A 63-year-old male patient diagnosed with human epidermal growth factor receptor 2-positive metastatic gastroesophageal junction adenocarcinoma achieved 23 months of progression-free survival following second-line therapy with the antibody-drug conjugate trastuzumab deruxtecan, according to a clinical report published in Frontiers in Pharmacology. The patient had previously experienced rapid disease progression after only 4.5 to 5.5 months on a standard first-line regimen consisting of trastuzumab, oxaliplatin, capecitabine, and the anti-programmed death-1 antibody sintilimab. Following the initiation of second-line trastuzumab deruxtecan administered at the standard dose of 6.4 milligrams per kilogram every three weeks, the patient completed 22 treatment cycles over nearly two years without requiring dose reductions. The observed progression-free interval substantially exceeded the median progression-free survival of 5.6 months recorded in the pivotal randomized phase 3 DESTINY-Gastric04 clinical trial. Clinicians noted that this individual course provides real-world clinical and pathological documentation regarding the efficacy and tolerability of full-dose trastuzumab deruxtecan within the second-line setting after failure of initial trastuzumab-based chemoimmunotherapy.

Gastric cancer represents the fifth leading malignancy in both global incidence and cancer-related mortality, accounting for 968,350 newly diagnosed cases and 659,853 deaths globally in 2022, with more than one-third of the global disease burden occurring in China. Human epidermal growth factor receptor 2 positivity is identified in approximately 10 to 20 percent of gastric cancer cases internationally and roughly 12 percent of patients in China. For over a decade, combination regimens pairing trastuzumab with cytotoxic chemotherapy served as the established first-line standard of care for advanced HER2-positive disease. More recently, regulatory authorities approved the addition of programmed death-1 blockade with pembrolizumab for tumors exhibiting programmed death-ligand 1 combined positive scores of one or greater. Despite these multi-agent front-line interventions, the majority of patients experience tumor progression within twelve months. While trastuzumab deruxtecan gained regulatory approvals for later lines of therapy based on earlier trials such as DESTINY-Gastric01 and DESTINY-Gastric06, real-world data documenting second-line outcomes have remained scarce following the drug’s recent second-line approval in China.

The patient presented initially with a four-month history of progressive dysphagia, maintaining an Eastern Cooperative Oncology Group performance status score of 1. Physical evaluations recorded a height of 168 centimeters, body weight of 66 kilograms, body mass index of 23.4 kilograms per square meter, and body surface area of 1.72 square meters. Diagnostic laboratory investigations revealed an elevated serum carcinoembryonic antigen level of 409.6 micrograms per liter, mild anemia with hemoglobin measured at 104 grams per liter, and elevated fasting blood glucose that did not require medical intervention. Endoscopic examination identified an elevated, circumferential ulcerative lesion spanning from the lower esophagus, located 33 centimeters from the incisors, across the cardia into the anterior wall of the gastric fundus and lesser curvature. The friable lesion bled readily upon contact, showed surface exudate, and caused luminal stenosis that still permitted the passage of a standard gastroscope. Pathological assessment confirmed moderately to poorly differentiated adenocarcinoma of the intestinal subtype under the Lauren classification system.

Subsequent baseline chest and abdominal computed tomography imaging demonstrated primary neoplastic lesions involving the gastric fundus, lower esophagus, and cardia, alongside metastatic involvement of the hepatogastric ligament, station eight mediastinal lymph nodes, bilateral pulmonary parenchyma, and a hypervascular nodule in the left adrenal gland. These findings established a clinical diagnosis of stage TxNxM1 gastroesophageal junction adenocarcinoma. Immunohistochemical analysis demonstrated strong HER2 protein expression scored as 3+, with approximately 90 percent of viable tumor cells exhibiting complete membranous staining and 10 percent showing 2+ staining, accompanied by a PD-L1 combined positive score of 20. Liquid biopsy next-generation sequencing detected a circulating tumor DNA concentration of 43.4 MTM per milliliter with a tumor fraction of 4.18 percent in plasma. The assay identified high tumor mutational burden of 11.52 mutations per megabase, microsatellite stability, and an ERBB2 gene copy number amplification of 3.4, which authors noted was potentially underestimated by ctDNA sequencing given the modest plasma tumor fraction.

The oncology team initially prescribed a first-line chemoimmunotherapy regimen comprising 500 milligrams of trastuzumab on day one, 200 milligrams of oxaliplatin on day one, 1,500 milligrams of capecitabine twice daily on days one through 14, and 200 milligrams of sintilimab on day two, repeated every three weeks. Although the patient reported relief of dysphagia and achieved an objective partial response by Response Evaluation Criteria in Solid Tumors version 1.1 after two cycles, subsequent imaging after four cycles demonstrated stable disease, and progressive disease occurred after six cycles due to enlargement of the left adrenal lesion. The progression-free interval for this first-line regimen was documented at 5.5 months from treatment initiation to radiographic confirmation. To address disease progression, clinicians transitioned the patient to second-line trastuzumab deruxtecan monotherapy delivered intravenously at 6.4 milligrams per kilogram once every three weeks. Restaging computed tomography scans following two cycles confirmed regression of the left adrenal metastasis, establishing a verified partial response.

The patient maintained this confirmed partial response for 21 consecutive months, while his overall Eastern Cooperative Oncology Group performance status improved from 1 to 0 during treatment. At cycle 17, clinicians elected to reintroduce sintilimab alongside ongoing trastuzumab deruxtecan because circulating carcinoembryonic antigen levels exhibited a persistent upward trajectory, rising from 5.91 micrograms per liter at cycle 11 to 8.21 micrograms per liter at cycle 17, despite the absence of progressive disease on concurrent computed tomography scans. The treating team then administered consolidative local radiotherapy targeting the pre-existing bilateral lung nodules to maximize disease suppression while continuing systemic antibody-drug conjugate infusions. Computed tomography performed one and a half months following cycle 22 ultimately identified disease progression marked by newly emergent metastatic lesions in the liver and right adrenal gland, ending the 23-month second-line progression-free survival interval.

A critical pharmacological feature of this agent is its bystander antitumor effect, wherein the released payload diffuses across lipid membranes into neighboring neoplastic cells regardless of their individual HER2 expression levels. Following disease progression on second-line therapy, ultrasound-guided re-biopsy of the newly emergent left medial liver metastasis demonstrated a shifted receptor profile consisting of 75 percent IHC 2+ and 25 percent IHC 1+ tumor cells, with complete absence of the baseline IHC 3+ component, illustrating that the bystander effect supported durable clinical control despite the emergence of predominantly HER2-low resistant subclones.

Throughout the 22 cycles of second-line therapy, the patient continued the standard 6.4 milligram per kilogram dose without requiring any dose reductions. Infusion intervals were occasionally prolonged beyond the intended three-week calendar schedule due to two defined clinical and logistical factors: the patient was an outpatient traveling from another province who occasionally experienced scheduling delays returning for scheduled infusions, and he developed a transient Grade 2 decrease in platelet count that necessitated treatment pauses without meeting established criteria for dose reduction. The authors highlighted that the apparent calendar discrepancy between completing 22 therapy cycles and achieving 23 months of progression-free survival directly reflected these intermittent treatment delays rather than premature disease progression, drug discontinuation, or therapeutic failure.

A critical consideration during trastuzumab deruxtecan administration is the risk of drug-related interstitial lung disease or pneumonitis, an adverse effect reported in 13.9 percent of participants in the global DESTINY-Gastric04 study but in only 3.2 percent of Chinese patients in the DESTINY-Gastric06 trial. Large-scale postmarketing surveillance data from Japan encompassing 1,070 gastric cancer patients identified age 75 years or older, pre-existing interstitial lung disease, prior radiation pneumonitis, and comorbid chronic obstructive pulmonary disease or emphysema as independent risk factors for interstitial lung toxicity. The presented patient exhibited none of these baseline vulnerabilities: he was 63 years of age, had no previous history of pulmonary disorders, and baseline thoracic computed tomography confirmed the complete absence of ground-glass opacities, traction bronchiectasis, honeycombing, or fibrotic abnormalities, with baseline pulmonary nodules classified as benign or metastatic rather than interstitial disease. Consequently, the patient completed nearly two years of full-dose therapy without developing clinical or radiological signs of pneumonitis.

The authors detailed several methodological constraints inherent to the case report, noting that formal assessment of skeletal muscle index was not performed at baseline or during follow-up to evaluate sarcopenia, a physiological variable increasingly recognized as influencing antibody-drug conjugate metabolism, clearance, and host tolerability. In addition, restricted biopsy material from the patient precluded comprehensive tumor microenvironment investigations, such as quantitative evaluations of stromal desmoplasia or spatiotemporal mapping of PD-L1 expression. The medical team affirmed that while this single-patient experience demonstrates substantial durable benefit and acceptable tolerability with full-dose trastuzumab deruxtecan after front-line resistance, broad clinical conclusions require confirmation in ongoing prospective randomized trials.

Subject of Research: Second-line trastuzumab deruxtecan treatment for HER2-positive gastroesophageal junction adenocarcinoma

Article Title: Progression-free survival of 23 months with second-line trastuzumab deruxtecan in HER2-positive gastroesophageal junction adenocarcinoma: a case report

Article References: Dong, Y., Zhang, L., Zhao, L., & Zhu, Y. (2026). Progression-free survival of 23 months with second-line trastuzumab deruxtecan in HER2-positive gastroesophageal junction adenocarcinoma: a case report. Frontiers in Pharmacology, 17, Article 1913044. https://doi.org/10.3389/fphar.2026.1913044

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1913044

Keywords: trastuzumab deruxtecan, gastroesophageal junction adenocarcinoma, HER2-positive gastric cancer, second-line therapy, antibody-drug conjugate, progression-free survival, sintilimab, targeted cancer therapy, Progression-free, survival, months, second-line