Introduction
Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor (EGFR) tyrosine kinase family that is encoded by the gene
ERBB2 [
1]. HER2 was first functionally implicated in human breast cancer pathogenesis in 1987 when it was discovered that ERBB2 overexpression was a significant predictor of both overall survival (OS) and time to relapse [
2]. ERBB2 is also overexpressed in subsets of patients with a variety of other cancers, including gastric, non-small cell lung, colon, bladder, and biliary cancers [
1,
3‐
6].
Gastric cancer (GC) has unique HER2 immunostaining characteristics, with an incidence of up to 30% of intratumoral heterogeneity [
7]. As such, the criteria for determining whether a tumor is HER2-positive differs between gastric and breast cancers [
8]. HER2-positive GC is defined as HER2 immunohistochemistry (IHC) 3 + or 2 + /in situ hybridization (ISH) + (
ERBB2/
CEP17 ≥ 2.0) and accounts for approximately 15% of GCs. Given the prevalence of HER2-postive GC, therapies targeting HER2 have been evaluated in this patient population.
In the ToGA trial, treatment with the anti-HER2 monoclonal antibody, trastuzumab, showed improved outcomes in combination with chemotherapy versus chemotherapy alone in patients with HER2-positive GC [
9]. The results of this trial led to the widespread approval of trastuzumab for HER2-postive GC. Other HER2-targeting agents have been evaluated for the treatment of HER2-positive GC but have failed to show survival benefits in patients with GC despite demonstrating significant activities in HER2-positive breast cancer. This indicates unique challenges for the development of anti-HER2 treatment for HER2-positive GC.
The concept of antibody–drug conjugates (ADCs) was developed to combine the advantages of highly specific monoclonal antibodies with the cytotoxic effects of chemotherapeutic drugs to deliver a therapeutic amount of a cytotoxic drug directly to the target tissue with lower systemic toxicity [
10]. While this concept is attractive as a potential strategy for the treatment of targetable tumors, the development of a successful ADC drug has some challenges. As an example, T-DM1, an ADC of trastuzumab and the cytotoxic microtubule inhibitor DM1, failed to show superiority to taxane in previously treated, HER2-positive advanced GC in the phase 2/3 GATSBY trial [
11]. The heterogenous nature of HER2 expression in GC may have affected the activity of T-DM1, which does not have a bystander antitumor effect [
12]. However, an ADC with a bystander antitumor effect may be the breakthrough needed to develop a successful ADC treatment for HER2-positive GC.
Trastuzumab deruxtecan (T-DXd, DS-8201) is an anti-HER2 human monoclonal IgG1 antibody, with the same amino acid sequence as trastuzumab, covalently linked to deruxtecan, which consists of an enzymatically cleavable peptide-based linker and a novel topoisomerase I inhibitor exatecan derivative (DXd), as its released payload [
10,
13]. It was first approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer by the Food and Drug Administration (FDA) in the US (December 2019) [
14], followed by approval in Japan (March 2020) for the same indication. It was recently approved in Japan (September 2020) as the first ADC in the world for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer that progressed on cancer chemotherapy [
15]. The current Japanese treatment guidelines recommend T-DXd as third- or later-line treatment for previously treated HER2-positive [
16]. Very recently in the US, T-DXd has been approved for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen [
17]. It is also approved in the EU for the treatment of HER2-positive metastatic breast cancer [
18].
In this review, we discuss the early development and characteristics of T-DXd, including its mechanism of action, structure, and preclinical findings. We then review the clinical findings of T-DXd in patients with HER2-positive GC, focusing on safety and tolerability. Treatment management for patients who experience T-DXd-related ILD and other adverse events (AEs) is discussed, and recommendations are provided based on the authors’ experience. Finally, future perspectives for T-DXd treatment in clinical practice, including therapeutic evaluations in ongoing clinical trials and author opinions on important future research, are discussed.
Pharmacokinetic properties
The pharmacokinetics of T-DXd were evaluated in the dose escalation part of the open-label phase 1 study (DS8201-A-J101; NCT02564900) that included patients with breast, gastric, or gastroesophageal cancer with varying HER2 status that was refractory to standard therapy [
28]. T-DXd showed a non-linear pharmacokinetic profile and the half-life of T-DXd increased at higher doses; drug exposure increased more than the dose ratio at doses above 3.2 mg/kg. Importantly, the pharmacokinetic analysis in this study showed there was no significant difference between the serum concentration of T-DXd and that of the antibody itself; thus, low systemic exposure of DXd was observed. The findings suggest that the linker of T-DXd is stable in the circulation. This observation is supported by a report of favorable in vitro stability of T-DXd in human plasma [
13]. Based on the phase 1 analyses of pharmacokinetics, efficacy, and safety, a recommended dose of 6.4 mg/kg every 3 weeks was set for patients with GC.
T-DXd levels are reduced in the circulation due to degradation, internalization into target cells, and non-specific uptake by cells belonging to the reticuloendothelial system, such as macrophages and monocytes, that have the capability of phagocytosing foreign substances. DXd undergoes hepatobiliary excretion [
29]; therefore, consideration may need to be given to patients with hepatic impairment. Currently, there are no dose adjustment recommendations for patients with mild or moderate hepatic impairment; however, the prescribing information for patients states that patients with moderate hepatic impairment should be closely monitored for increased toxicities related to DXd [
29,
30]. There are no data yet to guide recommendations in patients with severe hepatic impairment, indicating a possible need to address the usage of T-DXd in these patients in future studies. In clinical studies, the impact of AUC
0–17 days on coadministration of CYP3A and/or organic anion transporting polypeptide inhibitors with T-DXd has not been clinically meaningful [
30].
Conclusion
Although several HER2-targeted therapies have been investigated in HER2-positive advanced GC, until recently, trastuzumab was the only approved anti-HER2 agent. T-DXd was developed to overcome GC-specific challenges for HER2-targeted therapy, which might have been achieved largely through a bystander antitumor effect and a high DAR. T-DXd is the first HER2-targeting ADC that has demonstrated a superior response rate and survival benefit over standard chemotherapy. Overall, T-DXd has a manageable safety profile; however, patients should be carefully monitored for ILD in clinical practice. The recommendations in this review are intended to assist physicians with T-DXd treatment management.
Acknowledgements
Open Access fees were funded by Daiichi Sankyo Co., Ltd. We would like to thank Sarah Bubeck, PhD, of Edanz Pharma for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd.
Declarations
Conflict of interest
K Shitara reports paid consulting or advisory roles for Astellas, Eli Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, and GSK; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Eli Lilly, Ono, Sumitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, and Medi Science, outside the submitted work. E Baba reports grants and personal fees from Taiho, Chugai, Astellas, Merck Biopharma, Daiichi Sankyo, Ono, Kyowa-Kirin, Eisai, Eli Lilly, MSD, Sanofi, Yakult, and Takeda. K Fujitani reports personal fees from Bristol-Myers Squibb, Eli Lilly, Ono, Taiho, and Yakult. E Oki reports personal fees from Taiho, Takeda, Chugai, Eli Lilly, Ono, and Bayer. S Fujii has nothing to declare. K Yamaguchi reports grants and personal fees from Taiho, Chugai, Daiichi Sankyo, Ono, and Eli Lilly; personal fees from Takeda, Merck Serono, Bayer, and Bristol-Myers Squibb; and grants from MSD, Gilliad, Sumitomo Dainippon, Boehringer Ingelheim, and Sanofi.
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