Discussion
ADCs are a novel class of promising antitumor drugs which have made
great breakthrough in recent years. As a representative of
second-generation ADCs, trastuzumab emtansine (T-DM1), which is composed
of trastuzumab and a derivative of maytansine, was the first ADC
approved for solid tumor treatment. According to the EMILIA trial, T-DM1
showed superior efficacy and safety compared to lapatinib plus
capecitabine in posterior-line treatment of patients with advanced
HER2-positive breast cancer (BC) 37. Thereafter,
studies of other ADCs targeting HER2 showed encouraging survival
benefits as well. T-DXd was granted accelerated approval for the
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer who received two or more prior
anti-HER2-based regimens in the metastatic setting in 2019 based on the
phase II DESTINY-Breast 01 trial38, 39. T-DXd also
demonstrated promising antitumor activity in patients with heavily
pretreated HER2-expressing or HER2 -mutant solid tumors and
HER2-low advanced BC40-42. The phase III
DESTINY-Breast 03 study compared the efficacy and safety of T-DXd with
T-DM1 in patients with HER2-positive metastatic breast cancer previously
treated with trastuzumab and a taxane, and the results showed that T-DXd
significantly improved PFS and overall response with a 12-month PFS rate
of 75.8% vs. 34.1% (HR 0.28; 95% CI, 0.22 to 0.37; P<0.001)
and an ORR of 79.7% vs. 34.2%, respectively43. In a
preclinical study, ARX788 showed strong antitumor activity in
HER2-positive and HER2-low expression breast and gastric cancer
patient-derived xenografts as well as in a T-DM1-resistant
model44. Trastuzumab duocarmazine (SYD985) presented
remarkable activity in epithelial ovarian cancer cell lines with strong
and moderate to low HER2/neu expression45. These novel
anti-HER2 agents bring hope to the subpopulation. On the basis of the
promising survival outcomes, anti-HER2 ADCs have also been investigated
in many clinical trials of patients with GC and GEJC. However,
the clinical efficacy varies with
different HER2-targeted ADCs.
In this meta-analysis, we included 6 single-arm trials and 2 RCTs with a
total of 871 patients and thoroughly evaluated the efficacy and safety
of HER2-targeted ADCs in the treatment of patients with GC and GEJC.
T-DXd was used in four of the studies, and one study involved patients
with HER2-low expression only. Despite the HER2 expression status, the
pooled efficacy results showed that the ORR and DCR were 29% and 71%,
respectively. The pooled mOS and mPFS were 9.68 months and 4.06 months,
respectively. According to our subgroup analysis, the patients positive
for HER2 expression benefitted more from anti-HER2 ADCs, with an ORR of
39%. The ORR of HER2-low patients is 19%, and the result of ADC
treatment is moderately better than that of the standard second-line
treatment (ramucirumab in combination with
paclitaxel)46. Given that only two studies provided
data on the HER2-low patient subgroup and that survival time data were
unavailable, the efficacy of anti-HER2 ADCs in HER2-low GC and GEJC
needs to be validated in more studies in the future. However, there is
no doubt that the results of this meta-analysis confirmed HER2-targeted
ADCs were potential therapy options for previously treated GC/GEJC
patients regardless of HER2 expression status.
Among all currently developed anti-HER2 ADCs, T-DXd was the most
representative. It has been approved as second- or later-line treatment
for patients with HER2-overexpressing GC or GEJC. We calculated the
pooled results of the 3 studies that conducted T-DXd on HER2-positive GC
and GEJC patients32-34. The pooled ORR and DCR were
43% and 83%, respectively. The pooled mOS and mPFS were 12.36 month
and 5.60 months, respectively. These results were better than that of
overall anti-HER2 ADCs and no heterogeneity was observed in the results.
Notably, in contrast to the case in breast cancer, T-DM1 is not as
effective as expected in HER2-positive GC and GEJC. One possible reason
is that HER2 loss after trastuzumab and the higher intratumoral
heterogeneity in gastric cancer than in breast cancer affect the
activity of T-DM1 due to the lack of a bystander effect which can kill
both antigen-positive cells and adjacent antigen-negative tumor cells in
the heterogeneous tumors47. Another potential
explanation is that the payload of T-DM1 (emtansine) might be less
active in gastric cancer12, 27. The worst ORR result
was provided by the Banerji 2019 study which employed SYD985;
only one of 16 patients achieved an objective response, significantly
lower than the ORRs of the cohorts of enrolled patients with breast
cancer, urothelial cancer and endometrial cancer. However, the sample
size of this study is too small to draw a conclusion, and the clinical
activity of SYD985 in HER2-positive GC/GEJC patients needs to be
validated in more studies on a larger scale in the future.
In terms of safety, almost all patients experienced at least one AE
during the treatment. The pooled incidence of all-grade AEs was 98.8%.
Gastrointestinal and hematologic toxicity were the most common, with the
five most common AEs including nausea, decreased appetite, anemia,
decreased neutrophil count and asthenia. The pooled incidence of grade
≥3 TEAEs was 58.8%, and it is worth paying attention to the serious
hematologic toxicity such as anemia, decreased neutrophil count,
decreased white blood cell count and decreased platelet count. The
considerable incidence of high-grade AEs might be related to off-target
effects and the toxic payload. In this meta-analysis, the incidence of
ang grade TEAEs related to T-DXd was 100%. Additionally, despite the
unusual ocular toxicity exhibited in ARX788, it seemed like the most
safety ADC with a grade≥3 TEAE incidence of 13.3%.
Overall, based on their clinical efficacy and acceptable safety,
HER2-targeted ADCs have emerged as a promising class of anti-HER2
therapeutics and could serve as a new option for second- or later-line
treatment in GC and GEJC patients. At present, a variety of anti-HER2
ADCs are under clinical investigation. Beyond breast and gastric cancer,
the efficacy of these medications has also been explored in other solid
tumors, such as urothelial carcinoma, colorectal cancer and non-small
cell lung cancer. With the constant development of production
technology, next-generation ADCs with optimized structural designs may
simultaneously further improve activity and decrease toxicity in normal
tissues in the future.
There are some limitations in the study. First, because the
investigation of HER2-ADCs in GC and GEJC has just started in the last
few years, the number of eligible trials and the sample size are not too
large. Except for T-DXd, the other 5 types of drugs were used in just
one study each. Second, due to the limited data, thorough subgroup
analyses could not be conducted and the sources of high heterogeneity
across the results remain unclear. Finally, the fact that most of the
included studies were sing-arm trials may lead to an overestimation of
efficacy. In the future, large-scale RCTs are needed to further evaluate
and compare the efficacy of HER2-targeted ADCs with other anti-HER2
treatment regimens.