Primary Resistance to RET Inhibition in a RET Fusion-Positive Pancreatic Neuroendocrine Carcinoma

Abstract

We present a 54-year-old White male with a diagnosis of stage IV pancreatic neuroendocrine carcinoma. Next-generation sequencing of the tumor/blood identified a complex tumor genome, which included a rearranged during transfection (RET) gene fusion. The patient initially received cytotoxic chemotherapy with a significant radiographic response. After 4 cycles of chemotherapy, the patient was transitioned to a clinical trial using selpercatinib, a RET inhibitor, as maintenance therapy. Unfortunately, our patient developed progression of disease at the first treatment monitoring scan. Our patient suffered primary resistance to RET-targeted therapy. Proposed mechanisms of resistance include intrinsic resistance of the nuclear receptor co-activator 4-RET fusion to RET inhibition, the RET fusion representing a passenger alteration to another tumorigenic driver pathway and/or decreased efficacy of RET inhibition after platinum-based chemotherapy. Our patient's clinical course highlights the fact that "actionable" genomic alterations do not always equate to patient benefit.

Keywords: RET fusion; pancreatic neuroendocrine cancer; primary resistance; selpercatinib.

Figure 1.

Computed tomography abdomen (venous phase) at diagnosis (A, B) and after 4 cycles of chemotherapy (C, D). (A) Arrow = pancreatic head mass. (B) Innumerable hypoattenuating hepatic lesions with peripheral enhancement. (C) Arrow = pancreatic head mass. (D) Marked improvement in liver metastasis.

Figure 2.

Computed tomography abdomen (arterial phase) before (A, B) and after 2 months of selpercatinib (C, D). (A) Arrow = pancreatic head mass. (B) Arrow = anterior left hepatic lobe mass. (C) arrow = pancreatic head mass. (D) anterior left hepatic lobe mass largely resolved. Arrow, new hypoattenuating lesion.