ICI Therapy Shows Durable Responses in dMMR Gastroesophageal Adenocarcinoma: JAMA
USA: In real-world and single-center cohorts of dMMR gastroesophageal adenocarcinoma, immune checkpoint inhibitor (ICI)-based therapy demonstrated high and durable response rates in both metastatic and locoregional settings. The achievement of complete responses and lack of recurrence in responders suggests that surgery-sparing or nonoperative approaches may be feasible in selected patients. Early responses and the potential for shorter treatment duration, especially with dual immunotherapy, were also observed.
These findings, published in JAMA Surgery, highlight the transformative role of immunotherapy while emphasizing the need for better biomarkers and prospective validation.
Gastroesophageal adenocarcinoma (GEA) remains a challenging malignancy, with limited data available on outcomes stratified by microsatellite instability (MSI) status. To address this gap, researchers led by Jun Okui from The University of Texas MD Anderson Cancer Center conducted a retrospective cohort study evaluating treatment patterns and outcomes in patients with deficient mismatch repair (dMMR) or microsatellite instability–high (MSI-H) GEA.
The study, conducted between June 2020 and August 2025 at a tertiary cancer center in Texas, included 1,638 patients who underwent MSI testing out of 3,316 diagnosed cases. Among these, 83 patients (5.1%) were identified as having dMMR tumors. The cohort had a mean age of 62.5 years, with a predominance of male patients.
Survival outcomes varied significantly based on mismatch repair status and treatment approach. Patients with dMMR tumors showed favorable survival rates, with a 3-year overall survival of 84.7% in those undergoing curative-intent surgery and 68.5% in those managed without surgery. In comparison, patients with proficient mismatch repair had lower survival outcomes, particularly in the absence of surgery.
The study led to the following findings:
- Among 83 patients with dMMR tumors, 34 had metastatic disease and 49 had locoregional disease.
- A subset of these patients received ICI-based therapy, including nivolumab plus ipilimumab or pembrolizumab.
- In the metastatic group, 61.5% of evaluable patients achieved a best objective response.
- In the locoregional group, 52.2% achieved either clinical complete response (cCR) or pathological complete response (pCR).
- These findings indicate strong responsiveness of dMMR tumors to immunotherapy.
- Among locoregional cases treated with ICIs, some patients underwent surgery and achieved complete tumor resection.
- Other patients with complete clinical response were managed with active surveillance instead of surgery.
- Complete responses were observed early, after only a few cycles of treatment.
- No recurrence or death was reported among patients achieving complete response during a median follow-up of over two years.
- No significant differences were observed between responders and nonresponders in HER2 status, combined positive score, or CLDN18.2 expression.
- Lynch syndrome was more commonly observed among patients who responded to ICI therapy.
Overall, the findings indicate that ICI-based therapy is associated with substantial and durable responses in both metastatic and locoregional dMMR GEA. The results support the possibility of tailoring treatment approaches, including nonoperative strategies, in carefully selected patients. However, the authors emphasize the need for prospective studies and improved biomarkers to better predict which patients are most likely to benefit from immunotherapy.
Reference:
Okui J, Prakash LR, Lyu HG, et al. Immunotherapy Response in Microsatellite Instability–High Gastroesophageal Adenocarcinoma. JAMA Surg. Published online April 15, 2026. doi:10.1001/jamasurg.2026.0861
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