Human epidermal growth factor receptor-2 (HER2) is a well-known target for approximately 15% of gastric adenocarcinomas (GACs). Although a plethora of HER2-targeted agents are marketed, currently only two agents are approved for GAC. These two agents are used only in the metastatic setting. Trastuzumab is utilized in combination with front-line chemotherapy, and trastuzumab deruxtecan is given following failure of trastuzumab therapy.
1. Introduction
Metastatic gastric adenocarcinomas (GACs) carry a poor prognosis with limited therapy options after first-line failure
[1]. Some GACs (~15%) over-express human epidermal growth factor receptor-2 (HER2), making them candidates for HER2-targeted therapy. According to the guidelines, HER2 over-expressing GACs are classified by HER2 protein 3+ via immunohistochemistry (IHC), HER2 protein 2+ via IHC+ with an ERBB2/CEP17 ratio ≥ 2 using fluorescence in situ hybridization (FISH), or an average of
ERBB2 copy number ≥ 6 signals/cell. Newer HER2 therapies are challenging these designations by exploring effectiveness in those with lower expression (or assessments using other platforms such as liquid biopsy or Next Gen Sequencing).
ThisOur re
searchview focuses on the current understanding of HER2 agents in HER2-positive advanced GAC management.
2. Antibody Drug Conjugates (ADCs)
ADCs are a novel drug design in which antibodies are chemically linked to cytotoxic therapy
[2][3][4][5][15,23,24,25]. The antibody component exerts its anti-tumor effects by recognizing the antigen on the target cells, facilitating the formation of an antigen–antibody conjugate, which allows the cytotoxic payload to be rapidly internalized, leading to release of the cytotoxic component
[5][25]. Ideally, this mechanism should reduce off-target toxicity; however, as mentioned previously, trastuzumab deruxtecan, an ADC that consists of trastuzumab with a topoisomerase inhibitor, carries substantial toxicity
[6][7][10,11]. The hope is that newer generations of ADCs and continued development in this area will yield safer agents. Additional HER2 ADCs are being explored in HER2-positive GAC. RC48 is an ADC composed of hertuzumab, an anti-HER2 mAb conjugated to a microtubule inhibitor, monomethylauristatin E (MMAE)
[8][9][26,27]. A phase 2 trial in ICH 2+/3+ advanced GAC patients in the refractory setting showed an ORR of 24.8%, median PFS of 4.1 months, and median OS of 7.9 months
[5][8][9][25,26,27]. Those with HER2 IHC 2+/FISH− showed an ORR of 16.7%. Of note, RC48 was approved in China for GAC. Phase 3 in this population is under investigation using NCT04714190
[10][28]. Other HER2 ADCs are being explored in solid tumors. Preliminary results of ZW49 (auristatin) in heavily pretreated HER2-positive solid tumor patients showed an ORR of 31% with disease control of 72%
[11][12][29,30]. For the GAC patients (n = 11), the ORR was 37% with a disease control rate of 73%. ARX788 (amberstatin conjugate) showed encouraging phase 1 results in HER2 refractory GAC patients (n = 30) with an ORR of 37.9%, disease control of 55.2%, median PFS of 4.1 months, and median OS of 10.7 months
[13][31]. ARX788 was granted orphan drug status with the FDA in 2021
[14][32]. Examples along with their cytotoxic payload include MRG002 (microtubule disrupting agent monomethyl auristatin E), SYD985 (duocarmyicin), PF-06804103 (Aur0101), FS-1502 (monomethyl auristatin F), GQ1001 (DM1), A166 (microtubule cytotoxic agent), XMT-1522 (auristatin), BDC-1001 (toll-like receptor), ALT-P7 (monomethyl auristatin E), and SBT6050 (toll-like receptor)
[2][4][5][15,24,25]. Trial examples of these agents are described in
Table 1 [10][15][16][17][18][19][20][21][22][23][28,33,34,35,36,37,38,39,40,41].
Table 1. HER2-targeted antibody-drug conjugate examples currently under investigation [10][15][16][17][18][19][20][21][22][23]. HER2-targeted antibody-drug conjugate examples currently under investigation [28,33,34,35,36,37,38,39,40,41].
Drug Name |
HER2 bsAb |
Trial Number |
Phase |
Population |
RC48 |
Anti-HER2 + MMAE |
NCT04714190 NCT05514158 NCT05982834 |
3 1 1/2 |
Locally advanced/metastatic HER2 GAC Locally advanced/metastatic HER2 GAC Metastatic HER2 GAC |
ZW49 |
Anti-HER2 bsAb (ZW25) + Auristatin |
NCT03821233 |
1 |
Advanced HER2-expressing cancers |
MRG002 |
Anti-HER2 IgG1 + MMAE |
NCT04492488 NCT05141747 |
1 2 |
Advanced HER2 solid tumors Locally advanced/metastatic HER2-positive/HER2 low GAC |
FS-1502 |
Anti-HER2 + MMAF |
NCT03944499 |
1 |
HER2-positive advanced breast or solid tumors |
GQ1001 |
Anti-HER2 + DM1 |
NCT04450732 |
1 |
HER2-positive advanced solid tumors |
ARX788 |
Modified Trastuzumab + MMAF |
NCT03255070 |
1 |
HER2-positive advanced solid tumors |
BDC-1001 |
Trastuzumab biosimilar + TLR7/8 agonist |
NCT04278144 |
1/2 |
HER2-positive advanced solid tumors |