First-Line Immunotherapy Regimen Associated with Improved Survival in Gastroesophageal Cancer
A retrospective study of real-world data evaluates treatment patterns and survival outcomes for advanced HER2-negative gastroesophageal adenocarcinoma.
Key takeaways
- In an observational cohort of 2,340 patients with advanced HER2-negative gastroesophageal adenocarcinoma, the combination of immunotherapy (IO) with FOLFOX or CAPOX was the most frequent first-line treatment, used in 31.6% of patients overall and 47.6% of those with PD-L1 CPS of 1 or greater.
- Among 2,117 patients with at least 6 months of follow-up, first-line IO plus FOLFOX or CAPOX was associated with a median real-world overall survival of 12.3 months compared to 11.3 months with FOLFOX or CAPOX alone (hazard ratio, 0.81).
- The real-world clinical benefits of the immunotherapy combination were driven by patients with PD-L1 CPS of 1 or greater, with no differences in survival outcomes observed in patients with PD-L1 CPS of less than 1.
- Starting in 2024, the combination of zolbetuximab with FOLFOX or CAPOX was administered more frequently in patients with low or negative PD-L1 expression, including 6.1% of patients with CPS less than 1 compared to 1.9% of patients with CPS of 1 or greater.
- Because this research is observational, it cannot establish a direct cause-and-effect relationship between treatment choice and survival outcomes.
A retrospective study of clinical registry data in the United States has mapped the real-world treatment patterns and clinical outcomes of patients receiving first-line therapy for advanced or metastatic HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinoma. The study, published in The Oncologist in September 2026, analyzed data from 2,340 adult patients within the Flatiron database who initiated first-line treatment between May 1, 2021, and July 31, 2025.
Because this research is observational, it cannot establish cause and effect. However, the data offer a detailed look at how biomarker testing shapes clinical choices and how specific combinations perform in everyday clinical practice. The researchers evaluated the utilization and effectiveness of immunotherapy-based regimens compared to standard chemotherapy alone in patients with varying levels of programmed cell death ligand 1 (PD-L1) expression.
The findings highlight a shift toward biomarker-guided care. While combination immunotherapy is a common first-line option, overall survival in this population remains poor, emphasizing a continuing need for more effective treatment strategies.
What Happened
In the overall cohort of 2,340 eligible patients, the combination of immunotherapy (IO) with chemotherapy (specifically FOLFOX or CAPOX) was the most common first-line regimen, administered to 31.6% of patients. This regimen was used in 47.6% of patients with PD-L1 CPS of 1 or greater.
The analysis also tracked newer biomarker-targeted therapies. Starting in 2024, the combination of zolbetuximab with FOLFOX or CAPOX was administered more frequently in patients with low or negative PD-L1 expression. Specifically, it was given to 6.1% of patients with CPS less than 1 compared to 1.9% of patients with CPS of 1 or greater. Similarly, it was administered to 4.6% of patients with CPS less than 5 compared to 0.8% of patients with CPS of 5 or greater.
In a subcohort of 2,117 patients who had at least 6 months of follow-up, those who received IO plus FOLFOX or CAPOX had significantly longer real-world outcomes compared to those who received FOLFOX or CAPOX alone:
- Median real-world overall survival was 12.3 months for the IO combination group compared to 11.3 months for the chemotherapy-alone group (hazard ratio, 0.81 [95% CI, 0.69-0.94]). - Median time to next treatment or death was 8.0 months compared to 6.1 months (hazard ratio, 0.64 [95% CI, 0.55-0.75]). - Median time to treatment discontinuation was 6.0 months compared to 3.0 months (hazard ratio, 0.54 [95% CI, 0.47-0.63]).
Importantly, these differences in outcomes were driven by patients who had a PD-L1 CPS of 1 or greater, with no differences in outcomes observed in patients with a PD-L1 CPS of less than 1.
What The Evidence Shows
This study is an observational analysis based on real-world clinical records from the Flatiron database. Because it is observational rather than a randomized controlled trial, it cannot establish a direct causal relationship between the treatments and the observed survival outcomes. The evidence is categorized as emerging, as it reflects contemporary clinical practice and real-world outcomes in the United States between 2021 and 2025. The publication of these findings in The Oncologist in September 2026 provides documented support for the clinical utility of PD-L1 biomarker testing to guide immunotherapy use in advanced gastroesophageal adenocarcinoma.
What We Don't Know Yet
As an observational registry study, the findings are subject to potential selection biases and confounding variables that are inherent to real-world database analyses. The researchers relied on recorded electronic health record data, which may contain missing or incomplete information regarding biomarker testing and treatment details. Additionally, the study was restricted to patients within the United States Flatiron database, which may not fully represent clinical practices or patient populations in other countries.
What Comes Next
The published source does not outline specific next steps, planned clinical trials, or future research directions intended by the investigators. The study concludes by noting that despite the survival improvements associated with combination immunotherapy, overall survival for patients with advanced or metastatic gastroesophageal adenocarcinoma remains poor. This highlights a persistent and significant unmet medical need, pointing to the ongoing importance of refining biomarker-informed treatment selections to discover more effective therapeutic options.
What This Means
The study demonstrates that integrating immunotherapy with chemotherapy (FOLFOX or CAPOX) as a first-line treatment is associated with a survival advantage in real-world settings, but this advantage is restricted to patients whose tumors express PD-L1 with a CPS of 1 or greater. For patients without this biomarker expression (CPS less than 1), the combination did not show a clinical benefit over chemotherapy alone. This underscores the clinical necessity of biomarker-informed treatment selection. It also shows how clinical practice is rapidly evolving, as seen by the increased adoption of zolbetuximab combinations in patients with low PD-L1 expression starting in 2024.
Original Source
PubMed (NCBI E-utilities): https://pubmed.ncbi.nlm.nih.gov/42714224/
Questions readers ask
- What was the most common first-line treatment for advanced HER2-negative gastroesophageal adenocarcinoma in this study?
- The most common first-line regimen was the combination of immunotherapy (IO) with FOLFOX or CAPOX, which was administered to 31.6% of the overall patient cohort. This combination was used in 47.6% of patients who had a PD-L1 combined positive score (CPS) of 1 or greater.
- How did the immunotherapy combination compare to chemotherapy alone in terms of survival?
- In the analyzed subcohort, patients receiving the immunotherapy combination had a median real-world overall survival of 12.3 months compared to 11.3 months for those who received chemotherapy alone, with a hazard ratio of 0.81. However, these survival improvements were driven by patients with a PD-L1 CPS of 1 or greater, and no clinical differences were found in patients with a CPS of less than 1.
- How is zolbetuximab being used in patients with low PD-L1 expression?
- Starting in 2024, the combination of zolbetuximab with FOLFOX or CAPOX was administered more frequently in patients with low or negative PD-L1 expression. It was used in 6.1% of patients with a PD-L1 CPS of less than 1 compared to 1.9% of patients with a CPS of 1 or greater.
- Does this study prove that immunotherapy causes longer survival in all gastroesophageal cancer patients?
- No, this study is observational and cannot establish a direct cause-and-effect relationship. Furthermore, the findings show that the clinical benefits of the immunotherapy combination were limited to patients with PD-L1 CPS of 1 or greater, with no differences in outcomes for patients with CPS of less than 1.
What this means
The study demonstrates that integrating immunotherapy with chemotherapy (FOLFOX or CAPOX) as a first-line treatment is associated with a survival advantage in real-world settings, but this advantage is restricted to patients whose tumors express PD-L1 with a CPS of 1 or greater. For patients without this biomarker expression (CPS less than 1), the combination did not show a clinical benefit over chemotherapy alone. This underscores the clinical necessity of biomarker-informed treatment selection. It also shows how clinical practice is rapidly evolving, as seen by the increased adoption of zolbetuximab combinations in patients with low PD-L1 expression starting in 2024.
Limitations and uncertainties
- As an observational registry study, the findings are subject to potential selection biases and confounding variables that are inherent to real-world database analyses. The researchers relied on recorded electronic health record data, which may contain missing or incomplete information regarding biomarker testing and treatment details. Additionally, the study was restricted to patients within the United States Flatiron database, which may not fully represent clinical practices or patient populations in other countries.
