Retevmo (selpercatinib)

This is the first reported case of selpercatinib-induced acalculous cholecystitis in a patient. The report highlighted the potential efficacy of selpercatinib in elderly patients while underscoring the risk of severe adverse events and emphasizing monitoring and personalized dose management.

Using two mouse studies that model multi-organ metastases and breast tumor formation in the brain, we observed that RET inhibition significantly prevented the circulating tumor cells from forming brain metastases and suppressed the growth of intracranially implanted tumor cells, but did not significantly inhibit the progression of well-established brain metastases. Together, our findings demonstrated that RET is highly activated in BCBM and functioning as a novel mediator of BCBM, and that RET plays a new role as a viable therapeutic target for BCBM.

Selpercatinib and pralsetinib are the most frequently studied RET inhibitors. Notably, research on next-generation RET inhibitors as monotherapy approaches (e.g., LOXO-260, enbezotinib, SY-5007 and TY-1091) is currently underway...While selective RET inhibitors have demonstrated therapeutic potential, concerns regarding drug resistance and toxicity persist. Therefore, future strategies should prioritize the development of next-generation inhibitors and the optimization of combination regimens to improve outcomes for RET-altered thyroid cancer patients.

In Japanese patients treated with selpercatinib, efficacy in whole patients was similar to the worldwide population, whereas AEs (especially liver dysfunction) was more severe than worldwide population. This result highlights the need for careful dose management strategies for Japanese patients.

This case highlights the potential of selpercatinib in the perioperative setting, suggesting that it induces tumor regression and enabling of curative surgery in early-stage RET fusion-positive NSCLC. Our findings support the further investigation of selpercatinib in early stages and provide a rationale for future treatment strategies of early-stage RET fusion-positive NSCLC patients.

The United States Food and Drug Administration (FDA) has approved pembrolizumab for MSI-high tumors or tumors with a high TMB. Larotrectinib and entrectinib have been approved for the treatment of NTRK gene fusion-positive tumors. Additionally, the combination of dabrafenib and trametinib has been approved for BRAF V600E mutations, and selpercatinib has been approved for RET fusion-positive cancers as of 2022. Positive responses to agnostic therapy, a significant milestone in cancer treatment, depend on the identification of new agnostic biomarkers. Ongoing research is focused on defining additional molecular changes, such as programmed death-ligand 1 (PD-L1), Kirsten rat sarcoma virus (KRAS), neuregulin 1 (NRG1), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK), AKT serine/threonine kinase (AKT), human epidermal growth factor receptor 2 (HER2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and breast cancer gene (BRCA), as potential agnostic biomarkers in various cancer types.

We describe 2 adolescents with RET-fusion and noniodine avid metastatic PTC who both achieved increased iodine avidity after treatment with selpercatinib, a selective inhibitor of RET, allowing for the successful use of RAI. These cases highlight the potential to include targeted therapy to optimize the treatment with RAI in pediatric patients with noniodine avid advanced PTC.

P2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2025 --> Nov 2027 | Trial primary completion date: Nov 2025 --> Nov 2027

The combination of selpercatinib and cemiplimab was possible, with no new safety signals observed.

P2, N=1, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Jun 2026

Our results show that the multitargeted SRC TKI dasatinib significantly enhanced the efficacy of RET TKIs in RET fusion-positive (RET+) NSCLC and PTC cells...Importantly, synergy was also observed with eCF506 (NXP900), a next-generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib-resistant RET+ PTC cells. These results elucidate RET and SRC signaling crosstalk in RET+ NSCLC and PTC, suggesting that co-inhibiting SRC has clinical potential in TKI-naïve and -resistant RET+ cancers.

Collectively, BYS10 represents a novel, highly selective RET inhibitor with superior in vitro and in vivo activity against multiple RET alterations compared to Selpercatinib. Its recent Investigational New Drug (IND) approvals from the FDA and NMPA underscore its therapeutic potential for RET-driven malignancies.