Advancing precision oncology for esophagogastric cancer in the era of antibody-drug conjugates

Esophageal and gastric cancers represent the 5^th and 7^th leading cause of global cancer deaths, respectively (1). The HER2 gene is a key driver of tumour growth and is overexpressed in up to 30% of gastroesophageal esophagogastric adenocarcinomas (GEAs) (2). In GEA, HER2-targeted therapies are associated with improved outcomes but patients eventually progress often due to the loss of ERBB2 amplification and subsequent loss of dependence on the ERBB2-signaling pathway (2). After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan (T-DXd) in the refractory space have more recently changed clinical practice (2).

The investigators of the DESTINY-Gastric04 trial build upon the early efficacy findings from the phase II T-DXd studies in Asia (DESTINYGastric01 and DESTINY-Gastric06) (3,4), USA and Europe (DESTINY-Gastric02) (5) which led to its approval in multiple countries for the treatment of patients with unresectable or metastatic HER2-positive gastric cancer (mGC) or gastroesophageal junction adenocarcinoma (GEJA) who had previously received trastuzumab-based therapy. However, the absence of a global confirmatory phase III trial had limited access to or reimbursement for T-DXd in certain countries, leaving some patients unable to receive this active agent. Hence, the DESTINY-Gastric04 was intended as a confirmatory phase III trial of T-DXd as second-line therapy to allow broader access of this treatment to patients around the world. Here the investigators compared T-DXd with ramucirumab (an anti-vascular endothelial growth factor receptor 2 antibody) and paclitaxel which is another standard second-line treatment option for patients with advanced or metastatic gastric cancer regardless of HER2 status (6). All patients with mGC or GEJA underwent re-biopsy after progressing on first line trastuzumab and before enrolling on the trial to assess retention of HER2 positive status. This is an important consideration since ~30% of patients (7,8) lack HER2 expression after treatment with trastuzumab. Most patients had high levels of HER2 [immunohistochemistry (IHC) 3+] expression as noted in ~84% of the cohort. Among 494 previously untreated patients randomized 1:1 to T-DXd and ramucirumab-paclitaxel arms, median progression-free survival (PFS) was modestly improved to 6.7 vs. 5.6 months [hazard ratio (HR), 0.74; 95% confidence interval (CI): 0.59–0.92, P=0.007]. However, the trial successfully reached its primary end point of improvement in median overall survival (OS) comprising of 14.7 months in the T-DXd cohort vs. 11.4 months in the ramucirumab-paclitaxel cohort (HR, 0.70; 95% CI: 0.55–0.90, P=0.004). Confirmed objective response rates (ORRs) were 44.3% in the T-DXd group and 29.1% in the ramucirumab-paclitaxel group. The incidence of ≥ Grade 3 treatment related adverse events (TRAEs) was 50.0% in T-DXd patients and 54.1% in ramucirumab-paclitaxel patients, treatment related patient deaths were noted in 4 (1.6%) and 2 (0.9%) patients, respectively. Interstitial lung disease and pneumonitis are important adverse events associated with T-DXd therapy which were mainly low grade (Grade 1–2) in nature owing to proactive monitoring of symptoms and early management with glucocorticoids.

The investigators are to be commended for conducting this trial in a challenging patient population with several strengths relevant to current clinical practice. The DESTINY-Gastric04 trial was an international, open-label, randomized phase III study comprising of 494 participants across Europe, Asia, and the United States, thereby offering substantial generalisability. The inclusion of patients from diverse ethnic backgrounds, along with the balanced distribution of demographic variables, molecular and disease characteristics, and comparison of early progressors with respect to duration of first line trastuzumab (<6 vs. ≥6 months) across treatment arms, strengthens the study’s internal and external validity. Additionally, most patients received treatment from the opposing arm as a post-trial therapy, and the overall efficacy findings were retained after accounting for this balance in post-trial anti-cancer regimen. OS analyses adjusting use of subsequent treatments reinforced the robustness of the results, with an adjusted OS HR of 0.64 to 0.67. These methodological features can be useful to minimize confounding and selection bias, facilitating more robust and reliable comparisons of treatment effects. However, it should be emphasized that although the investigators conducted prespecified sensitivity analyses and employed a rank-preserving structural failure time model (RPSFTM) to adjust for the impact of subsequent therapies which reportedly reinforced the OS benefit of T-DXd, it remains difficult to fully exclude confounding from post-progression treatment in a setting where T-DXd and other active agents are widely accessible. While the RPSFTM offers a more rigorous method to account for treatment crossover, its accuracy depends on assumptions that are inherently untestable, including a constant treatment effect over time and across subgroups. Given the modest PFS difference relative to the more pronounced OS gain, these findings should be interpreted with caution. Additionally, heterogeneity in subsequent therapy use, treatment sequencing, and supportive care practices—such as variations in immunotherapy access, chemotherapy dosing, or palliative interventions—may have contributed to OS prolongation independent of the assigned second-line regimen. Overall, this trial has meaningfully improved outcomes for esophagogastric cancer patients and represents an important milestone in development of the leading antibody-drug conjugates (ADCs) therapeutic asset.

In terms of treatment efficacy, the greater percentage of patients with response to T-DXd than ramucirumab-paclitaxel may have contributed to their extended OS. More specifically, there is a notable extension of the duration of response (DOR) at the 12-month timepoint; 30% in T-DXd arm vs. 15% in ramucirumab-paclitaxel arm. In addition, the combination of trastuzumab and pembrolizumab with a platinum-based doublet chemotherapy from KEYNOTE-811 has been established as the new standard of care for first-line treatment of HER2-positive and programmed death-ligand 1 (PD-L1) combined positive score ≥1 mGC or GEJA (9). The DESTINY-Gastric04 subgroup analysis demonstrated a consistent benefit in both PFS and OS, irrespective of prior exposure to immune checkpoint inhibitors. Moreover, the sustained and confirmed ORRs of T-DXd across multiple previous trials suggest that prior treatment history does not significantly alter its efficacy (10,11). These collective findings underscore the effectiveness of T-DXd as the next line treatment following the KEYNOTE-811 regimen.

Subgroup analysis from the DESTINY-Gastric04 trial has further demonstrated relatively higher PFS (6.9 with T-DXd vs. 5.5 months with ramucirumab-paclitaxel) and significantly pronounced improvement in OS (18.0 with T-DXd vs. 11.5 months with ramucirumab-paclitaxel) specifically among gastroesophageal junction (GEJ) patients. GEJ tumours more frequently exhibit HER2 overexpression compared to gastric cancers (12,13), where T-DXd efficacy is positively correlated with HER2 expression density leading to these improved outcomes. Interestingly, the investigators also note an OS benefit with T-DXd use than compared to ramucirumab-paclitaxel in patients with ≥2 metastatic sites at baseline (14.7 vs. 10.4 months, respectively). The study reported ~70% of patients harbouring ≥2 metastatic sites at baseline, with ~60% of study patients containing liver metastasis. Previous studies suggest a greater rate of HER2 positivity in patients with liver metastasis (14) and non-peritoneal metastases in multiple organs (15). Therefore, differences in these OS outcomes may have been partly affected by the distribution patterns of anatomic sites of disease with variation in HER2 expression levels. Patients with HER2 IHC 2+/ISH+ (in situ hybridization+) tumors demonstrated a pronounced OS benefit with T-DXd compared to ramucirumab-paclitaxel (17.7 vs. 7.4 months; HR, 0.35; 95% CI: 0.18–0.66), despite a more modest and statistically nonsignificant PFS improvement (4.4 vs. 3.6 months; HR, 0.64; 95% CI: 0.37–1.11). In contrast, the IHC 3+ subgroup depicted a slight trend (albeit nonsignificant) towards improved OS (14.4 vs. 13.4 months; HR, 0.79; 95% CI: 0.61–1.03) with a significant PFS benefit (6.7 vs. 5.6 months; HR, 0.76; 95% CI: 0.60–0.97). While the limited sample size of the IHC 2+/ISH+ cohort likely contributes to these findings, differential treatment tolerance may also play a role. Improved adherence or fewer dose interruptions in this subgroup could have facilitated prolonged exposure to T-DXd, thereby enhancing survival outcomes. Additionally, tumor heterogeneity within the IHC 2+/ISH+ population, including variable HER2 expression levels not fully captured by biopsy sampling, may have led to a subset of patients deriving substantial benefit, thereby amplifying the observed OS advantage. T-DXd administration also led to improved OS in European patients as compared to ramucirumab-paclitaxel (15.9 vs. 11.0 months) but not in Asian patients (14.4 vs. 14.6 months). Although overall HER2 positivity rates in these two patient populations tends to be similar (16), other speculative reasons explaining this result could include more homogeneous intratumoral HER2 expression in European patients (17), and differences in histologic subtypes (intestinal vs. diffuse) which affect HER2 expression (18). Regional differences in access to post‑trial therapies may partly explain the higher OS of T-DXd in European patients. In the AVAGAST trial, postprogression chemotherapy was administered to 37% of Western European patients versus only 14% in eastern Europe, with higher rates in Asia (61–77%) (19). Such disparities in subsequent therapy likely influenced survival, suggesting that differential access to effective post‑progression treatments contributes to observed regional OS differences.

The rate of TRAEs prompting dose reduction or discontinuation was similar across both study arms. However, TRAEs dose interruptions were lower in T-DXd (38.5%) vs. ramucirumab-paclitaxel group (51.1%). In contrast, higher interruption rates in the ramucirumab-paclitaxel arm may have reduced cumulative dosing. This can compromise efficacy—especially with cytotoxics such as paclitaxel which depend on regular scheduling. While the impact on efficacy is multifactorial, several factors may have contributed to the observed differences. The relatively longer median T-DXd treatment duration (5.4 vs. 4.6 months) and longer DOR for T-DXd, together with fewer dose interruptions, suggest a partial contribution to improved efficacy. These findings may reflect improved treatment tolerance and potentially better maintenance of dose intensity in the T-DXd arm.

However, despite the clinical value of the DESTINY-Gastric04 trial, it is prudent to acknowledge the limitations of this study. In terms of treatment response, the DOR was investigator based and radiologic responses were most likely not standardized by central review, which predisposes outcomes to observer bias. With respect to treatment toxicity, although the T-DXd mechanism of action entails a bystander effect via its cytotoxic payload which can diffuse out of HER2+ cells and cause the death of neighbouring HER2-low or negative tumor cells (Figure 1). However, this can also harm nearby healthy tissue resulting in a notable toxicity profile as observed by the similar rate of ≥ Grade 3 TRAEs in both arms. The similar rate of ≥ Grade 3 TRAEs and quality of life (QoL) scores in both study arms highlights that this effect is partly due to the relatively high dose of T-DXd (6.4 mg/kg) in the current study population. Improvements in T-DXd’s safety profile and patient QoL is essential to fully capitalize on its efficacy benefits as observed in the current study. Ongoing investigations using an attenuated T-DXd dose of 5.4 mg/kg in the DESTINY-Gastric05 will help determine if this clinical equipoise is achievable.

Figure 1 Mechanism of action of trastuzumab deruxtecan against HER2 tumour cells. T-DXd, trastuzumab deruxtecan.

Limited biomarker data was presented in the DESTINY-Gastric04 trial, although the study protocol indicates collection of baseline, on-treatment, and end-of-treatment biopsy specimens in addition to blood samples (for cell free DNA analysis). For future exploratory analysis, it would be of clinical value to identify patterns of resistance to first line trastuzumab using baseline biopsied specimens to determine their association with varying degrees of radiological clinical benefit with investigational ADCs. This would aid risk stratification and patient selection beyond HER2 scoring methods. Future efforts by the investigators may also entail utilization of available samples to perform additional, comprehensive correlative studies to evaluate possible biological drivers of T-DXd treatment response in the current clinical population. These would be ideally stratified by geographic region to better assess demographic influences on therapeutic outcomes. The authors may wish to share these exploratory findings in follow-up translational studies.

The current trial permitted use of both local and central laboratory tests to confirm HER2 positivity, but these can be discrepant in gastric/GEJ cancer (20) due to variability in techniques and interpretation of biopsy results by local laboratories. It remained equivocal as to whether the biopsies were derived from the primary tumour, metastatic lesions, or a combination of both sites of disease. This is an important caveat since HER2 status can lack concordance between primary tumour and disseminated disease (21), thereby limiting the utility of a tissue-based biopsy. HER2 status may not always be captured by a single tumour biopsy due to variation in HER2 expression owing to spatial and temporal heterogeneity (21). Hence, repeat tissue biopsies as performed in the current trial may not be feasible in real world clinical practice as there is the risk of subjecting a patient to an invasive procedure resulting in lack of retention of HER2 positive status. Additionally, it may not be possible to perform repeat biopsies in resource limited settings in routine clinical practice as it would add to the burden of financial toxicity in the current clinical population.

Serial circulating tumour DNA (ctDNA) profiling is expected to become a practical alternative when tissue re-biopsy is not feasible. These liquid biopsies can offer a minimally invasive, repeatable tool for screening, monitoring, and detection of recurrence-associated genomic alterations. Their utility is particularly evident when metastatic sites are inaccessible or high-risk for tissue sampling. According to the biomarker analysis from DESTINY-Gastric01, plasma HER2 amplification may serve as a useful guide for treatment selection, albeit performed in an Asian population heavily pre-treated with variable systemic agents (22). ctDNA based methods in trastuzumab refractory esophagogastric adenocarcinoma patients have demonstrated higher rates of ADC treatment response prediction in patients who were baseline ERBB2 amplification positive than in those who were negative (22), a finding further corroborated in other anti-HER2 agents (23). Moreover, ctDNA can capture genomic alterations associated with resistance mechanisms, enabling a more personalized patient management approach. However, the sensitivity of plasma-based detection for HER2 amplification remains suboptimal: ERBB2 amplification is concordant with only 45–57% of HER2-positive cases by immunohistochemistry, highlighting a key challenge for clinical implementation (22,23). This is partly driven by technical issues; ctDNA assays must contend with inherently low tumour-derived DNA fractions, particularly in settings of low disease burden or minimal shedding, which limits sensitivity for copy number alterations (24). Additionally, wide variability exists across platforms [digital polymerase chain reaction (PCR), next-generation sequencing (NGS), low-coverage whole genome sequencing] in terms of limit-of-detection, bioinformatics pipelines, input volumes and pre-analytical handling procedures (24), undermining reproducibility and cross-laboratory standardisation. From a clinical and operational perspective, ctDNA methods are not yet harmonised or regulatory-cleared for routine HER2 amplification screening, and quality assurance programmes and inter-laboratory proficiency testing remain nascent. Moreover, the cost and resource intensity of ultra-deep sequencing panels pose significant access barriers, especially in resource-limited settings. In the current environment of technical uncertainty and implementation variability, a negative ctDNA result cannot yet be considered sufficient to rule out HER2 positivity reliably, thereby limiting the suitability of ctDNA as a substitute for tissuebased HER2 assessment in advanced gastric/GEJ adenocarcinoma. Further technological advances are anticipated to overcome these current limitations before ctDNA can replace tissue-based assessment in the current clinical setting. Additional investigations are also warranted to validate whether plasma HER2 amplification could replace tissue IHC/ISH for HER2 scoring in the future. Finally, it is crucial for future investigations to assess implementation of well-defined response assessment methods that align with established guidelines and clinical practice (RECIST v.1.1), such as LB-RECIST for liquid biopsies (25).

Two notable HER2 directed ADCs have emerged in the GEA domain; disitamab vedotin and trastuzumab duocarmazine. Disitamab vedotin exerts its anti-tumour effects via its cytotoxic payload, monomethyl auristatin E, which disrupts the microtubule network of the cancer cell, leading to its death. This agent in combination with chemo-immunotherapies represents a promising alternative, particularly in earlier treatment lines and in HER2-low or moderate expression settings. Recent data from a phase II Chinese study in gastric cancer demonstrated ORRs of 72% and up to 82.4% in HER2 low and high patients, respectively (26). Trastuzumab duocarmazine, while mechanistically compelling (a trastuzumab-linked duocarmycin payload with a bystander effect), remains less advanced in the esophagogastric domain: its first-in-human phase I expansion included a small gastric cancer cohort and demonstrated modest activity (e.g., 6% ORR in 16 gastric cancer patients) and ocular toxicity as a signal (27). From a toxicity standpoint, each ADC has its specific profile; T-DXd’s lung toxicity risk demands vigilance; disitamab vedotin has a manageable safety profile in treatment combinations although long-term data are pending; and in trastuzumab duocarmazine ocular toxicities may limit dose intensity or adoptability. Notably, Byondis has deprioritised trastuzumab duocarmazine development in gastric/GEJ cancer, with current research efforts focusing on breast and endometrial cancers following regulatory setbacks in the breast cancer indication and potentially significant efficacy signals in the DESTINY-Gastric series of clinical trials. In comparing these agents, T-DXd currently offers the most robust evidence of survival benefit in the established HER2-positive second-line setting. Disitamab vedotin is expanding the therapeutic scope toward HER2-low and first-line disease while being explored in a phase III trial (NCT06944496), potentially expanding the eligible population. Trastuzumab duocarmazine, though biologically promising, may require renewed strategic focus and optimization. Several new HER2 directed ADCs such as zanidatamab zovodotin, ARX788, DP303c and BL-M07D1 are currently under investigation and emerging data will further clarify the role of T-Dxd in this increasingly dynamic therapeutic landscape.

Given the superiority of T-DXd over ramucirumab-paclitaxel, T-DXd can be advocated as the preferred, global standard of care for HER2 positive mGC/GEA in the second line setting. Patients with a HER2 negative status after first line trastuzumab can opt for ramucirumab-paclitaxel and T-DXd can be reserved for later treatment line settings. Ongoing studies will also delineate whether T-DXd in combination with chemo-immunotherapies will continue to evolve the esophagogastric treatment landscape in the first line (DESTINY-Gastric05) and perioperative (EPOC2003) settings.

The predictive forecasting role of ctDNA in clinical practice continues to evolve, although a confirmatory tissue biopsy would currently serve as a feasible option following trastuzumab failure in patients lacking HER2 amplification on ctDNA tests. Incorporation of ctDNA-based analyses in future trials is essential to elucidate resistance mechanisms to T-DXd and to inform rational design of combination regimens particularly where treatment sequencing must be considered. For instance, understanding how the type and duration of initial systemic therapies influence T-DXd sensitivity is critical to inform clinical decisions before commencing this treatment. Additional studies are utilizing the role of ctDNA as a prognostic marker for early intervention with T-DXd, such as the DECIPHER phase II trial assessing the effect of T-DXd on reducing micrometastatic disease burden in HER2 positive GEA patients who are ctDNA positive after chemotherapy and surgery. These strategies will further optimize the clinical application of T-DXd to improve outcomes in a challenging population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article has undergone external peer review.

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-28/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-28/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025;85:361-83. [Crossref] [PubMed]
3. Shen L, Chen P, Lu J, et al. 172P Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2-positive locally advanced/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary efficacy and safety from the phase II single-arm DESTINY-Gastric06 (DG06) trial. Ann Oncol 2023;34:S1542-S1543.
4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020;382:2419-30. [Crossref] [PubMed]
5. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol 2023;24:744-56.
6. Shitara K, Van Cutsem E, Gümüş M, et al. Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer. N Engl J Med 2025;393:336-48. [Crossref] [PubMed]
7. Seo S, Ryu MH, Park YS, et al. Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer 2019;22:527-35. [Crossref] [PubMed]
8. Pietrantonio F, Caporale M, Morano F, et al. HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research. Int J Cancer 2016;139:2859-64. [Crossref] [PubMed]
9. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer. N Engl J Med 2024;391:1360-2. [Crossref] [PubMed]
10. Janjigian YY, Oh DY, Rha SY, et al. Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03. J Clin Oncol 2022;40:295.
11. Shen L, Chen P, Lu J, et al. 129MO Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2-positive (HER2+) advanced gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric06 (DG-06) final analysis. Ann Oncol 2024;35:S1454-S1455.
12. Shan L, Ying J, Lu N. HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol 2013;8:76. [Crossref] [PubMed]
13. Rajagopal I, Niveditha SR, Sahadev R, et al. HER 2 Expression in Gastric and Gastro-esophageal Junction (GEJ) Adenocarcinomas. J Clin Diagn Res 2015;9:EC06-10. [Crossref] [PubMed]
14. Saito T, Nakanishi H, Mochizuki Y, et al. Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer. Gastric Cancer 2015;18:711-9. [Crossref] [PubMed]
15. Guchelaar NAD, de Neijs MJ, Noordman BJ, et al. The prognostic value of peritoneal metastases in patients with gastric cancer: a nationwide population-based study. EClinicalMedicine 2025;81:103109. [Crossref] [PubMed]
16. Kim WH, Gomez-Izquierdo L, Vilardell F, et al. HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study. Appl Immunohistochem Mol Morphol 2018;26:239-45. [Crossref] [PubMed]
17. Wakatsuki T, Yamamoto N, Sano T, et al. Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer. J Gastroenterol 2018;53:1186-95. [Crossref] [PubMed]
18. Lei YY, Huang JY, Zhao QR, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. World J Surg Oncol 2017;15:68. [Crossref] [PubMed]
19. Sawaki A, Yamada Y, Yamaguchi K, et al. Regional differences in advanced gastric cancer: exploratory analyses of the AVAGAST placebo arm. Gastric Cancer 2018;21:429-38. [Crossref] [PubMed]
20. Huemer F, Weiss L, Regitnig P, et al. Local and Central Evaluation of HER2 Positivity and Clinical Outcome in Advanced Gastric and Gastroesophageal Cancer-Results from the AGMT GASTRIC-5 Registry. J Clin Med 2020;9:935. [Crossref] [PubMed]
21. Pectasides E, Stachler MD, Derks S, et al. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov 2018;8:37-48. [Crossref] [PubMed]
22. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nat Med 2024;30:1933-42. [Crossref] [PubMed]
23. Catenacci DV, Kang YK, Uronis HE, et al. Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma. Oncology (Williston Park) 2023;37:176-83. [Crossref] [PubMed]
24. Zhao J, Reuther J, Scozzaro K, et al. Personalized Cancer Monitoring Assay for the Detection of ctDNA in Patients with Solid Tumors. Mol Diagn Ther 2023;27:753-68. [Crossref] [PubMed]
25. Martelli V, Vidal J, Gibert J, et al. Clinical validation of liquid biopsy-RECIST (LB-RECIST) in metastatic colorectal cancer (mCRC) patients: findings from the PLATFORM-B study. ESMO Open 2025;10:105760. [Crossref] [PubMed]
26. Shen L, Peng Z, Li C, et al. Disitamab vedotin (DV) plus toripalimab (Tor) and chemotherapy (C)/trastuzumab (Tra) as first-line (1L) treatment of patients (pts) with HER2-expressing locally advanced or metastatic (la/m) gastric cancer. J Clin Oncol 2025;43:LBA4012.
27. Banerji U, van Herpen CML, Saura C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 2019;20:1124-35. [Crossref] [PubMed]