RET positive

Real-world data showed selpercatinib to be effective in patients with RET fusion-positive NSCLC in Japan, with a favorable safety profile and no new safety concerns.

We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

This case suggests that selpercatinib rechallenge may be effective in difficult-to-treat RET-positive NSCLC patients, including those with uncontrolled CNS disease.

Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.

Selpercatinib was discontinued, and treatment with intravenous hydration, febuxostat, and furosemide was initiated. This case highlights that potent targeted therapy can trigger TLS even in the absence of conventional risk factors. Early recognition and aggressive management are essential to mitigate risk and allow continuation of effective treatment.

Following confirmation of multiple lung metastases, the patient was treated with doxorubicin monotherapy. Subsequent next-generation sequencing (NGS) revealed a RET fusion, leading to the diagnosis of an RET-rearranged spindle cell neoplasm. This case highlights the importance of genomic testing for certain spindle cell sarcomas and the potential benefit of RET-specific inhibitors against RET-altered sarcomas.

Emerging evidence from clinical trials supports the efficacy of RET inhibitors in RET-altered PDAC. Broader integration of genomic testing in PDAC may uncover new therapeutic opportunities and improve patient outcomes.

Among the 18 RET fusion-positive samples, one was identified as an extremely rare case (RUFY3::RET), and two were determined to be novel fusions (FN1::RET, PPP1R21::RET). The findings of this study demonstrate that exon coverage imbalance analysis serves as a robust complement to computational RNA-seq analysis pipelines for the detection of clinically relevant RET fusions.

RET pathogenic variants V804M, K666N, and C609Y were the most identified variants, particularly through broad panel testing, indicating increased incidental diagnosis of MEN2. The identification of previously unlisted variants underscores the need for dynamic guideline updates and ongoing curation to optimize clinical management of RET pathogenic variant carriers.

Reducing the selpercatinib dose and implementing a low long-chain triglyceride diet led to symptom relief, stable ascites, and maintained tumor response. This case highlights effective management of tyrosine kinase inhibitor (TKI)-induced CA without compromising cancer control.