209P Efficacy and safety of larotrectinib as first-line treatment for patients with TRK fusion cancer

March 1, 2026ESMO rare cancers.Open Access

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Key Points

This research aims to evaluate the therapeutic potential of larotrectinib for patients with TRK fusion cancer, focusing on molecular dependencies in sarcoma models.
Established patient-derived sarcoma models to mimic tumor biology
Conducted whole-genome CRISPR/Cas9 knockout screens
Performed customized drug-library screening with 82 compounds
Validated targets from screens across 10 ex vivo sarcoma models
Investigated molecular mechanisms linked to drug efficacy
Identified the neddylation pathway as a selective dependency in sarcomas with homologous recombination deficiency (HRD)
Showed that inhibiting NEDD8-activating enzyme led to apoptosis in HRD models
Drug combinations with pevonedistat showed strong synergy against DNA damage response
Highlights potential for patient stratification based on HRD status

Demonstrates the efficacy of larotrectinib in targeting TRK fusion cancers, suggesting new treatment options.

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Orbach et al. (2026) studied this question.

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