Trastuzumab, Trastuzumab Deruxtecan Show Efficacy in HER2+ Solid Tumors

Trastuzumab and trastuzumab deruxtecan (T-DXd) are approved to treat several varieties of HER2-positive (HER2+) cancers. These cancers are HER2+ metastatic breast cancer, HER2-low and -ultralow metastatic breast cancer, any HER2+ metastatic solid tumor, HER2+ advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, and HER2-mutant metastatic non–small cell lung cancer.^1,2

At the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, new multifaceted analyses were presented on the clinical utility of trastuzumab and trastuzumab deruxtecan across a variety of settings in HER2+ gastric and GEJ cancers, a rapidly evolving field of research. Collectively, the findings underscore their roles as transformative standard-of-care options, moving from treatment for refractory cases toward earlier lines of intervention for HER2-driven malignancies.

Real-World Meta-Analysis of T-DXd³

These results demonstrated significant efficacy and manageable safety profiles across clinical trials and real-world gastric cancer data. The investigation was taken up because of limited real-world data on T-DXd’s efficacy and safety, even in light of its various approved indications, the authors explained. Using PubMed, Embase, Scopus, and ClinicalTrials.gov, they searched for studies that evaluated T-DXd in metastatic/recurrent gastric/GEJ cancers, and they included data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Across the 8 studies, 915 patients were represented; 3 of the studies were phase 2 clinical trials and 5 were retrospective investigations. Patients had a median age of 66.5 years (range, 27-89), and male patients predominated (75.4%). Asian was the most common ethnicity represented (70.4%). Eastern Cooperative Oncology Group performance status of 0 to 1 was more common vs 2 or higher (77.9% vs 21.8%). Intestinal adenocarcinoma was seen in 53.6% of the patients, and 22.9% had diffuse-type adenocarcinoma, with 77.6% having primary gastric tumors and 22.4% having GEJ tumors. IHC3+ status (75.8%) and IHC2+ status (22.4%) were well represented.

Positive results were seen across all disease outcomes: ORR, 47.7%; DCR, 82.5%; PFS, 4.92 months; OS, 9.86 months; and grade 3 AEs in less than half of patients (48.2%), although the rate of neutropenia (24.5%) was deemed significant. Discontinuation and dose reduction rates were also positive, at 12.2% and 21.5%.

HERALD and GOZILA Studies⁴

In this analysis, T-DXd produced superior survival outcomes compared with real-world physician's choice of treatments for HER2-amplified advanced solid tumors identified via cell-free DNA (cfDNA). CfDNA data from HERALD and GOZILA were utilized to gain a clearer understanding of T-DXd’s benefit, with the authors noting the challenges inherent in randomized trials of patients with HER2 advanced solid tumors. The primary end point was OS, and secondary end points were PFS and ORR among 104 (T-DXd arm, n = 62; physician’s choice comparator arm, n = 42) patients representing 18 cancers who were screened between December 2019 and January 2022. Patients in the comparator arm had at least 1 prior line of therapy and had initiated treatment within 2 months of their cfDNA collection. The median overall follow-up was 10.8 months.

Despite being well matched across age (64 and 63 years), sex (male, 48% and 67%), prior lines of treatment (3 in both arms), and plasma HER2 copy number (8.64 and 6.73), fewer patients in the physician’s choice arm vs the T-DXd arm received HER-2 targeted therapy (45.2% vs 100%). However, outcomes were superior across the board for OS, PFS, and ORR in the patients who received T-DXd:

• OS: 14.5 vs 4.6 months (HR, 0.44; 95% CI, 0.28-0.68)
• PFS: 6.6 vs 1.8 months (HR, 0.30; 95% CI, 0.20-0.46)
• ORR: 56.5% vs 11.9% (OR, 4.74, 95% CI, 2.02-11.11)

A subanalysis of just the patients with gastrointestinal cancers (55% in the T-DXd arm vs 95% in the comparator arm) produced similar results:

• OS: 10.8 months (T-DXd arm) vs 4.6 months (physician’s choice) (HR, 0.64; 95% CI, 0.39-1.06)
• PFS: 5.1 months vs 1.8 months, respectively (HR, 0.44; 95% CI, 0.27-0.72)
• ORR: 44.1% vs 12.5% (OR, 3.53; 95% CI, 1.43-8.71)

Phase 1 Investigation⁵

Adding trastuzumab for HER+ status to a first-line regimen of emavusertib plus folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and a PD-1 inhibitor (nivolumab or pembrolizumab) for metastatic or unresectable esophageal, GEJ, or gastric cancer has proven encouraging, these authors highlight. For their dose escalation/expansion investigation, their primary objectives are safety, toxicity, and recommended phase 2 dose of emavusertib plus FOLFOX/PD-1 inhibitor with or without trastuzumab. Treatment cycles are 14 days, during which emavusertib is given first at 150 mg twice daily and then 200 mg twice daily.

Among the 7 patients included in this analysis, 3 of whom initially received 150 mg and 4 of whom received 200 mg, there have been no dose-limiting toxicities. The expansion dose is the 200-mg dose of emavusertib. Four of the patients are HER-negative and 2 are HER2-positive in the expansion cohort; 1 patient was replaced for study nonadherence. No serious adverse events have been reported so far. Median time on study is 4.9 months (range, 0.5-25).

In the escalation phase, there has so far been 1 complete response, 1 partial response, and 1 case of stable disease in the patients receiving 150 mg; however, the patient who achieved the complete response did experience disease progression after 25 months. For the escalation and expansion phases, 2 partial responses and 4 cases of stable disease have been seen in the patients who are receiving 200 mg.

References

1. Enhertu (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi-Sankyo/AstraZeneca; 2025. Accessed January 14, 2026. https://www.enhertuhcp.com/en
2. Herceptin (trastuzumab). Prescribing information. Genentech; 2026. Accessed January 14, 2026. https://www.herceptin.com/patient/early-breast-cancer/about-herceptin/what-is-it.html
3. Batra N, Sukana M, Ammakola Y, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in HER2 positive advanced gastric/gastroesophageal junction cancer: a meta-analysis of real-world studies and clinical trials. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 402.
4. Mizuno T, Taniguchi H, Satoh T, et al. Comparative effectiveness of trastuzumab deruxtecan versus real-world treatment in HER2-amplified advanced solid tumors detected by cell-free DNA: an exploratory analysis of the HERALD and GOZILA study. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 833.
5. Phase 1 trial of emavusertib (CA-4948) in combination with FOLFOX/PD-1 inhibitor +/- trastuzumab for untreated gastric and esophageal cancer. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 417.