HER2 overexpression occurs in 15–20% of advanced gastric and gastroesophageal junction (GEJ) adenocarcinomas. Anti-HER2 monoclonal antibody plus fluoropyrimidine/platinum chemotherapy established the first-line standard, demonstrating significant overall survival benefit in the pivotal phase 3 trial.
A HER2-directed antibody-drug conjugate (ADC), comprising an anti-HER2 antibody, cleavable linker, and topoisomerase I inhibitor payload, demonstrated an objective response rate of 41.8% in heavily pretreated HER2-positive advanced gastric/GEJ cancer (DESTINY-Gastric02). Its bystander effect may confer activity across varying HER2 expression levels. Key clinical challenges include HER2 IHC interobserver variability, intratumoral HER2 heterogeneity, acquired resistance, and ADC-associated toxicities including interstitial lung disease. VEGFR2-targeted antibody combinations remain relevant in HER2-negative or post-progression settings.
Gastrointestinal oncologists, medical oncologists, and pathologists managing HER2-positive advanced gastric/GEJ adenocarcinoma will benefit from discussion on HER2 testing, sequencing of HER2-directed therapies, resistance mechanisms, and ADC-related toxicity management.
How do you approach HER2 re-testing and re-biopsy decisions in gastric/GEJ patients progressing on first-line HER2-directed therapy, and how does HER2 heterogeneity influence your sequencing strategy? What monitoring protocols have you implemented for ADC-related toxicities, particularly interstitial lung disease, in patients with advanced gastric/GEJ cancer?
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Venu Madhav Konala2wI approach HER2 retesting selectively at progression, particularly when a patient is being considered for another HER2-directed therapy, because gastric/GEJ tumors can show substantial intratumoral heterogeneity and HER2 expression may change after treatment. Re-biopsy can therefore help determine whether persistent HER2 expression supports continued HER2-directed sequencing, while loss or marked heterogeneity may favor a non-HER2 strategy. For ADCs such as trastuzumab deruxtecan, I use close clinical monitoring for new respiratory symptoms and maintain a low threshold for imaging and evaluation of suspected ILD/pneumonitis; the provided program specifically highlights ILD/pneumonitis as an important toxicity, with most events reported as low grade in DESTINY-Gastric04.