The FDA has approved pralsetinib (GAVRETOTM, Blueprint Medicines Corporation) for adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) that requires systemic therapy and for patients with RET fusion-positive thyroid cancer who require systemic therapy and whose disease is refractory to radioactive iodine therapy.
The approval was based on ARROW (NCT03037385), an open label, multi-cohort phase 1/2 clinical trial led by first author Mimi Hu, MD, a Professor in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center. ARROW enrolled 438 patients with RET-altered solid tumors, 55 of whom had advanced or metastatic RET-mutant MTC previously treated with cabozantinib or vandetanib, 29 of whom had not received prior treatment with these agents, and 9 of whom were radioactive iodine-refractory. The study's primary end points were overall response rate and duration of response.
In patients with advanced or metastatic RET-mutant MTC previously treated with cabozantinib or vandetanib, pralsetinib produced a response in 60% of patients, 79% of whom experienced a response lasting at least 6 months. In patients not previously treated with cabozantinib or vandetanib, pralsetinib produced a response in 66% of patients, 84% of whom had a response that lasted 6 months or longer. Patients whose disease was refractory to radioactive iodine experienced an overall response rate of 89%, with 100% of responders achieving a response of at least 6 months.
The most common adverse events occurring in at least 25% of patients included constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. The most common grade 3/4 laboratory abnormalities occurring in at least 2% of patients included decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium, decreased sodium, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelets, and increased alkaline phosphatase.
"Pralsetinib demonstrated potent and durable clinical activity in RET-positive MTC regardless of prior treatment with approved multikinase inhibitors or RET mutation and was well tolerated," concluded the authors.
The recommended dose of pralsetinib is 400 mg orally once daily, with no food intake for at least two hours before taking pralsetinib and at least one hour after.
For More Information
Hu M, Subbiah V, Wirth LJ, et al (2020). Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4):S1026-S1033. Abstract 19130. DOI:10.1016/annonc/annonc293US Food & Drug Administration (2020). FDA approves pralsetinib for RET-altered thyroid cancers. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-ret-altered-thyroid-cancers?utm_medium=email&utm_source=govdelivery
Clinicaltrials.gov (2020). Phase 1/2 study of the highly-selective RET inhibitor, pralsetinib (BLU-667), in patients with thyroid cancer, non-small cell lung cancer, and other advanced solid tumors (ARROW). NLM identifier: NCT03037385
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