FDA Approves Pralsetinib for RET+ Thyroid Cancers

The FDA approved pralsetinib for the treatment of adult and pediatric patients who are 12 years old or older with advanced or metastatic RET-mutant medullary thyroid cancer and require systemic therapy.

The FDA has approved pralsetinib (Gavreto) for the treatment of adult and pediatric patients who are 12 years old or older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and require systemic therapy. The agent is also indicated for patients who have RET fusion–positive thyroid cancer and require systemic therapy and who are refractory to radioactive iodine (RAI), if appropriate.1,2

Accelerated approval for the RET inhibitor in this setting is based on findings from the multicohort, open-label phase 1/2 ARROW trial (NCT03037385) of patients with various solid tumors harboring RET alterations. Continued approval for pralsetinib in these indications may be contingent upon verification of clinical benefit in confirmatory trial(s).

"Traditionally, we have treated patients with RET-altered thyroid cancers with multi-kinase inhibitors, non-selective therapies with modest efficacy and clinically significant side effects. The FDA approval of pralsetinib, a once-daily RET-targeted therapy, advances the standard of care for these patients," said Mimi Hu, MD, professor in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center, and an investigator on the ARROW trial, in a statement. "As a clinical researcher with a focus on thyroid cancer, I am encouraged by the safety profile and durable responses shown by Gavreto in RET-altered thyroid cancers in both treatment-naïve and previously treated patients."

In the cohort of patients with RET-mutant MTC, patients (n = 55) who were previously treated with either cabozantinib (Cabometyx) or vandetanib (Caprelsa) had an overall response rate (ORR) of 60% (95% CI, 46%-73%). Of these responders, 79% had responses lasting at least 6 months. Among those who were not previously treated with these multikinase inhibitors (n = 29), the ORR was 66% (95% CI, 46%-82%) and 84% of responders had responses lasting 6 months or longer.

Among a cohort of patients with RET fusion–positive solid tumors, 9 patients had RAI-refractory thyroid cancer. In this group of patients, the ORR was 89% (95% CI, 52%-100%) and all of these responding patients had responses that lasted at least 6 months.

The median duration of response was not yet reached for any of these 3 groups.

The ARROW trial is a first-in-human trial that examined the safety and efficacy of pralsetinib in patients with RET gene alterations in their tumors. It consisted of a dose-escalation phase and an expansion phase. The phase 2 expansion portion of the study included cohorts for patients with RET fusion–positive non–small cell lung cancer, RET mutation–positive MTC, and those with other RET fusion–positive solid tumors. Eligible patients were those with advanced solid tumors harboring RET alterations and no other driver mutations. In the phase 2 portion of the study, treatment with pralsetinib was administered at 400 mg orally once daily.

Primary end points of the phase 2 portion include centrally reviewed ORR per RECIST v1.1 criteria and safety.

The most common adverse events were constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. Common grade 3/4 laboratory abnormalities included decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased platelets, and increased alkaline phosphatase.

With the approval, the FDA recommended that pralsetinib be taken on an empty stomach with no food intake for at least 2 hours prior to taking pralsetinib and at least 1 hour after.

The new drug application was reviewing using the FDA’s Real-Time Oncology Review program and an Assessment Aid voluntary submission.

Previously the FDA granted the agent breakthrough therapy and orphan drug designations. Additionally, pralsetinib was previously approved for the treatment of patients with RET fusion–positive non–small cell lung cancer.


1. FDA approves pralsetinib for RET-altered thyroid cancers. News release. FDA. December 1, 2020. Accessed December 1, 2020. https://bit.ly/2VqIqsi

2. Blueprint Medicines Announces FDA Approval of GAVRETO™ (pralsetinib) for the Treatment of Patients with Advanced or Metastatic RET-Mutant and RET Fusion-Positive Thyroid Cancer. News release. Blueprint Medicines. December 1, 2020. Accessed December 1, 2020. https://prn.to/39vlEaH