SELLEST OSAST
When a gastroesophageal tumor is positive for HER2, PD-L1, and claudin 18.2, which target should you treat first and how do you decide? On this episode of the BackTable GI Oncology Creator Weekend™, host Dr. Kate Baker interviews Dr. Geoffrey Buckle, a GI medical oncologist at UCSF, and Dr. Ronan Hsieh, a GI oncologist at Swedish Cancer Institute in Seattle, for a breakdown of therapy selection and management in advanced HER2-positive upper GI cancers. They start with a detailed case, covering biomarker workup, how to choose a first-line regimen without head-to-head data, and how to manage nutrition and palliative radiation when a patient presents with dysphagia and weight loss.
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Timestamps
00:00 - Introduction
01:41 - Case Presentation and Biomarker Workup
05:07 - First-Line Treatment Selection
11:27 - Oligoprogressive Disease and Local Therapy
16:02 - HER2 Testing and Tumor Heterogeneity
20:19 - ctDNA in Upper GI Cancers
22:27 - HERIZON-GEA-01 and Zanidatamab
27:18 - Triplet Versus Doublet and Diarrhea Management
29:17 - Second-Line Therapy and Rebiopsy
32:33 - Trastuzumab Deruxtecan and Interstitial Lung Disease
36:33 - Later-Line Options and HER2-Low Disease
39:17 - Future Directions and Closing Remarks
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More about this episode
The conversation expands to interpreting equivocal HER2 results, tumor heterogeneity, and the importance of a second pathology review before committing to a treatment strategy. Dr. Hsieh explains how he approaches the HERIZON-GEA-01 trial data and the need to manage triplet therapy toxicity, especially diarrhea. The group discusses second-line rebiopsy to confirm HER2 status, the role of circulating tumor DNA (ctDNA), counseling and monitoring for interstitial lung disease on antibody-drug conjugates, and what to do for HER2 IHC 2+ FISH-negative tumors. They close with future directions, including trials moving HER2-directed therapies into earlier disease, the challenge of limited therapy lines, and why every line counts in this patient population.
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Resources
Shitara K, et al. Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer (HERIZON-GEA-01). N Engl J Med. 2026
https://pubmed.ncbi.nlm.nih.gov/42202319/
FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction and esophageal adenocarcinoma (August 2026)
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanidatamab-hrii-and-tislelizumab-jsgr-her2-positive-gastric-gastroesophageal-junction
Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023
https://pubmed.ncbi.nlm.nih.gov/37871604/
Trastuzumab in combination with chemotherapy versus chemotherapy alone for HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet. 2010
https://pubmed.ncbi.nlm.nih.gov/20728210/
Trastuzumab Deruxtecan in HER2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial (DESTINY-Gastric01). J Clin Oncol. 2023
https://pubmed.ncbi.nlm.nih.gov/36379002/
GEMINI-PeriOp GC: Novel Agents or Combinations as Perioperative Treatment in Locally Advanced Resectable Gastroesophageal Adenocarcinoma (trial record)
https://clinicaltrials.gov/study/NCT07069712
Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023
https://pubmed.ncbi.nlm.nih.gov/37524953/
Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer (MATTERHORN). N Engl J Med. 2025
https://pubmed.ncbi.nlm.nih.gov/40454643/
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer and Esophageal and Esophagogastric Junction Cancers (current versions)
https://www.nccn.org/guidelines/category_1
Dr. Geoffrey Buckle, UCSF Health physician profile
https://www.ucsfhealth.org/providers/geoffrey-buckle
Dr. Ronan Hsieh, Swedish physician profile
https://www.swedish.org/doctors/medical-oncology/wa/seattle/ronan-hsieh-1457880031
Dr. Kate Baker, BackTable Tumor Board contributor page
https://www.backtable.com/shows/tumor-board/contributors/dr-kate-baker
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