 per 100,000 person years (1). Despite the breakthroughs in immunotherapy and target therapy of GC in recent years, we are still upfront great obstacles to overcome treatment resistance and precisive medicine. The median overall survival (OS) of metastatic GC is still no more than 2 years.

We noticed the distinct principles and pattern of response to treatment between eastern and western world. For example, neoadjuvant chemoradiation therapy but not neoadjuvant chemotherapy is more common in United States (US) than East Asia. The criteria for neoadjuvant therapy patients also vary across countries, according to data from different clinical trials. Districts collaboration accelerate the development speed of GC by sharing clinical and translational research information. Thus, the union gathering adjacent countries matters to research progress.

The development of East Asia GC research plays a vital role to the world. From ToGA to CheckMate-649, leading principal investigators (PIs) from East Asia provided current evidence of target therapy and immunotherapy to the world (2,3). However, different from the former stage where Japan and Korea researchers lead most the global phase III trials, the collaboration pattern in East Asia changed in line with the rapid progress of China. The development of native immunotherapy or antibody-drug conjugates (ADCs) drug platforms is comparable to US and Japan (4,5). Clinical and translational studies revealed the special biological behavior of Chinese GC patients (6).

For advanced GC, achievement of long-term survival of patients is still an unmet need. Hence, collaboration in drug research and development (R&D) is an urgent clinical need, especially in the scope of East Asia. Here, we hope to review the collaboration history of East Asia, and the future of the new era.

The past imbalance of East Asia GC development

Japan and South Korea engaged in the contemporary GC research earlier than China. In the past few decades, R&D of GC has been led by Japan and South Korea over a long period of time. China often played a subordinate role in the impletion of global multicenter randomized controlled trials (RCTs).

For chemotherapy, S-1 as a current standard oral fluorouracil regimen in East Asia, was generated from Japan (7,8). CLASSIC study which provided the standard adjuvant treatment in locally advanced GC was leaded by Korea (9). The huge success of the ToGA trial initiated the new era of anti-HER2 target therapy among GC patients, while China only participated in this landmark study and contributed subjects (2), the same as JACOB study in the era of target therapy (10). With the breakthrough of immunotherapy in the field of solid tumors, multiple international RCTs have been conducted to evaluate the utility of immune checkpoint inhibitors in the treatment of advanced GC. In line with the rapid progress in R&D in China, native programmed death 1 (PD-1) blockade products start to reshape the former circumstances (11).

Rapid progress in Chinese drug development

In recent years, immunotherapy and targeted therapy of GC have achieved rapid development in China (Table 1). The approval of PD-1 antibodies and targeted therapeutics (e.g., trastuzumab and ramucirumab) by the Food and Drug Administration (FDA) or National Medical Products Administration (NMPA) for advanced GC, inspired the development of additional new medical products. From 2013 until now, there have been more than 8,000 clinical trials on cancer, involving 339 cases in GC (12). More and more drugs based on existing molecular targets bring new opportunities for GC therapy.

In immunotherapy, in pace with the success of CheckMate-649, which provided the current standard choice of PD-1 inhibitor plus chemotherapy in first-line treatment, ORIENT-16 and RATIONAL-305 also reported positive results of sintilimab and tislelizumab in first-line therapy, which are both native PD-1 blockades from China (11). Tislelizumab and envafolimab, another programmed death ligand 1 (PD-L1) inhibitor administrated via subcutaneous injection, were both approved by NMPA in second-line mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) GC treatment (13). There are still other ongoing national and global phase II or III RCTs leaded by China that may change the treatment landscape.

Except the success of immunotherapy, innovative target therapy and ADC drugs R&D also flourished. For example, RC48, domestically developed by RemeGen, is a novel recombinant human anti-HER2 ADC, which could trigger antibody-dependent cellular cytotoxicity (ADCC) on HER2-overexpressed cancer cells. This drug showed anti-tumor activity in patients with HER2 2+ and fluorescence in situ hybridization (FISH) negative advanced GC who were refractory or intolerant to at least two lines of standard chemotherapy, and it has been approved by NMPA (5). The success of RC48 may reshape the concept of HER2 positivity. KN026 a bispecific antibody targeting PD-L1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plus KN046 a bispecific antibody targeting extracellular domain (ECD) 2 and 4 of HER2 extra-membrane domain, showed favorable response rate in first-line HER2 positive GC without chemotherapy. Other agents targeting claudin 18.2 (CLDN18.2), fibroblast growth factor receptor (FGFR), and c-mesenchymal-epithelial transition (c-MET) also showed promising results in early phase trials.

Recently, CARsgen Therapeutics developed CT041, an anti-CLDN18.2 chimeric antigen receptor (CAR)-T cell therapy, which displayed a manageable safety profile and a response rate of 57.1% in advanced GC patients (14). New drugs for GC therapy have sprung out in recent years, as China is paying unremitting efforts to invest in innovative drugs development.

The steadily increasing number and quality of clinical trials in China could be the evidence. In 2017, the number of completed phase 1 clinical trials in China mainland ranked second place in the world, with 180 trials done per year (15). In recent years, Chinese researchers not only focused on participating global research, but also devoted themselves to design and conduct international research.

Future East Asia collaboration

Thanks to the open mind of NMPA in recent years, high-quality clinical trials are especially welcomed in China. As a broader land for clinical research and the great advantages of large population base, the data from China is important to the world. Here, we propose suggestions for future collaborations.

For phase 1 trials, we call for a spontaneous and broader opening site for East Asia countries. More attention to GC on early phase clinical trials is important. As other developing countries in East Asia have weak discourse power in international GC development, the inclusion of other East Asia countries such as Vietnam, Laos, and Myanmar, etc. in phase II or III clinical trials, is of great importance for the approval of novel agents and treatment strategies in these countries. China with great influence and resources in politics and economies has the ability and responsibility to widespread the newest GC research.

In consideration of adjacent districts and closely shared genetic features of GC patients, the establishment of collaborative group for GC consisting of Center for Drug Evaluation (CDE), leading PIs, and biopharma companies, may build a friendly environment for drug R&D. By sharing the data on epidemiological, prevalence and treatment outcomes of East Asian countries could help improve the patients care and regional database. Exchange programs that provide expertise and training opportunities could help build capacities and communications among foreign experts.

Challenges in East Asia collaborations

Although GC showed high incidence in East Asia, the heterogeneity in OS data may add the difficulty to study design. Japan reported discordance of survival data to China and other countries, which were hard to repeat. ATTRACTION-4, which launched mostly in Japan reported more than 20 months median OS. While in CheckMate-649, the median progression-free survival (PFS) in the nivolumab plus chemotherapy arm, the final median OS was no more than 15 months. In ATTRACTION-4, we did not see the statistical significance, the long OS in the placebo arm may shadow the difference. Also, in DESTINY-gastric-01 study, trastuzumab deruxtecan showed long survival prolongation in third line and later line patients, however, in DESTINY-gastric-02, trastuzumab deruxtecan showed 41.8% response rate and the median PFS was 5.6 months in second-line treatment (16). The different outcomes may be due to level of support care delicate stratification of GC patients.

There is a lack of standardization in diagnostic and treatment protocols for GC across the East Asian regions, leading to variations in healthcare and outcomes. The approach to peritoneal cytology positivity or bulky lymph node is still on debate and distinct among different countries, adds the difficulty to study design.

Also, East Asian comprises of diverse populations with varying socio-economic backgrounds, health behaviors, and genetic predispositions towards GC. This can make it challenging to develop a cohesive approach towards preventing and treating the disease. Many countries in the region have limited resources for healthcare, making it difficult to invest in R&D, screening programs, and access to treatments.

Districts collaboration accelerates the development of GC. The model of East Asia cooperation may be reshaped by the rapid progress of China in recent years. The involvement in broader East Asia countries for clinical trials and close communication among the adjacent countries should be encouraged. Discordance in clinical response and principle in GC treatment adds the difficulties in study design. The next stage of East Asia collaboration is filled with chances and challenges.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (General Program, No. 82272764 to LS), the Key Program of Beijing Natural Science Foundation (No. Z210015 to ZP), Clinical Medicine Plus X-Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018 to ZP) and Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (No. BMU2022PYB026 to TX).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Yasuhide Yamada) for the series “Progress and Future Direction to Treat Advanced Gastric Cancer” published in Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-33/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-33/coif). The series “Progress and Future Direction to Treat Advanced Gastric Cancer” was commissioned by the editorial office without any funding or sponsorship. TX reports support for the present manuscript from Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation (No. BMU2022PYB026). ZP reports support for the present manuscript from the Key Program of Beijing Natural Science Foundation (No. Z210015) and Clinical Medicine Plus X-Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018). LS reports support for the present manuscript from the National Natural Science Foundation of China (General Program, No. 82272764). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97. [Crossref] [PubMed]
3. Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature 2022;603:942-8. [Crossref] [PubMed]
4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020;382:2419-30. [Crossref] [PubMed]
5. Peng Z, Liu T, Wei J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Commun (Lond) 2021;41:1173-82.
6. Lin SJ, Gagnon-Bartsch JA, Tan IB, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut 2015;64:1721-31. [Crossref] [PubMed]
7. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548-57. [Crossref] [PubMed]
8. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810-20. [Crossref] [PubMed]
9. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-21. [Crossref] [PubMed]
10. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 2018;19:1372-84. [Crossref] [PubMed]
11. Xu J, Jiang H, Pan Y, et al. LBA53 Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study. Ann Oncol 2021;32:S1331.
12. Shen L. Anticancer drug R&D of gastrointestinal cancer in China: Current landscape and challenges. Innovation (Camb) 2022;3:100249. [Crossref] [PubMed]
13. Shen L, Li J, Deng Y, et al. Envafolimab (KN035) in advanced tumors with mismatch-repair deficiency. J Clin Oncol 2020;38:3021.
14. Qi C, Gong J, Li J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med 2022;28:1189-98. [Crossref] [PubMed]
15. Zhao S, Zhao H, Lv C, et al. Anticancer drug R&D landscape in China. J Hematol Oncol 2020;13:51. [Crossref] [PubMed]
16. Ku GY, Di Bartolomeo M, Smyth E, et al. 1205MO Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen. Ann Oncol 2022;33:S1100.