Introduction
Stomach cancer, which includes gastric cancer (GC) and gastro-oesophageal junction cancer (GEJC), is the fifth most common malignancy and the fourth leading cause of cancer death globally, responsible for over 1 million new cases and 769000 new deaths in 20201, 2.Despite the decline in incidence rate worldwide during the past few decades, gastric cancer remains a significant contributor to the global cancer burden with a persistently high case fatality rate3, 4. Although many treatment options have been developed, survival in GC patients remains poor because most patients present with advanced disease at diagnosis. Intratumoral and intertumoral heterogeneity also leads to poor prognosis5.
The selection of a treatment regimen for GC patients is associated with the disease stage and biomarker expression status6. HER2 (also known as ERBB2) is a member of the human epidermal growth factor receptor family and is an important proto-oncogene. Amplification of the HER2 gene and overexpression of the HER2 protein have been implicated in the tumorigenesis and poor prognosis of many types of cancer7-11. Approximately 20% of GC/GEJC patients harbor HER2 amplification or overexpression12, 13. Trastuzumab is the first monoclonal antibody targeting HER2. According the phase III ToGA trial, using trastuzumab plus chemotherapy could prolong the overall survival of HER2-positive GC/GEJC patients compared to use chemotherapy alone (13.8 vs. 11.1 months, HR=0.74; 95% CI 0.60-0.91; p =0∙0046)14. Based on the results, the combination of trastuzumab and platinum-fluoropyrimidine doublet has been established as the standard regimen for the first-line treatment of patients with HER2-positive GC/GEJC. Although the emergence of trastuzumab represented a breakthrough in anti-HER2 treatment, the second-line treatment options for patients progressing after trastuzumab-based treatment remain limited. Several studies that applied trastuzumab beyond progression showed inconsistent results. According to the current NCCN guidelines, it is not recommended to continue trastuzumab in second-line therapy15-19. Moreover, combined treatment regimens also failed to show superior survival benefits in the second-line setting20-22. There is an unmet need for effective anti-HER2 second-line treatment regimens.
Antibody-drug conjugates (ADCs) are a new kind of anticancer drug in which monoclonal antibodies (mAbs) and cytotoxic payloads are connected via a chemically synthetic linker. The mechanism of action of ADCs is that the antibody component recognizes and binds the specific antigen, upon which the ADC-antigen complex is internalized into the tumor cells, and the linker is cleaved in the lysosome, releasing the toxic drugs and allowing them to exert their effects. Compared to traditional medications for cancer therapy, the unique structure of ADCs enables these drugs to offer both the specific cell-targeting ability of mAbs and the cell-killing effect of chemotherapeutic drugs, which is anticipated to significantly improve overall survival and reduce side effects.
Human epidermal growth factor receptor 2 (HER2) is the most common target used in ADCs in studies23, 24. To date, over 60 HER2-targeted ADCs have been tested in clinical trials25. Trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), the two HER2-targeted ADCs, were granted approval for the treatment of HER2-positive breast cancer with different indications in 2013 and 2019, respectively26. Recent studies have shown that GC/GEJC patients can also benefit from HER2-targeted ADCs and T-DXd has been recommended as the second-line therapy in gastric cancer patients who received prior trastuzumab-based therapy by NCCN on the basis of the phase II DESTINY-Gastric01 trial with an ORR of 43% and the mOS was 12.5 months (9.6-14.3 months)19. However, the results of the GATSBY trial showed that the ORR of the patients treated with T-DM1 was only 21% and mOS was 7.9 months (6.7-9.5 months). Compared to taxane, T-DM1 did not show overall survival superiority in the treatment of advanced HER2-positive GC/GEJC patients27.
Given the discrepancies shown in the different drugs in GC/GEJC, thus, we performed a meta-analysis to figure out the efficacy and safety of HER2-targeted ADCs in GC/GEJC patients and the characteristics of benefit population, moreover, to provide reference for the studies of ADCs and the utilization in GC/GEJC patients in the future.