Beyond trastuzumab: redefining first-line HER2-positive gastroesophageal cancer with bispecific HER2 targeting

Why human epidermal growth factor receptor 2 (HER2)-positive gastroesophageal cancers still need better first-line therapy?

The therapeutic landscape of advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC) has evolved considerably over the past decade; however, outcomes remain suboptimal, even in biomarker-defined subsets. HER2-positive disease which accounts for approximately 15–30% of cases, has long been anchored to trastuzumab-based therapy following the landmark ToGA trial, which established trastuzumab plus platinum-fluoropyrimidine chemotherapy as the first biomarker-driven standard of care in metastatic GC/GEJC (1). For more than a decade, this regimen remained the sole frontline standard for patients with HER2-positive GC/GEJC. More recently, the addition of the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab to trastuzumab and chemotherapy in the pivotal phase III KEYNOTE-811 trial significantly improved progression-free survival (PFS) and overall survival (OS), particularly among patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1, establishing a new treatment benchmark (2). Despite these advances, durable responses remain limited, with key challenges being identified as HER2 heterogeneity, therapeutic resistance and incomplete target inhibition. This raises an important question: are we embarking on an era beyond trastuzumab, in which next-generation HER2-directed therapies may refine the frontline treatment paradigm for HER2-positive GC/GEJC?

Zanidatamab—a different way to target HER2

With this background, the phase 1b/2 study by Lee et al. (NCT04276493) evaluating zanidatamab in combination with tislelizumab and capecitabine plus oxaliplatin (CAPOX) as first-line treatment for patients with untreated advanced, metastatic or unresectable HER2-positive GC/GEJC, represents an important step toward redefining frontline therapy (3). Zanidatamab, previously also studied in HER2-positive biliary tract cancers (4), is a humanized bispecific antibody that simultaneously binds two non-overlapping HER2 epitopes (extracellular domain 2 and 4), promoting receptor clustering, enhanced internalization, and HER2 downregulation. This dual binding sets it apart from trastuzumab’s mechanism of action and may overcome mechanisms of trastuzumab- driven resistance related to receptor heterogeneity and incomplete HER2 inhibition. Additionally, zanidatamab activates potent immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity (5). Zanidatamab has shown strong preclinical activity in HER2-expressing gastric tumor cell lines compared with trastuzumab alone or in combination with pertuzumab (5), providing a strong rationale for clinical evaluation. The addition of tislelizumab, an engineered anti-PD-1 antibody designed to minimize Fcγ receptor binding on macrophages, theoretically augments antitumor immunity by preventing T-cell exhaustion while avoiding macrophage-mediated clearance of activated T cells (6). Together with chemotherapy, which forms the cytotoxic backbone, this combination may enhance antigen presentation and tumor immunogenicity.

Efficacy signals and contextualization with phase 3 data

The results reported by Lee et al. are noteworthy. Among 33 patients treated across two dosing cohorts (weight-based and flat dosing), the confirmed objective response rate (cORR) was 75.8%, the disease control rate was 100%, and the median duration of response (DoR) reached 23.3 months after a median follow-up of 30.1 months. More than a quarter of patients (27.3%) sustained responses exceeding 2 years. The median PFS of 16.7 months and median OS of 32.4 months, with a 24-month survival rate of 60.5%, are particularly encouraging in the context of a non-randomized study (3). By comparison, the KEYNOTE-811 trial reported a median PFS of approximately 10 months and a median OS of 20.0 months in the intent-to-treat population receiving pembrolizumab plus trastuzumab and chemotherapy (7). One notable distinction of this regimen from the KEYNOTE-811 approach is the replacement of trastuzumab with a biparatopic HER2-targeted agent in addition to adding immunotherapy to the chemotherapy backbone. This distinction raises the possibility that deeper HER2 inhibition, rather than immune modulation alone, may be critical in improving outcomes. While cross-trial comparisons must be interpreted with great caution due to differences in patient populations, geographic representation, sample size, and study design, the numerical advantage observed is substantial enough to warrant attention.

Recently, results from a global phase 3 trial (HERIZON-GEA-01) (NCT05152147), comparing chemotherapy (CT) plus trastuzumab (Arm A) versus CT plus zanidatamab (Arm B) or CT plus zanidatamab and tislelizumab (Arm C), were presented and published (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2517729). After a median follow-up of 25.9 months, the median OS in Arm C versus Arm A was 26.4 months and 19.2 months [hazard ratio (HR) 0.72; P=0.004] respectively, and in Arm B versus Arm A was 24.4 and 19.2 months (HR 0.80; P=0.056), respectively. The median PFS in Arm C versus Arm A was 12.4 and 8.1 months (HR 0.63; P<0.0001), respectively and in Arm B versus Arm A was 12.4 and 8.1 months (HR 0.65; P<0.0001), respectively (8,9). These results substantiate the findings reported by Lee et al., and the field eagerly awaits confirmation of whether this drug will alter the current treatment paradigm.

Pharmacokinetics (PK) and dosing considerations

An important practical contribution of this study is the PK characterization demonstrating comparable drug exposure between weight-based dosing (30 mg/kg) and flat dosing (1,800/2,400 mg based on a body weight threshold of 70 kg). The geometric means of key PK parameters, including AUC and maximum serum concentration (Cmax), were virtually identical across the two cohorts in both cycles 1 and 2. This finding supports the feasibility of a simplified flat dosing regimen, which may improve clinical adoption by reducing dosing errors and simplifying pharmacy preparation. However, whether dosing differences impact long-term efficacy or toxicity remains an open question that warrants further investigation in larger trials. The flat dosing regimen was subsequently adopted in the phase 3 HERIZON-GEA-01 trial, the results of which have since validated this approach.

Limitations and generalizability

Several limitations of this study warrant careful consideration when interpreting the results. Firstly, this is a small study with a sample size of only 33 patients. While the observed efficacy signals are robust, they remain hypothesis-generating and are susceptible to overestimation due to selection bias. The absence of a control arm further limits the ability to compare outcomes with current standards of care directly. The trial enrolled patients exclusively from China and Korea, and given the well-documented geographic variations in GC/GEJC clinical presentation, molecular subtypes, and treatment patterns, the generalizability of these findings to Western and other global populations must be approached with caution (10,11). The predominance of male patients (87.9%) and gastric primary tumors (84.8%) further limits the representativeness of the study population. Additionally, the study did not evaluate dynamic changes in HER2 and PD-L1 expression during treatment, an important limitation given evidence that HER2-targeted therapy can downregulate HER2 expression while upregulating PD-L1 (12), which could have provided valuable insights into mechanisms of resistance and optimal treatment sequencing strategies.

Safety profile and toxicity management

The safety profile, while described as manageable, warrants close scrutiny. Toxicity was substantial, with grade ≥3 treatment-related adverse events (TRAEs) occurring in two-thirds of patients (66.7%). Diarrhea was reported in 100% of patients and was the most common grade ≥3 TRAE, occurring in 27.3%, a notably higher rate than typically observed with trastuzumab-based regimens and likely attributable to zanidatamab’s unique mechanism of HER2 clustering and internalization. This represents a clinically meaningful burden that raises concern about tolerability in broader clinical practice without appropriate education. Reassuringly, no patients discontinued zanidatamab due to diarrhea. Mandatory antidiarrheal prophylaxis with loperamide appeared to attenuate the severity, with grade 3 treatment-related diarrhea occurring in 6 of 24 (25%) patients who received prophylaxis compared with 3 of 9 (33.3%) patients without prophylaxis. Similar rates of grade ≥3 diarrhea (20–24.5%) were reported in zanidatamab- containing arms of HERIZON-GEA-01, which incorporated the mandatory loperamide prophylaxis for the first 7 days (8). By contrast, the rate of grade ≥3 diarrhea with single-agent zanidatamab studied in biliary tract cancer was 5% (4). These observations support the incorporation of proactive antidiarrheal prophylaxis protocols in future trials and clinical practice when zanidatamab is combined with chemotherapy. Cardiac events, a well-known class effect of HER2-targeted therapies, were observed in a small number of patients (9.1% with grade ≥3 confirmed events), with no grade 4–5 cardiac events reported. Tislelizumab-related immune-mediated adverse events occurred in approximately one-third of patients (33.3%) but were generally manageable with established treatment algorithms. Fatal TRAEs were reported in two patients (6.1%), including one case of pneumonitis and pneumonia and one sudden death, attributed to combination treatment and capecitabine, respectively.

Biomarker considerations: PD-L1 and HER2 expression

From a biomarker perspective, several observations merit attention. Tumor responses were observed irrespective of PD-L1 expression status per tumor area positivity (TAP) scoring, whether using a 1% or 5% cutoff. The study was, however, not powered to evaluate PD-L1 as a predictive biomarker, the assessment was performed retrospectively, and the limited sample size precludes definitive conclusions. In the HERIZON-GEA-01 study, again, PD-L1 status was not a stratification factor. In the subgroup analyses, PFS benefit was reported across both PD-L1 groups (TAP <1% or ≥1%) with both zanidatamab containing arms versus CT plus trastuzumab. For OS in Arm C versus Arm A, the subgroup findings are counterintuitive given what is known about PD-L1 as a biomarker, with confidence intervals for the hazard ratio crossing 1 in the PD-L1-positive subgroup (8). It is important to note that TAP scoring, used in both the Lee et al. study and HERIZONE-GEA-01, is not interchangeable with the CPS methodology employed in KEYNOTE-811 and in current regulatory approvals of pembrolizumab-based therapy for HER2-positive GC/GEJC. However, Moehler et al. have reported strong concordance between TAP and CPS scoring (≥82%) across esophageal squamous cell carcinoma, GC/GEJC, and tislelizumab trials (13). The subgroup analyses per PD-L1 TAP scores in the HERIZON-GEA-01 study are certainly intriguing. It is sufficient to say that activity with zanidatamab is seen across tumors irrespective of PD-L1 status.

The issue of HER2 testing discordance between local and central laboratories, observed in six patients (18.2%), also deserves attention. All six centrally HER2-negative patients still achieved partial response or stable disease with target lesion shrinkage, raising the question of whether zanidatamab’s biparatopic binding allows it to retain efficacy across a broader range of HER2 expression levels than traditional monospecific antibodies. While clarification was anticipated from HERIZON-GEA-01, patients with HER2 2+ by immunohistochemistry and in-situ hybridization amplified disease comprised less than 20% of the total population, and the limited sample size has made interpretation of PFS and OS in this subgroup challenging (8). This pattern is not unique to GC/GEJC. Similar results have been reported for zanidatamab in biliary tract cancers, where overall response rate, median PFS and median OS are all markedly lower in the HER2 2+ cohort as compared to the HER2 3+ cohort (6% vs. 52%, 1.7 vs. 7.2 months and 5.2 vs. 18.1 months, respectively) (14). With more mature data and broader clinical experience, it may become clearer whether HER2 staining intensity influences outcomes with zanidatamab in HER2-positive GC/GEJC.

Conclusions

The combination of zanidatamab, tislelizumab, and chemotherapy represents a compelling approach to frontline treatment of HER2-positive GC/GEJC. The encouraging efficacy signals from this phase 1b/2 study, including a high response rate, durable responses, and a median OS exceeding 32 months, have been substantiated by the phase 3 HERIZON-GEA-01 trial, which demonstrated statistically significant improvements in both PFS and OS compared with trastuzumab-based therapy. These findings position zanidatamab as the first novel HER2-directed biparatopic antibody to outperform trastuzumab in a randomized setting and support a paradigm shift in first-line therapy for HER2-positive gastroesophageal adenocarcinoma. Moving forward, successful integration of zanidatamab into clinical practice will depend on careful management of the toxicity profile, particularly diarrhea, identification of biomarkers to guide patient selection, and defining optimal treatment sequencing in an increasingly competitive therapeutic landscape.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0471/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0471/coif). R.M. has served on advisory board for Amgen, Astellas, AstraZeneca, BeOne, BMS, Daiichi Sankyo, Gilead, Jazz Pharmaceuticals, Legend Biotech; has performed consulting services for Jazz Pharmaceuticals, Replimune; serves on the DSMB for Arcus Biosciences; and received Grant/Research Support from Robert A Winn Career Development Award. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are 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/.

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