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.