ArticleESMO gastrointestinal oncology2026
Prognostic relevance of secondary actionable fusions in MLH1-deficient dMMR/MSI-H gastrointestinal tumors treated with pembrolizumab.
Article in ESMO gastrointestinal oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Immune checkpoint inhibitors (ICIs) are standard treatment for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) gastrointestinal tumors but resistance remains relevant. Secondary actionable fusions may be enriched in MutL homolog 1 (MLH1)-deficient colorectal cancer (CRC) with mitogen-activated protein kinase wild-type biology, whereas their prevalence in non-CRC tumors and impact on ICI outcomes remain poorly defined. We evaluated secondary fusions in MLH1-deficient dMMR/MSI-H tumors treated with pembrolizumab. Materials and methods: This predefined molecular subanalysis of the GAstrointestinal INestable cohort included patients with advanced dMMR/MSI-H gastrointestinal tumors with MLH1 loss treated with pembrolizumab. Molecular profiling used an RNA sequencing-based panel covering relevant fusion targets, complemented by pan-tropomyosin receptor kinase (TRK) immunohistochemistry and RET proto-oncogene (RET) FISH. Results: Twenty patients were included (9 CRC and 11 non-CRC tumors). Secondary actionable fusions were detected in 4/9 CRC (44.4%; three Conclusions: Secondary actionable fusions may identify MLH1-deficient dMMR/MSI-H CRC with shorter long-term survival despite pembrolizumab responses. These exploratory findings support molecular profiling and warrant validation.
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