Gastric Cancer (2021) 24:567–576 https://doi.org/10.1007/s10120-021-01164-x REVIEW ARTICLE Trastuzumab deruxtecan for the treatment of HER2‑positive advanced gastric cancer: a clinical perspective Masahiko Aoki1 · Satoru Iwasa1 · Narikazu Boku1 Received: 2 December 2020 / Accepted: 22 January 2021 / Published online: 1 March 2021 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2021 Abstract Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is a subtype for which new drugs and specifc treat- ment strategies should be developed. Trastuzumab deruxtecan (T-DXd) is a novel HER2-targeted antibody–drug conjugate containing topoisomerase I inhibitor as a payload. In the randomized phase 2 study (DESTINY-Gastric01) for HER2-positive advanced gastric or gastroesophageal junction cancer (AGC), patients treated with T-DXd showed a signifcantly higher response rate compared with the chemotherapy of physician’s choice, associated with remarkably prolonged progression- free and overall survival. T-DXd also exhibits anti-tumor activity to HER2-negative tumor cells close to HER2-positive cells (so-called bystander killing efect). T-DXd was efective even for HER2-low expressing breast and gastric cancer in several clinical studies. Taking advantage of these strong points and synergism with other cytotoxic, molecular-targeted and immunological agents, it is expected that T-DXd will bring further progression in treatment both for strongly and weakly HER2 positive AGC in various treatment settings including perioperative chemotherapy. Keywords Human epidermal growth factor receptor 2 (HER2) · Gastric cancer · Trastuzumab deruxtecan (T-DXd) Introduction of HER2 gene or overexpression of HER2 protein are found in 10–20% of GC [4]; American Society of Clinical Oncol- Human epidermal growth factor receptor 2 (HER2) is a ogy/College of American Pathologists guidelines defne 185 kDa protein with tyrosine kinase activity that belongs HER2-positive GC as immunohistochemistry (IHC) 3 + , or to the epidermal growth factor receptor (EGFR) family. IHC 2 + and in situ hybridization (ISH) + [5]. While HER2- HER2 is associated with increased tumor cell proliferation, positive AGC is reported to be aggressive [4], the prognostic reduced apoptosis, and enhanced migration. Indeed, HER2- impact of HER2-status is still controversial [6, 7]. positive breast cancers have a signifcantly poorer prognosis Several clinical studies for HER2-positive AGC have than HER2-negative breast cancers if patients are not placed been conducted (Table 1). In the ToGA study [8], patients on anti-HER2 therapy [1]. Clinical trials of trastuzumab (a received chemotherapy or chemotherapy plus trastuzumab monoclonal antibody that binds to the extracellular domain in the frst-line setting. Chemotherapy plus trastuzumab con- of HER2) began in 1992, and its efcacy in HER2-positive ferred signifcantly longer OS, leading to approval of trastu- breast cancer led to its frst approval in 1998 [2]. zumab for HER2-positive AGC. Following positive results Gastric cancer (GC) is the third-leading cause of cancer- of new anti-HER2 drugs for breast cancer, not a few clinical related deaths worldwide [3]. Even though various chemo- studies of lapatinib[9]9, trastuzumab emtansine [T-DM1] therapeutic agents have been developed for advanced gastric/ [11–13] and pertuzumab [14] for HER2-positive AGC, gastroesophageal junction cancer (AGC), median overall including trastuzumab beyond progression [15], were con- survival (OS) of AGC patients is about 1 year. Amplifcation ducted, but none of them elicited a statistically signifcant improvement in treatment for HER2-positive AGC. Several mechanisms of resistance may explain these neg- * Narikazu Boku [email protected] ative results in HER2-positive AGC. First, compared with breast cancer, HER2 staining pattern of AGC is heterog- 1 Division of Gastrointestinal Medical Oncology, National enous, and it is also diferent between the primary and meta- Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, static lesions [16, 17]. Second, prior trastuzumab treatment Tokyo 104-0045, Japan Vol.:(0123456789)1 3 568 M. Aoki et al. Table 1 Randomized trials for Trial Phase Regimen Line Median OS (mo) Median PFS (mo) human epidermal growth factor receptor 2 (HER2) positive ToGA8 3 FP/XP + Trastuzumab 1st 13.8 6.7 advanced gastric cancer FP/XP 11.1 5.5 HR 0.74; p = 0.0046 HR 0.71; p = .0002 LOGiC9 3 CapeOX + Lapatinib 1st 12.2 6.0 CapeOX 10.5 5.4 HR 0.91; p = 0.3492 HR 0.82; p = 0.0381 JACOB14 3 XP + Trastuzumab + Pertuzumab 1st 17.5 8.5 XP + Trastuzumab 14.2 7.0 HR 0.84; p = 0.057 HR 0.73; p = 0.0001 T-ACT15 2 Paclitaxel + Trastuzumab 2nd 10.2 3.7 Paclitaxel 10.0 3.2 HR 1.23; p = 0.20 HR 0.91; p = 0.33 TyTAN10 3 Paclitaxel + Lapatinib 2nd 11.0 5.5 Paclitaxel 8.9 4.4 HR 0.84; p = 0.1044 HR 0.85; p = 0.2411 GATSBY13 3 T-DM1 2nd 7.9 2.7 Docetaxel/Paclitaxel 8.6 .2.9 HR 1.15; p = 0.86 HR 1.13; p = 0.31 DESTINY- 2 T-DXd 3rd 12.5 5.6 Gas- Irinotecan/Paclitaxel 8.4 3.5 tric0132 HR 0.59; p = 0.0097 HR 0.47 XP, capecitabine and cisplatin; FP, 5-FU and cisplatin; CapeOX, capecitabine and oxaliplatin; HR, hazard ratio; mo, months; OS, overall survival; PFS, progression-free survival; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; may lead to a reduction of HER2 expression [18–20]. cells, deruxtecan is released into intercellular spaces and Finally, tumors may have intrinsic and/or acquired resist- then transferred to neighboring HER2-negative tumor cells; ant mechanism that reactivates pro-survival pathways such so-called bystander killing efect can overcome intra-tumor as PI3K/AKT signaling [15, 18, 19]. All these factors pose heterogeneity and reduced HER2 expression (Fig. 1). problems to be resolved for the development of new drugs T-DXd exhibited anti-tumor efcacy in HER2-positive and/or treatment strategy for anti-HER2 drugs for HER2- breast cancer patients [25, 29, 30] and AGC patients in a positive AGC. phase 1 study [31]. Based on the results of the phase 1 stud- ies, the Food and Drug Adiministration (FDA) approved T-DXd for AGC as breakthrough therapy designation, and Trastuzumab deruxtecan (T‑DXd; DS‑8201a) the “sakigake” designation scheme was applied in Japan. Subsequently, T-DXd was compared to the chemotherapy Antibody–drug conjugates (ADCs) are classified in a of physician’s choice (irinotecan or paclitaxel) in the rand- new entity of anti-tumor agents. Two ADCs, T-DXd and omized phase 2 trial, DESTINY-Gastric01 [32]. This trial T-DM1, have been approved for metastatic breast cancer in enrolled HER2-positive AGC patients in whom disease had the United States and Japan. T-DXd is an ADC containing progressed after 2 or more lines of chemotherapy including deruxtecan, a topoisomerase I inhibitor, as a payload with trastuzumab. The primary endpoint was met, with a signif- a high drug-to-antibody ratio (8:1), while T-DM1 contains cantly higher objective response rate (ORR) (51.3% versus emtansine with a drug-to-antibody ratio of 3.5:1. In T-DXd, 14.3%; p value < 0.0001), prolonged OS (median 12.5 versus the peptide linker is stable in plasma, but after adhesion 8.4 months; hazard ratio [HR] 0.59; 95% confdence interval and internalization into cancer cells, the peptide linker is [CI] 0.39–0.88; p value 0.0097) and progression-free sur- cleaved by lysosomal enzymes releasing deruxtecan, which vival (PFS) (median5.6 versus 3.5 months; HR 0.47; 95% has higher anti-tumor activity than irinotecan [21–25]. In CI 0.31–0.71; p value 0.0003). As a result, T-DXd has been contrast, emtansine is less active for GC compared to other approved as salvage-line chemotherapy for HER2-positive malignancies [26], and it has a weaker anti-tumor efect AGC in Japan. However, it is necessary to pay attention in gastric cancer mouse models than deruxtecan. Notice- to adverse events of T-DXd such as grade ≥ 3 neutropenia ably, T-DXd has anti-tumor efects in HER2-negative tumor (51.2%), anemia (37.6%) and thrombocytopenia (11.2%). Of cells that are close to their HER2-positive counterparts [27, note, interstitial lung disease (ILD)/pneumonitis occurred 28]. When internalized T-DXd kills HER2-positive tumor in 9.6% of patients. Most ILD were low grade (9 out of 1 3 Trastuzumab deruxtecan for the treatment of HER2-positive advanced gastric cancer: a clinical… 569 T-DXdbinds to HER2 protein T-DXdinternalized in cell Release deruxtecan HER2-positive tumor cell Peptide linker Anti-tumor effect Deruxtecan released into intercellular spaces after cell death Transfer to neighboring HER2-negative tumor cells (Bystander killing effect) Trastuzumab deruxtecan (T-DXd) HER2-negative tumor cell Anti-tumor effect Fig. 1 Graphical overview of trastuzumab deruxtecan (T-DXd). enzymes releasing deruxtecan. When internalized T-DXd kills human T-DXd is an antibody–drug conjugates (ADC) containing deruxtecan, epidermal growth factor receptor 2 (HER2) positive tumor cells, der- a topoisomerase I inhibitor, as a payload with a high drug-to-antibody uxtecan is released into intercellular spaces and then transferred to ratio (8:1). In T-DXd, the peptide linker is stable in plasma, but after neighboring HER2-negative tumor cells; so-called bystander killing adhesion to cancer cells, the peptide linker is cleaved by lysosomal efect 12 patients); grade 3 in 2 patients and grade 4 in 1 patient. cell-death ligand 1 (PD-L1) combined positive score ILD was observed less frequently in AGC than breast can- (CPS) ≥ 1 AGC [40]. In the Japanese Gastric Cancer Treat- cer (13.6%) [29].