Preliminary Safety and Efficacy of Tarlatamab in Medullary Thyroid Carcinoma

PURPOSE Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor with high rates of delta-like ligand 3 (DLL3) expression. MTC has limited treatment options after failure of kinase inhibition. DLL3-targeting therapies such as tarlatamab may be effective treatments for MTC. METHODS After providing informed consent, four patients with MTC were treated with tarlatamab after progression on all established therapies. Patients were treated using the step-up dosing described in patients with small cell lung cancer (SCLC). Efficacy was measured using RECIST v1.1, as well as changes in biomarkers, calcitonin, and carcinoembryonic antigen. Safety was evaluated by the rates of treatment-related adverse events (TRAEs) and the rate of severe (grade ≥3) TRAEs based on Common Terminology Criteria for Adverse Events v5.0. RESULTS Tarlatamab showed antitumor activity in 4 of 4 (100%) patients with MTC. In the three patients with RECIST evaluable disease, two experienced partial responses and one had stable disease. Three of four patients experienced biochemical responses. One patient who did not have a biochemical response had a RECIST partial response. All four patients experienced at least one grade ≥3 TRAE. Severe TRAEs included grade 5 colon perforation, grade 4 cytokine release syndrome (CRS), grade 4 immune effector cell–associated neurotoxicity syndrome (ICANS), and grade 3 leukopenia, neutropenia, hypophosphatemia, and anorexia. The grade 4 CRS and grade 4 ICANS were refractory to standard treatments. CONCLUSION Tarlatamab showed encouraging antitumor activity in patients with MTC, and it may be an effective treatment for this population. However, the safety data from these initial patients raise concern that the step-up dosing established for patients with SCLC may not be optimal for patients with MTC and potentially other neuroendocrine tumors. More research is needed to evaluate the safety and efficacy of tarlatamab in other populations.