Case Report: Zoledronic acid-induced hyperprogression in oncology: a case study of RET-driven neuroendocrine carcinoma treated with Selpercatinib.

Selpercatinib is a highly selective RET inhibitor with potent activity in RET-driven malignancies. Zoledronic acid is a standard bone-modifying agent for bone metastases, but its potential to induce hyperprogressive disease (HPD) is unclear. We present a 59-year-old woman with neuroendocrine carcinoma of unknown primary carrying a RET p.V804M mutation and widespread metastases. She achieved partial remission for 6 months with Selpercatinib plus denosumab. After switching to zoledronic acid, she developed HPD within 1 month, with severe bone pain, sharply elevated NSE, and radiological progression. Her condition deteriorated rapidly, and she died 8 months post-diagnosis. A strong temporal correlation suggests a potential triggering role of zoledronic acid, but causality is unproven. Tumor aggressiveness and acquired resistance to Selpercatinib are plausible alternative explanations. Mechanisms involving FPPS inhibition, Ras dysregulation, and γδ T-cell activation remain speculative. This hypothesis-generating case indicates that switching bone-modifying agents during RET inhibitor therapy requires close monitoring. Further studies are needed to confirm the safety and mechanisms underlying HPD.