West Oncology Conference 2025: Non-Colorectal GI Cancer Updates with Dr Tyler Johnson
Presented by:
Tyler Johnson, MD, Stanford University School of Medicine
Conference:
2025 West Oncology Conference
Introduction: Navigating the Expanding Landscape of Non-Colorectal GI Cancers
At the 10th Annual West Oncology Conference held in 2025, Dr Tyler Johnson began his presentation by acknowledging the challenges of covering non-colorectal gastrointestinal (GI) cancers in a single talk. These malignancies encompass multiple tumor types, including gastric, esophageal, pancreatic, biliary, and small bowel cancers each with a unique and diverse treatment landscape. In this presentation his goal was to distill key practice-changing findings from recent trials and provide practical takeaways for clinicians, with a focus on four critical updates for the non-colorectal GI cancers:
FLOT is now the standard perioperative therapy for gastric and gastroesophageal junction (GEJ) adenocarcinomas.
Zolbetuximab, a novel Claudin 18.2-targeted therapy, is now available and should be incorporated into treatment decision-making.
Elderly and frail patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) require special treatment considerations.
The role of immunotherapy in perioperative gastric cancer remains unclear, but ongoing trials like MATTERHORN will provide answers.
FLOT: A New Standard in Perioperative Gastric and GEJ Adenocarcinomas
Dr Johnson first addressed findings from the ESOPEC trial, which compared FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) to the use of neoadjuvant chemoradiation (i.e., the CROSS regimen) for patients with resectable gastric and GEJ adenocarcinomas.
Key Findings from ESOPEC
Dr Johnson noted that FLOT was associated with superior overall survival (OS) as compared to the CROSS in patients with adenocarcinoma (not squamous cell carcinoma) of the esophagus, GEJ, or stomach. In addition, pathologic complete response (pCR) rates were significantly higher with FLOT. Given the findings from this trial, Dr Johnson suggested that FLOT should now be considered the standard of care for fit patients with locally advanced, resectable gastric/GEJ adenocarcinoma.
Clinical Considerations
Putting the findings from ESOPEC in clinical perspective, from a practical standpoint, Dr Johnson noted that FLOT was overall a more toxic regimen than CROSS, with many patients requiring dose modifications. In addition, he noted that neuropathy occurring from oxaliplatin in the FLOT regimen can be significant, particularly for older patients. As such, for patients who cannot tolerate FLOT, alternatives like CROSS may still be considered. Lastly, Dr Johnson notes a lingering uncertainty remains regarding the role of adjuvant immunotherapy nivolumab in this setting, based on results from the CheckMate-577 trial, for patients who have received perioperative FLOT.
Claudin 18.2 and Zolbetuximab in Advanced Gastric/GEJ Cancer
Dr Johnson then noted the findings from the SPOTLIGHT trial, which evaluated the use of zolbetuximab, a monoclonal antibody targeting Claudin 18.2 (CLDN18.2), in patients with human epidermal growth factor receptor 2 (HER2) negative, locally advanced/metastatic gastric and GEJ adenocarcinomas. Key findings from SPOTLIGHT showed that zolbetuximab plus chemotherapy improved progression-free survival (PFS) and OS compared to chemotherapy alone. Notably, those patients with high Claudin 18.2 expression (defined as ≥75% of tumor cells) derived the greatest benefit. He also noted the presence of a “tail” on the survival curve, suggestive of durable responses for a subset of patients.
Clinical Considerations
Putting the findings from SPOTLIGHT in perspective, Dr Johnson suggested that Claudin 18.2 should now be tested in all gastric/GEJ adenocarcinomas (particularly for patients with HER2-negative disease). He noted that, at present, zolbetuximab is best suited for patients who are HER2-negative, have low programmed death ligand (PD-L1) CPS score, and who are microsatellite stable (MSS). Dr Johnson cited the most common side effects of this agent as being nausea and vomiting are common side effects, particularly during the first few cycles. He further noted that the combination of chemotherapy, immunotherapy, and zolbetuximab is currently being studied in another trial, ILLUSTRO. In terms of its current place in therapy, Dr Johnson believes that zolbetuximab is likely preferable to immunotherapy for patients with Claudin 18.2 positivity and low PD-L1 expression, whereas for HER2-positive or high PD-L1 CPS patients, the best sequencing strategy remains unclear.
Special Considerations for Elderly/Frail Patients with Metastatic Pancreatic Cancer
Dr Johnson noted that most patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are elderly or frail, however, clinical trials for new therapies will often exclude such patients. In this regard, he noted findings from the GIANT trial (EA2186) which examined the optimal chemotherapy regimen for elderly or frail patients with newly diagnosed mPDAC.
Findings from GIANT demonstrated no significant difference in overall survival (OS) or progression-free survival (PFS) when comparing outcomes for the two chemotherapy regimens tested (gemcitabine + nab-paclitaxel versus 5-FU + liposomal irinotecan). Additional results from the trial showed that ECOG performance status (PS) was the strongest predictor of outcomes, as patients with PS 2 fared significantly worse. Overall survival remained poor in the trial, underscoring the aggressive nature and poor outcomes in mPDAC.
Clinical Considerations
In view of the results from GIANT, Dr Johnson suggested that appropriate geriatric assessments should be used to guide treatment selection in mPDAC, as chronologic age alone is not sufficient. He further noted that gemcitabine monotherapy may be an appropriate option for frail patients who cannot tolerate the toxicity of multi-agent chemotherapy. Referral to geriatric oncologists should also be considered, when possible, to optimize treatment selection.
The Future of Immunotherapy in Perioperative Gastric Cancer
In the final portion of his presentation, Dr Johnson reviewed the role of immune checkpoint inhibitors (ICIs) in perioperative treatment for gastric and GEJ adenocarcinomas, which remains unclear. He highlighted two key trials, MATTERHORN (comparing FLOT + durvalumab versus FLOT alone), and KEYNOTE-585 (comparing FLOT + pembrolizumab versus FLOT alone). Preliminary Findings from MATTERHORN showed that the addition of durvalumab to FLOT improved pathologic complete response (pCR) rates, although long-term OS and PFS data are still pending. He also noted results from CheckMate-577 which showed a survival benefit for adjuvant nivolumab after neoadjuvant chemoradiation, although its role in patients treated perioperative/y with FLOT remains unknown.
Clinical Considerations
In view of these findings, for patients with metastatic disease, Dr Johnson noted that ICIs improve survival when combined with chemotherapy in PD-L1+ patients, but their perioperative benefit has not yet been proven. As such, until final results from MATTERHORN and KEYNOTE-585 are available, the role of ICIs in perioperative therapy will remain investigational.
Non-Colorectal Cancer Updates: Dr Johnson’s Key Takeaways
FLOT is now the standard of care for fit patients with resectable gastric and GEJ adenocarcinomas.
Claudin 18.2 testing should be routine, and zolbetuximab should be considered in HER2-negative, low PD-L1 CPS patients.
Elderly and frail patients with metastatic pancreatic cancer require individualized treatment strategies, often with gemcitabine-based regimens.
The role of immunotherapy in perioperative gastric cancer remains uncertain, with ongoing trials expected to provide clarity.
Final Thought: The Future of GI Oncology
Dr. Johnson concluded his presentation with a reminder: “Precision medicine is not just about finding the right drug—it’s about finding the right drug for the right patient at the right time.” With continued refinement of biomarker-driven therapies, personalized treatment strategies, and expanded use of immunotherapy, Dr Johnson believes the treatment landscape for non-colorectal GI cancers will continue to evolve rapidly. As such, clinicians must remain adaptable, informed, and proactive in integrating these new data into their clinical practice.
Speaker Disclosure Information: Dr Johnson reported no relevant disclosures for this presentation.
You can see the full presentation by Dr Tyler Johnson at the 2025 West Oncology Conference on our YouTube channel here.