Acquired TPM3::NTRK1 fusion as a novel off-target resistance mechanism to selpercatinib in RET-positive lung adenocarcinoma: a case report.

Acquired resistance remains a major challenge in RET fusion-positive non-small cell lung cancer treated with selective RET inhibitors. NTRK fusions represent a rare off-target resistance mechanism in this setting, with limited clinical data to guide management. We report the first case of an acquired TPM3::NTRK1 fusion as a resistance mechanism to selpercatinib in KIF5B::RET-positive lung adenocarcinoma. A male in his late 40s, a non-smoker, underwent surgical resection for NSCLC after incidental detection of a pulmonary lesion. Following disease recurrence, KIF5B::RET was identified as the sole oncogenic driver and the patient achieved durable disease control for 46 months on selpercatinib, with three episodes of oligoprogression managed by stereotactic body radiotherapy. At systemic progression, RNA-inclusive tissue next-generation sequencing (Guardant360 Tissue) identified TPM3::NTRK1 (variant allele fraction 30.9%; RNA 6,109 transcripts per million) and residual KIF5B::RET (variant allele fraction 6.9%), with no secondary RET kinase domain mutations. A concurrent liquid biopsy (cfDNA) assay failed to detect either fusion, with tumor fraction <0.05%, highlighting the limitations of cfDNA-based platforms for fusion detection at low tumor shedding. Combination selpercatinib and larotrectinib was commenced, demonstrating metabolic response on PET-CT at eight weeks with concurrent clinical improvement. This case identifies acquired NTRK1 fusion as a rare, actionable bypass resistance mechanism to selective RET inhibition, distinct from previously reported NTRK3 fusions, and underscores the importance of RNA-based tissue reassessment at progression to guide rational combination targeted therapies.