
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01448-0
10.1016/j.esmoop.2024.103679
103679
Review
HER2-low gastric cancer: is the subgroup targetable?
Shimozaki K. 12
Fukuoka S. 1
Ooki A. akira.oki@jfcr.or.jp
1∗
Yamaguchi K. 1
1 Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo
2 Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
∗ Correspondence to: Dr Akira Ooki, Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-3, Koto-ku, Tokyo, Japan. Tel: +81-3-3520-0111; Fax: +81-3-3520-0111 akira.oki@jfcr.or.jp
22 8 2024
9 2024
22 8 2024
9 9 103679© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Therapeutic developments in the targeting of human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer have followed the dramatic success of HER2-expressing breast cancer treatment, which has facilitated the expansion of indications for anti-HER2 agents to include not only conventional HER2-positive breast cancer, but also HER2-low and HER2-ultralow subgroups. The targetability of HER2-low gastric cancer, however, has yet to be established. Hence, further studies are needed to comprehensively understand the clinicopathological features, specific gene alterations, and distinct tumor immune microenvironment of HER2-low gastric cancer and compare them with those for HER2-positive or -negative gastric cancer. Antibody–drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable. In this context, a deeper understanding of the novel anti-HER2 agents, including antibody–drug conjugates, bispecific T-cell engager antibodies, and a combination of these agents, as well as new forms of immunomodulatory agents are also required. Redefining and re-categorizing HER2 status through not only immunohistochemistry/fluorescence in situ hybridization but also evaluating ERRB2 copy number gain or protein overexpression levels measured using DNA or RNA sequencing might be helpful for identifying populations with HER2-expressing tumors who would ideally benefit from anti-HER2 treatment. The current paper reviewed recent clinical trials, focusing particularly on HER2-low gastric cancer together with basic/translational findings, and discuss perspectives on further therapeutic development in the treatment of this distinct subgroup.

Highlights

• Treating HER2-low gastric cancer remains challenging given the limited efficacy of current HER2-targeted therapies.

• Comprehensive understanding of the biological and immunogenic features of HER2-low gastric cancer is needed.

• Antibody–drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable.

• Redefining and re-categorizing HER2 status may help identify those who would ideally benefit from anti-HER2 treatment.

Key words

HER2
trastuzumab deruxtecan
antibody–drug conjugate
bispecific antibody
gastric cancer
==== Body
pmcIntroduction

Approximately 15%-20% of patients with advanced gastric and gastroesophageal junctional cancers (AGCs) exhibit overexpression or amplification of human epidermal growth factor receptor 2 (HER2, also known as ERBB2), a transmembrane tyrosine kinase receptor encoded by the ERRB2 gene located in chromosome 17q12, which has been established as an important biomarker and key driver of tumorigenesis in AGC.1 Similar to that in breast cancer, HER2 status of AGCs is typically determined via immunohistochemistry (IHC) and in situ hybridization (ISH). The ToGA trial found that trastuzumab, a monoclonal antibody targeting HER2, significantly improved overall survival (OS) when combined with chemotherapy for HER2-positive AGC,2 defined as HER2 IHC 3+ or 2+/fluorescence in situ hybridization (FISH)-positive, by inducing direct cytostatic activity and antibody-dependent cellular cytotoxicity (ADCC), which inhibited HER2-mediated signaling and prevented the cleavage of the extracellular domain (ECD) of HER2.3 The success of the ToGA trial promoted the use of trastuzumab plus chemotherapy as the first-line treatment of HER2-positive AGCs worldwide.

Among the subgroups of HER2-positive AGCs, ‘HER2-low’ AGCs, which are usually defined as IHC 2+ and FISH-negative or IHC 1+ in accordance with HER2-low breast cancer, have not shown any benefit from anti-HER2 therapy in decades. In fact, the post hoc analysis of the ToGA trial2 revealed that although chemotherapy plus trastuzumab significantly improved the OS of patients with HER2-positive AGCs [hazard ratio (HR) for death, 0.65; 95% confidence interval (CI) 0.51-0.83], no such trend was observed in patients with HER2 IHC 0 or 1+ and FISH-positive AGCs (HR, 1.07; 95% CI 0.70-1.62). Moreover, a significant interaction was observed between trastuzumab efficacy and these two groups (P = 0.036). Such disappointing results of the ToGA trial had prompted HER2-low gastric cancer to be recognized as equal to HER2-null (IHC 0) and collectively managed as ‘HER2-negative’. Hence, HER2-low AGCs have not been the subject of therapeutic development and have largely been considered untargetable.

Recently, HER2-low status in solid tumors has gained the spotlight with the appearance of antibody–drug conjugates (ADCs) targeting HER2 in breast and gastric cancer. The efficient and selective cytotoxicity of ADC payloads being internalized into HER2-positive tumor cells, as well as its bystander killing effect, is distinctive and crucial to inducing apoptosis of adjacent HER2-low-expressing tumor cells and HER2-nonexpressing tumor cells. Moreover, ADCC can modulate the tumor microenvironment and improve the efficacy of immunotherapy for so-called ‘immuno-cold’ gastric cancer.4,5 Thus, the positivity surrounding the therapeutic development of ADCs has broadened in recent years, and we expect that HER2-low gastric cancer could be also a candidate for anti-HER2-targeting strategies.

This review outlines the clinical features, evidence, and challenges related to targeting HER2-low gastric cancer and discusses the future perspectives for this distinct subgroup. In the following sections, we have categorized ‘HER2-high’ status as IHC 3+ or 2+/FISH-positive, ‘HER2-low’ status as IHC 2+/FISH-negative or 1+, and ‘HER2-null’ status as IHC 0 for convenience.

Success in broadening the indications of HER2-targeted therapy in breast cancer

Initial studies on the therapeutic development surrounding the targeting of the HER2-low subgroup had first emerged in breast cancer. DESTINY-Breast04 was a global phase III trial that evaluated the efficacy and safety of trastuzumab deruxtecan in 866 chemotherapy-naive patients with hormone receptor-positive, HER2-low metastatic or recurrent breast cancer previously treated with endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in comparison to the investigator’s chemotherapy of choice.6 Notably, the mentioned study revealed a significant and clinically meaningful improvement in the progression-free survival (PFS) of the treatment group (HR, 0.51; 95% CI 0.40-0.64; P < 0.0001).6 Similarly, the treatment arm showed a significant improvement in OS compared with the standard arm (HR, 0.64; 95% CI 0.48-0.86; P = 0.003). The efficacy of trastuzumab deruxtecan was consistent across all subgroups, including those with HER2 1+ disease, which prompted the rapid approval of trastuzumab deruxtecan for the treatment of HER2-low breast cancer by the Food and Drug Administration (FDA).

In line with the aforementioned findings, ongoing discussions regarding the re-definition or subclassification of HER2 status in breast cancer are currently taking place. Notably, HER2 ‘ultralow’ has been characterized as HER2 IHC 0 with 0 to <1+ membrane staining. Estimates shown that ∼25% of hormone receptor-positive, ‘HER2-negative’ breast cancers are categorized as HER2-ultralow.7,8 Typically, these patients had not been identified as candidates for HER2-targeted drugs; however, the superiority of trastuzumab deruxtecan over chemotherapy in patients with hormone receptor-positive HER2-low and HER2-ultralow breast cancer is currently being evaluated in the confirmatory phase III DESTINY-Breast06 (NCT04494425).9 Based on available data, one can surmise that the identification of HER2-low breast cancer and its therapeutic development are quite far ahead of HER2-low gastric cancer.

Clinicopathological features and immunogenicity of ‘HER2-low’ gastric cancer

Although the clinicopathological features of HER2-low gastric cancer remain to be elucidated in detail, studies have shown that this subgroup of gastric cancer may have distinct biological behaviors and tumor microenvironment compared with HER2-high or HER2-null gastric cancer, thereby complicating treatment strategies. In the aforementioned ToGA trial,2,10 screening for HER2 2+ and FISH-negative or IHC 1+ disease revealed prevalence rates of 5.4% and 18.6%, respectively, for a total prevalence of 24%. Nakayama et al.,11 who compressively evaluated the clinicopathological features of 734 patients with advanced gastric cancer, found that the incidence of certain clinical factors, including intestinal-type histology, and the presence of liver metastases gradually increased in patients with HER2-null, -low, and -high and that the presence of peritoneal metastases was inversely correlated with serum carcinoembryonic antigen (CEA) levels according to the subgroups.11 Owing to the success of trastuzumab-containing chemotherapy, the prognosis of HER2-high gastric cancer has improved over the last decades; unfortunately, the prognosis of HER2-low gastric cancer remains poor.11,12 Other studies have reported similar trends in the clinicopathological characteristics and prognosis of HER2-low gastric cancer13,14 (Table 1). Unlike that in HER2-high gastric cancer,15 the association between HER2-low gastric cancer and other novel biomarkers, including claudin 18.2,16, 17, 18 mismatch repair deficiency and/or microsatellite instability, or fibroblast growth factor receptor 2b (FGFR2b),19, 20, 21, 22 have yet to be comprehensively investigated, highlighting the need for studies examining the significance of each biomarker for targeted treatment.Table 1 Clinicopathological features of patients with AGC according to HER2 status.

Characteristics	Comparison between HER2-low (IHC 2+/ISH+ or 1+) and HER2-high (IHC 3+ or 2+/ISH+) or HER2-null (IHC 0)	References	
Incidence, %	• 21%-24.7%

	11,13,14	
Age	• No tendency compared with HER2-high or HER2-null groups

	11,13,14	
Sex	• Male dominant

• Intermediate incidence compared with the HER2-high and HER-2 null groups

	11,13,14	
Location of primary tumor	• Stomach dominant, the incidence of EGJ primary is lower than that of HER2-high

	11	
Lauren classification	• 55.8% Diffuse-type histology

• Intermediate incidence compared with the HER2-high and HER-2 null groups

	11	
Disease status	• Incidence of metastatic disease at diagnosis is highest among the subgroups

	11	
Metastatic sites	• Intermediate incidence of peritoneal metastases compared with the HER2-high and HER2-null groups

• Intermediate incidence of liver metastases compared with the HER2-high and HER2-null groups

	11	
Prognosis	• Shorter survival than the HER2-high group and similar survival as the HER2-null group

• May benefit from addition of immune checkpoint inhibitor plus chemotherapy

	11,13,14	
Immunogenicity and tumor microenvironment	• Higher PD-L1 TPS than the HER2-null group

• IFN-γ gene signature more enriched than the HER2-high group

• Tumor microenvironment more immune-inflamed than the HER2-high group but similar to that in the HER-null group

	23	
dMMR/MSI status	• dMMR/MSI-high more frequent than the HER2-high group but similar to that in the HER2-null group

	13	
Gene alteration	• ERRB3, FGFR2, PIK3CA

	13	
Pathway analyses	• Cell cycle pathway more enriched than either group

• PI3K and TGF-beta signaling pathway more enriched than the HER2-high group

	13	
AGC, advanced gastric and gastroesophageal junctional cancer; dMMR, deficient mismatch repair; EGJ, esophagogastric junction; HER2, human epidermal growth factor receptor 2; IFN-γ, interferon-γ; IHC, immunohistochemistry; ISH, in situ hybridization; MSI, microsatellite instability; PD-L1, programmed death-ligand 1; PI3K, phosphoinositide 3-kinase; TGF-beta, transforming growth factor-β; TPS, tumor proportion score.

Data on specific gene alterations occurring in HER2-low gastric cancer have been quite limited. Notably, Lee et al.,13 who carried out genomic profiling of HER2-low gastric cancer using a targeted RNA sequencing panel, reported that the cell cycle, phosphoinositide 3-kinase (PI3K), and transforming growth factor-β (TGF- β) signaling pathways were more enriched in HER2-low tumors than in HER2-high tumors, suggesting a distinct pathway activation in the proliferation of HER2-low gastric cancer.13 No study, however, has yet fully investigated whether HER2-low gastric cancer harbors distinct clinicopathological features and genetic alterations compared with the HER2-null subgroup, which requires further scrutiny. The potential distinguishability of HER2-low gastric cancer from the HER2-null subgroup should be carefully discussed at present.

Some studies have suggested potential differences in tumor microenvironment and immunogenicity between HER2-low and HER2-high or HER2-null gastric cancers. After performing whole-exome sequencing and whole-transcriptome sequencing on 8678 gastric cancer samples, Alqahtani et al.23 reported that HER2-low gastric cancer expressed programmed death-ligand 1 (PD-L1) on tumor cells unlike HER-null cells and that the tumor mutational burden was significantly higher in the HER2-low subgroup than in the HER2-high or HER2-null groups, whereas the inconsistent result was reported in other studies. They also revealed distinct gene alteration profiles between the HER2-low and HER2-high subgroups, suggesting that TP53 mutation and amplification of MYC, CCNE1, CCND3, CDK6, SMARCE1, and RARA were more frequent in the HER2-high group, whereas ARID1A, PIK3CA, KRAS, GNAS, KMT2D, CDH1, and ATM mutation rates were more frequent in the HER2-low group. Gene signature analysis revealed an association between HER2-low gastric cancer and immune gene expression. Furthermore, high immunogenic profiles such as tumor infiltration of immune cells, including B cells, CD8+ T cells, natural killer (NK) cells, and cytotoxic lymphocytes, were observed in HER2-low tumors, suggesting that HER2-low gastric cancer might have a distinct tumor microenvironment compared with HER2-high gastric cancer. These findings support the possible efficacy of introducing immunotherapy for the treatment of this subgroup. In fact, a study by Lee et al.13 in a total of 1338 patients with gastric cancer in Korea reported that adding immunotherapy to chemotherapy under first-line settings would be more beneficial for those with HER2-low advanced gastric cancer than for those with HER2-null gastric cancer. Despite the lack of established data, further investigation might allow for the categorization of HER2-expressing gastric cancer according to tumor microenvironment and immunogenicity.

Current status of therapeutic development in HER2-low gastric cancer

In contrast to the accomplishments in the treatment of breast cancer, wherein various anti-HER2 drugs have been proven efficacious,24, 25, 26 several therapeutic strategies, including trastuzumab plus pertuzumab in combination with chemotherapy (JACOB trial27), lapatinib (an HER2 tyrosine kinase inhibitor) in combination with platinum-doublet chemotherapy or paclitaxel as first- or second-line treatment (TRIO-013/LOGiC trial28 and TyTAN trial29), and trastuzumab emtansine (T-DM1) (GATBY trial30), have failed to show any benefit in HER2-high gastric cancer, indicating the difficulties in targeting HER2-low gastric cancer via conventional approaches. KN026, a bispecific anti-HER2 antibody that can simultaneously bind HER2 domains II (pertuzumab binding site) and IV (trastuzumab binding site), showed limited efficacy against HER2-low-expressing gastric cancer compared with HER2-high-expressing gastric cancer.31 At the very least, single anti-HER2 antibodies, including trastuzumab, pertuzumab, and their combinations, cannot obviously be expected to exert sufficient antitumor effects in HER2-low gastric cancer.

Trastuzumab deruxtecan showed excellent antitumor activity in mouse xenografts with low HER2 expression and was more effective than another ADC formulation conjugated with a similar topoisomerase I inhibitor at half the dose. These results suggest that the high drug–antibody ratio of trastuzumab deruxtecan can deliver a sufficient payload to cancer cells and exert its effects, even in those with low HER2 expression.32 Using mice inoculated with a mixture of HER2-expressing and HER2-nonexpressing cells, trastuzumab deruxtecan, but not T-DM1, was highly efficacious in mice inoculated with a mixture of HER2-expressing and HER2-null cells, whereas trastuzumab deruxtecan was expected to be more effective against tumors with heterogeneous HER2 expression given the stronger bystander killing effect of the bound cytotoxic drug on neighboring cells.32 Thus, available findings suggest that next-generation ADCs with enhanced drug reach and ADCC activity may play a central role in the development of treatments of HER2-low solid tumors, including gastric cancer. ARX788 is another anti-HER2 ADC consisting of an HER2-targeting antibody and a cytotoxic tubulin inhibitor amberstatin (AS269) with a drug to antibody ratio of 2, which is site-specifically conjugated to the antibody using a highly stabilized linker.33,34 The payload released after improving the intracellular processing of ARX788 and ARX788 minimized systemic exposure to the free payload34,35 and exhibited antitumor activity in HER2-low expression gastric cancer patient-derived xenograft models.33

The clinical antitumor activity of trastuzumab deruxtecan had also been observed in patients with HER2-null (but HER2-mutated) non-small-cell lung cancer (DESTINY-Lung 01), with only HER2-null non-small-cell lung cancer showing a complete response.36 Accordingly, some studies have reported on the efficacy of ADC for HER2-low gastric cancer. In the exploratory cohort of the phase II DESTINY-Gastric 01 trial, heavily pretreated patients with HER2 IHC 2+ and FISH-negative gastric cancer confirmed via central laboratory testing (cohort 1, n = 21) and those with HER2 IHC 1+ gastric cancer (cohort 2, n = 24) were enrolled and treated with trastuzumab deruxtecan.37 The mentioned study confirmed an objective response rate (ORR) of 26.3% (95% CI 9.1% to 51.2%) and 9.5% (95% CI 1.2% to 30.4%), a median PFS of 4.4 months (95% CI 2.7-7.1 months) and 2.8 months (95% CI 1.5-4.3 months), and a median OS of 7.8 months (95% CI 4.7 months-not reached) and 8.5 months (95% CI 4.3-10.9 months) in cohorts 1 and 2, respectively. Although the mentioned study provides preliminary evidence for the validity of targeting HER2-low gastric cancer, the efficacy of trastuzumab deruxtecan for HER2-low gastric cancer still remains insufficient when compared with its efficacy for HER2-low breast cancer, highlighting the strong need for improvements in the treatment approaches or drug development for HER2-low gastric cancer. The exploratory biomarker analysis of the DESTINY-Gastric01 trial found that a cut-off serum HER2 ECD value of 11.6 could stratify the response and OS in the HER2-low cohort.38 Moreover, clinical trials investigating trastuzumab deruxtecan monotherapy for HER2-low solid tumors have shown moderate efficacy, suggesting challenges in targeting HER2-low tumors other than breast cancer (Table 2). A novel ADC could effectively reach tumor cells even without overexpression of the targeted cell surface proteins. Furthermore, we may have only been observing the efficacy of deconjugated payloads circulating throughout the body,39 raising doubt as to whether HER2-low expression can truly drive tumorigenesis. Certainly, no apparent difference in efficacy had been noted between trastuzumab deruxtecan and irinotecan monotherapy for HER2-low gastric cancer.37,40 As such, next-generation ADCs or combinations of multiple agents with distinct modes of action could be key to targeting HER2-low cancers.Table 2 Efficacy of trastuzumab deruxtecan in HER2-low solid tumors.

Tumor types	Breast	Gastric	Colorectal	Biliary tract	Pancreatic	Endometrial	Cervical	Ovarian	Bladder	
Trial name	DESTINY-Breast046	DESTINY-Gastric0137,38	DESTINY-Colorectal0183	HERB84	DESTINY-PanTumor0285	
NCT	03734029	03329690	03384940	NA	04482309	
Phase	III	II	II	II	II	
Line	2 or 3	≥3	≥3	≥2	≥2	
HER2	2+/ISH− or 1+	2+/ISH−	1+	2+/ISH−	1+	2+/ISH− or 1+ or 0/ISH+	2+a	2+a	2+a	2+a	2+a	
ORR	52.6%	26.3%	9.5%	0%	0%	12.5%	5.3%	47.1%	40.0%	36.8%	35.0%	
Median PFS, months (95% CI)	10.1 (9.5-11.5)	4.4 (2.7-7.1)	2.8 (1.5-4.3)	2.1 (1.4-4.1)	1.4 (1.3-2.1)	4.2 (1.3-6.2)	2.8 (1.4-9.1)	8.5 (4.6-15.1)	4.8 (2.7-5.7)	4.1 (2.3-12.6)	7.8 (2.6-11.6)	
Median OS, months (95% CI)	23.9 (20.8-4.8)	7.8 (4.7-NE)	8.5 (4.3-10.9)	7.3 (3.0-NE)	7.7 (2.2-13.9)	8.9 (3.0-12.8)	4.9 (2.4-15.7)	16.4 (8.0-NE)	11.5 (5.1-NE)	13.0 (4.7-21.9)	13.1 (11.0-19.9)	
CI, confidence interval; HER2, human epidermal growth factor receptor 2; ISH, in situ hybridization; NE, not evaluable; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

a ISH not required for inclusion criteria.

Ongoing clinical trials for HER2-low AGC

Table 3 summarizes the clinical studies investigating the efficacy of HER2-targeted therapies for patients with gastric cancer, including the HER2-low cohort. As mentioned in the preceding text, next-generation ADCs, such as those capable of penetrating the tumor more efficiently and have enhanced bystander killing effects, involve combining ADCs with immune checkpoint inhibitors, including a novel and selective immunostimulant agent, T-cell-engaging bispecific antibodies that bring tumor cells with HER2 expression and T cells close, or some type of chimeric antigen receptor T-cell therapy (Figure 1).Table 3 Clinical trials targeting for HER2-low gastric cancer.

Drug	NCT	Phase	Inclusion criteria for the HER2-low group	Types of agents	Summary of the mechanisms of action, preclinical data, and clinical trial results	
Trastuzumab deruxtecan	03329690 (DESTINY-Gastric0137)	II	Cohort 1: IHC 2+/ISH−
Cohort 2:1+	ADC	• ORR: 26.2% (cohort 1), 9.5% (cohort 2)

• Median PFS: 4.4 months (cohort 1), 2.8 months (cohort 2)

• Median OS: 7.8 months (cohort 1), 8.5 months (cohort 2)

	
04379596 (DESTINY-Gastric0341)	Ib/II	IHC 2+/ISH− or IHC 1+	• T-DXd plus fluoropyrimidine and volrustomig (arm 3B)

• T-Dxd plus fluoropyrimidine and rilvegostomig (arm 4B)

	
05894824	I/II	IHC 2+/ISH− or IHC 1+	• T-DXd plus ramucirumab for second line

	
NA (EPOC2203)	I/II	IHC 2+/ISH− or IHC 1+	• T-DXd plus CAPOX and nivolumab for first line

	
SHR-A1811	04513223	I/II	IHC 2+/ISH− or IHC 1+	ADC	• Payload: SHR9265 (DNA topoisomerase 1 inhibitor)44

• 4/12 Patients achieved PR45

	
BL-M07D1	06031584	Ib/II	IHC 2+/ISH− or IHC 1+	ADC	• Payload: Ed-04 (DNA topoisomerase 1 inhibitor)46

	
RC48	05980481	II/III	IHC 2+/ISH− or IHC 1+	ADC	• Payload: monomethyl auristatin E50

• Potentially promotes STING pathway activation

• RC48 plus toripalimab: ORR 46%49

• RC48 plus toripalimab plus CAPOX for first line50

	
MRG002	05141747	II	IHC 2+/ISH− or IHC 1+	ADC	• Payload: monomethyl auristatin E51

• Antibody component MAB802 reduces antibody-dependent cell-mediated cytotoxicity with increased fucosylation of the Fc region of the antibody

	
IKS014	05872295	I	IHC 2+/ISH− or IHC 1+	ADC	• Payload: monomethyl auristatin F52

	
PRS-343	0519044558	II	Arm B: IHC 2+/ISH− or IHC 1+	Bispecific T-cell engager antibody	• HER2 binding domain and a CD137 binding domain57,86

• Preliminary efficacy and safety profile in monotherapy and in combination with atezolizumab for HER2+ solid tumors86

• PRS-343 in combination with tucatinib was investigated

	
SAR443216	0501355460	Ib	Dose expansion cohort: IHC 2+/ISH− or 1+, ERRB2 activating mutation	Trispecific T-cell engager antibody	• HER2 binding domain, a CD3 binding domain and a CD28 binding domain59,61

• Activating T cells and inducing T-cell-mediated cytotoxic activity

	
HF-K1	05861895	I	IHC 2+/ISH− or IHC 1+	Immunoliposome	• Immunoliposome of doxorubicin encapsulated by lipid membranes containing TL0162

• TL01 is a fragment conjugated lipid of trastuzumab Fab lesion

	
ADC, antibody–drug conjugate; CAPOX, capecitabine and oxaliplatin; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; STING, stimulator of interferon genes; T-DXd, trastuzumab deruxtecan.

Figure 1 Mechanisms of action of therapeutic agents investigated for HER2-low gastric cancer. HER2, human epidermal growth factor receptor 2; STING, stimulator of interferon genes.

Trastuzumab deruxtecan, an indisputable pioneer in the treatment of HER2-low gastric cancer, has been further investigated for its potential efficacy for HER2-low gastric cancer. Indeed, the ongoing phase Ib/II multi-cohort DESTINY-Gastric03 trial (NCT04379596) is currently evaluating the efficacy of trastuzumab deruxtecan in combination with fluoropyrimidine plus volrustomig, a novel programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) bispecific antibody, for the treatment of HER2-low gastric cancer (arm 3B).41 Although the WJOG7112G trial (T-ACT) found that trastuzumab in combination with paclitaxel had no significance beyond progression,42 the combination of trastuzumab with ramucirumab and paclitaxel for HER2-positive gastric cancer showed promising results, with an ORR, median PFS, and median OS of 54%, 7.1 months, and 13.6 months, respectively, suggesting the noteworthy efficacy of combining trastuzumab and anti-VEGF therapy.43 Moreover, a single-arm phase Ib/II trial is currently ongoing to evaluate the safety and efficacy of trastuzumab deruxtecan in combination with ramucirumab as second-line treatment of patients with HER2-low gastric cancer in Korea (NCT05894824). Another trial in Japan (jRCT2031230477) is investigating the efficacy of first-line trastuzumab deruxtecan in combination with nivolumab, capecitabine, and oxaliplatin (ESPOC2203) for HER2-low previously untreated gastric cancer.

Interestingly, one study showed that SHR-A1811, a novel ADC consisting of a humanized anti-HER2 IgG1 monoclonal antibody and a DNA topoisomerase I inhibitor (SHR9265) as a payload, with a high drug–antibody ratio of 6, showed excellent membrane permeability and strong cell killing activity in both HER2-high and -null cell lines when co-cultured, suggesting a bystander effect.44 In a phase I trial assessing the efficacy of SHR-A1811 for advanced gastric cancer with HER2 expression defined as IHC 1+, 2+, 3+ or ISH-positive, SHR-A1811 promoted tumor shrinkage in 12 patients with HER2-low gastric cancer, among whom 4 achieved a partial response (NCT04513223).45 Another study (NCT06031584) on BL-M07D1, a potent ADC with a payload containing the topoisomerase I inhibitor Ed-04,46 has been identifying the appropriate patient population, including those with HER2-low gastric cancer.

Disitamab vedotin (RC48) is a potent ADC with a novel anti-HER2 monoclonal antibody hertuzumab, which conjugates to monomethyl auristatin E (MMAE), and an improved bystander effect against tumor cells.47 Aside from direct cytotoxicity, RC48 potentially promotes antitumor immunity, including activation of the stimulator of interferon genes (STING) signaling pathway by inducing the release of damage-associated molecular patterns (DAMPs).48 This dual mechanism of action, namely direct cytotoxicity and immune activation, highlights the potential of RC48 for not only targeted therapy, but also stimulating antitumor immunity for HER2-low gastric cancer. A phase I trial evaluating the safety of RC48 plus toripalimab for HER2-expressing advanced gastric cancer showed that 12 of the 28 patients (43%) achieved complete or partial response, among whom 5 of the 9 patients with HER2-low gastric cancer had an ORR of 46%.49 The promising combination of RC48 plus toripalimab has been further investigated in front-line settings (NCT05980481).50

MRG002, another ADC composed of a humanized anti-HER2 monoclonal antibody conjugated to MMAE, via a valine–citrulline linker, showed antitumor activity in in vitro and in vivo xenograft models across various levels of HER2 expression.51 Moreover, MRG002 is currently being investigated for its efficacy against HER2-positive (cohort 1) and HER2-low (cohort 2) advanced gastric cancer (NCT05141747). Another study showed that IKS014, an experimental ADC with site-specific conjugation to the monomethyl auristatin F via an optimized linker, exhibited enhanced ADCC and complement-dependent cytotoxicity.52 Despite the insufficient data available, a phase I trial includes an experimental dose cohort of HER2-low gastric cancer (NCT05872295).

The STING signaling pathway might be impaired in ERRB2-amplified tumors.53 XMT-2056 is an HER2-targeted STING agonist ADC, a new form of ADC, that is designed to target a novel HER2 epitope (distinct from either pertuzumab or trastuzumab) and locally activate the STING signaling pathway in both tumor-resident immune cells and tumor cells.54 In vitro and in vivo studies have shown that XMT-2056 exhibited promising antitumor activity in gastric and breast cancer cell lines with various levels of HER2 expression when combined with trastuzumab, pertuzumab, or trastuzumab deruxtecan, partially due to its binding to non-overlapping epitopes of HER2 and complimentary mechanisms of action. The FDA has granted orphan drug designation to XMT-2056, and a phase I trial on the same is currently ongoing, although HER2-low tumors have not been included in this early clinical trial (NCT05514717).

Cinrebafusp alfa (PRS-343) is a first-in-class bispecific antibody–Anticalin fusion protein targeting HER2 and the costimulatory immune receptor 4-1BB on T cells. 4-1BB, also known as CD137, is a costimulatory immunoreceptor expressed on T cells, B cells, and NK cells that has been identified as a promising therapeutic target in preclinical and clinical studies; however, studies have shown that agonistic anti-CD137 antibodies cause severe toxicity induced by systemic immune activation, which has been recognized as a considerable challenge.55,56 PRS-343 has been designed to activate the 4-1BB pathway in a tumor-localized and -dependent manner by bridging 4-1BB-positive T cells with HER2-expressed tumor cells via novel bispecific antibody engineering.57 A phase I dose escalation study found that PRS-343 monotherapy was well tolerated and showed promising efficacy in patients with HER2-positive solid tumors. Thus, a multi-cohort phase II study is currently ongoing to evaluate the efficacy of PRS-343 as second-line treatment of patients with advanced gastric cancer (NCT05190445).58 This phase II trial seeks to evaluate the combination of PRS-343 and tucatinib for HER2-low gastric cancer. SAR443216,59,60 a trispecific CD3/CD28/HER2 T-cell engager designed to bind HER2-expressing tumor cells and CD3 and CD28 receptors expressed on T cells, is expected to induce enhanced and effective T-cell-mediated cytotoxic activity.61 Following up on the promising antitumor activity observed in in vitro and in vivo studies, a phase I trial dose escalation and expansion trial, which includes gastric cancer patients with HER2-low expression or HER2 activating mutations, is currently ongoing (NCT 05013554).

A completely new form of HER2-targeting agent including HF-K1, a trastuzumab Fab-conjugating immunoliposome that encapsulates doxorubicin inside the liposome lumen with a drug to lipid ratio of ∼230, is also under investigation for both HER2-positive and HER2-negative solid tumors. HF-K1 is expected to specifically deliver doxorubicin to HER2-expressing tumors while reducing toxicity. Given that HF-K1 has shown antitumor activity in xenograft models with HER2-low expression, a phase I trial on targeting HER2-low solid tumors is currently ongoing (NCT05861895).62

Current challenges and future perspectives

Researches have continued to debate whether ‘HER2-low’ gastric cancer could be distinguished from the HER2-null subgroup or targetable with anti-HER2 therapy. Although some novel exploratory agents have been investigated for HER2-low gastric cancer or solid tumors, their reported efficacy has still been unsatisfactory. The circumstances surrounding the discussion about the HER2-low subgroup involves very complicated issues. HER2-low gastric cancer slightly responds to anti-HER2 agents simply because only a few HER2-overexpressing tumor cells are blended in the majority of HER2 low-expressing or nonexpressing cells. Conversely, if at least some amount of the HER2 is expressed on tumor cells, ADCs with a high affinity can bind to HER2-expressing tumor cells, and its ‘bystander killing effect’ can actually kill nearby HER2-nonexpressing tumor cells. In this context, the degree to which the HER2 signaling pathway is involved in tumorigenesis may not matter for HER2-low tumors.

The differences between breast cancer and gastric cancer (and other solid tumors) should be recognized. For instance, HER2 is ubiquitous not only in breast cancer cells but also normal breast ductal cells, indicating that HER2 is usually expressed to some degree in breast cancer and that the lack of HER2 could reflect the low sensitivity of the diagnostic assay.63 Moreover, accurate evaluation and standardization of HER2 testing could be challenging, with variable results being obtained across different methods and pathologists. Differences in the IHC scoring for HER2 evaluation of gastric and breast cancers have also been observed given the distinct IHC staining pattern in both cancers, including the higher prevalence of tumor heterogeneity in gastric cancer (Table 4).64,65 The different IHC criteria for breast and gastric cancers may influence the incidence of ‘HER2-low’ gastric and breast cancers. These differences can also partially explain the differences in their potential responsiveness to anti-HER2 agents. HER2 IHC status does not accurately enrich responders to targeted drugs. In fact, the DESTINY-Breast 04 trial showed that patients with HER2 IHC 1+ disease who received trastuzumab deruxtecan had a PFS similar to those with HER2 2+ disease.6Table 4 Immunohistochemistry criteria for breast and gastric cancers.

	Breast87	Gastric88	
Immunohistochemistry score	Biopsy or resection	Biopsy	Resection	
0	No staining; incomplete or faint/barely perceptible staining in ≤10% of tumor cells	No reactivity or membranous reactivity in any tumor cell	No reactivity or membranous reactivity in <10% of tumor cells	
1+	Incomplete or faint/barely perceptible in >10% of tumor cells	Cluster of five or more tumor cells with a faint/barely perceptible membranous reactivity irrespective of the percentage of tumor cells stained	Faint/barely perceptible membranous reactivity in ≥10% of tumor cells; cells are reactive only in a portion of their membrane	
2+a	Weak to moderate complete membranous staining in >10% of tumor cells	Cluster of five or more tumor cells with a weak to moderate complete, basolateral, or lateral membranous reactivity irrespective of percentage of tumor cells stained	Weak to moderate complete, basolateral, or lateral membranous reactivity in ≥10% of tumor cells	
3+	Complete intense circumferential membranous staining in >10% of tumor cells	Cluster of five or more tumor cells with a strong complete, basolateral, or lateral membranous reactivity irrespective of the percentage of tumor cells stained	Strong complete, basolateral, or lateral membranous reactivity in ≥10% of tumor cells	
a In situ hybridization testing should be ordered.

The heterogeneity of HER2-expressing gastric cancers also needs to be understood, including the intratumoral, intrapatient (discordance between primary and metastatic sites), and temporal (changes from HER2-high to HER2-low/null during anti-HER2 treatment and from HER2-low to HER2-high during anti-HER2-naive treatment) differences in HER2 status, particularly among those with HER2-low tumors.66, 67, 68, 69, 70, 71, 72 In the aforementioned DESTINY-Gastric01 trial, some patients diagnosed with HER2-low (and of course, trastuzumab-naive) cancer based on the archived tissue samples were subsequently found to have HER2-high disease when evaluated using tissues collected just before trastuzumab deruxtecan initiation, indicating the dynamics of HER2 status during trastuzumab-naive treatment and during trastuzumab-containing treatment in those with HER2-high tumors. Thus, the appropriate evaluation and re-evaluation of HER2 status could also influence the response to HER2-targeted therapy in HER2-expressing gastric cancer. For accurate evaluation, multiple biopsies from the proximal portion of the tumor might reliably determine HER2 protein expression status in gastric cancer.73 Despite these efforts, patients with initially HER2-low/null disease who we subsequently diagnosed with HER2-high disease on re-evaluation might not efficiently benefit from trastuzumab-containing chemotherapy.74

Currently, HER2 status is mainly evaluated using IHC, a qualitative method. A more accurate, comprehensive, and quantitative evaluation of HER2 status, however, could help with the identification of those with ‘HER2-low’ disease and prescription of more suitable treatment approaches for patients with HER2-low gastric cancer. The VARIANZ study revealed a discordance in HER2 evaluation between central and local assessments and suggested that patients locally assessed to have HER2-positive gastric cancer do not respond to trastuzumab-containing regimen when central assessment confirmed HER2-negative cancer.75 This indicates potential discordance in conventional IHC assessment between pathologists, which could directly affect the efficacy of anti-HER2 treatment. In addition, the percentage of HER2-expressing tumors, HER2/CEP17 ratio, and HER2 mRNA expression levels were increased in patients with HER2 positivity confirmed via both central and local assessments, indicating the need for optimal thresholds for each marker. Through whole-transcriptome sequencing, Hashimoto et al.76 revealed that HER2 positivity via IHC does not adequately capture HER2 mRNA overexpression. Additionally, they found that a certain percentage of HER2-negative tumors harbor high HER2 mRNA expression.76 Therefore, our findings suggest the need for modifying current diagnostic criteria or adapting novel diagnostic modalities that can quantitatively assess HER2 expression status, including mRNA expression and circulating tumor DNA-based sequencing assays.77

After the success of trastuzumab for HER2-high gastric cancer, HER2 has established itself as the leading target for therapies against gastric cancer. In the past few years, HER2 has grown its position to become the next frontier in the treatment of breast cancer, with the appearance of trastuzumab deruxtecan. Ever increasing attention has also been placed on the therapeutic development of advanced gastric cancer. As widely acknowledged, conventional anti-HER2 antibodies have limited efficacy for HER2-low or HER2 heterogeneous gastric cancer, suggesting a distinct magnitude of dependency on the HER2 signaling pathway between HER2-expressing gastric cancer and breast cancer. The novel therapeutic agents, especially some forms of ADCs,39 certainly play a key role in overcoming the difficulties associated with targeting HER2-low gastric cancer, with signs of improvement in the treatment of HER2-low gastric cancer actually beginning to emerge.78 In addition, the combination of an anti-HER2 agent and new types of immune-activating methods have shown promising efficacy in early-phase clinical trials, and a completely new form of antibodies could efficiently bring immune cells to HER2-low cancer cells. Fortunately, the success achieved in the treatment of not only HER2-low but also HER2-ultralow breast cancer can provide valuable insights into the treatment of HER2-low gastric cancer.79, 80, 81, 82

We recognize that the management of HER2-low gastric cancer as a distinct subgroup remains challenging due to its relatively low incidence, intratumoral heterogeneity, or cross-pathologist discrepancy. In this context, the development of comprehensive therapies against ‘HER2-expressing’ gastric cancer is strongly desired, and redefining the HER2 status based on more refined, quantitative, and comprehensive methods for evaluating HER2 expression and/or amplification using comprehensive assays, rather than the current diagnostic modalities according to IHC and FISH, could help expand the targetable HER2 subgroup and maximize the true potential efficacy of each novel agent.

Conclusion

Our review highlights the current position and challenges of HER2-low gastric cancer, revealing that treating HER2-low gastric cancer remains challenging given the limited efficacy of current HER2-targeted therapies and validity of classifying or assessing HER2 status in gastric cancer. Owing to novel therapeutic agents, including ADC, bispecific antibody, or immunotherapy, HER2-low gastric cancer can be defined as the least ‘targetable’ subgroup. Further studies are needed, however, to investigate the biological differences between HER2-low and -null gastric cancers. Enhanced and standardized diagnostic methods and criteria may be required to accurately categorize HER2 status into high, low, and null. The association between HER2-low status and other established biomarkers in gastric cancer should be investigated in detail to comprehensively understand their therapeutic targetability. To optimize and maximize the efficacy of HER2-targeted treatment of HER2-low gastric cancer, the development of biomarkers that predict responses to HER2-targeting agents in HER2 low-expressing tumors could be also helpful. We emphasize the need for a deeper understanding of not only the tumorigenesis and distinct tumor immune microenvironment of HER2 low-expressing tumors, but also the characteristics of anti-HER2-targeted agents and their mode of action in redefining this subgroup as ‘targetable’ and ‘distinguishable’ and managing this distinct subgroup through a definitive approach.

Funding

None declared.

Disclosure

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AO received speaker honoraria from Merck Serono, Chugai, Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo, and Ono Pharmaceutical. KY received speaker honoraria from Chugai Pharmaceutical Co. Ltd, Bristol-Myers Squibb, Merck Serono, Takeda, and Eli Lilly, and received consultant fee from Takeda Pharmaceutical Co. Ltd., and honoraria from Tsumura Co. Ltd., Nihon Kayaku Co. Ltd., and Chugai Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.
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