Systemic Therapies for Advanced Medullary Thyroid Carcinoma.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Medullary thyroid carcinoma (MTC) is a rare thyroid cancer, often indolent but can be aggressive and metastatic.
• Current treatments for advanced MTC include multikinase inhibitors (MKIs) and selective RET inhibitors.
• RET mutations are key drivers in MTC, with RAS mutations also implicated.

Purpose of the Study:

• To review the current systemic therapies for advanced MTC.
• To discuss the limitations and toxicities of existing treatments.
• To highlight ongoing investigations for more effective MTC therapies.

Main Methods:

• Review of current literature on MTC systemic therapies.
• Analysis of the efficacy and toxicity profiles of MKIs and RET inhibitors.
• Discussion of mechanisms of drug resistance in MTC.

Main Results:

• MKIs like cabozantinib and vandetanib have anti-angiogenic effects and mild anti-RET activity but significant toxicities.
• Selective RET inhibitors (selpercatinib, pralsetinib) show significant efficacy and better tolerability in RET-altered MTC.
• Drug resistance due to acquired mutations limits durable responses to current therapies.

Conclusions:

• While newer RET inhibitors represent progress, durable responses in advanced MTC are challenged by resistance.
• Development of novel and more effective treatments for progressive MTC is a critical unmet need.
• Further research into overcoming drug resistance is essential for improving MTC patient outcomes.