ESMO gastrointestinal oncology · 2026
Prognostic relevance of secondary actionable fusions in MLH1-deficient dMMR/MSI-H gastrointestinal tumors treated with pembrolizumab.
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Martínez Lago N, Sánchez Ares M, Carral Maseda A, Pérez Martelo M, Covela Rúa M, Fernández Montes A, de la Cámara Gómez J, González Villarroel P, Reboredo López M, Padín Iruegas M E, Abdulkader Nallib I
Аннотация
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 NTRK1, one RET) and were not detected in non-CRC tumors. Among 19 assessable patients, objective response rate was 84.2% and disease control rate 89.5%. Median overall survival (OS) was not reached in fusion-negative CRC, 43.0 months in fusion-positive CRC, and 20.2 months in non-CRC. Within CRC, OS differed by neurotrophic receptor tyrosine kinase 1 fusion status (log-rank P = 0.034), although limited by sample size.
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.
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 NTRK1, one RET) and were not detected in non-CRC tumors. Among 19 assessable patients, objective response rate was 84.2% and disease control rate 89.5%. Median overall survival (OS) was not reached in fusion-negative CRC, 43.0 months in fusion-positive CRC, and 20.2 months in non-CRC. Within CRC, OS differed by neurotrophic receptor tyrosine kinase 1 fusion status (log-rank P = 0.034), although limited by sample size.
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.