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.