FDA Approval Sought for Pralsetinib to Treat Advanced RET+ Thyroid Cancers

A new drug application (NDA) has been submitted to the FDA for pralsetinib (BLU-667) for the treatment of patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion–positive thyroid cancers, according to an announcement from Blueprint Medicines, the developer of the drug.

A new drug application (NDA) has been submitted to the FDA for pralsetinib (BLU-667) for the treatment of patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion—positive thyroid cancers, according to an announcement from Blueprint Medicines, the developer of the drug.1

The NDA was submitted under the Real-Time Oncology Review pilot program, an initiative launched by the FDA’s Oncology Center of Excellence, which is focused on utilizing a more efficient review process to ensure the safe, effective therapies are made available to patients as early as possible without sacrificing review quality by the agency.

“Pralsetinib has broad potential to address the medical needs of patients with RET-altered cancers, who have not traditionally benefited from targeted therapy even though their tumors have a known disease driver,” Andy Boral, MD, PhD, Bluebird Medicine’s chief medical officer said in a recent press release. “There are now pending marketing applications for pralsetinib in RET-altered non—small cell lung cancer (NSCLC) and thyroid cancers, supporting our goal to advance treatment standards for these patients. We are working closely with the FDA and aim to bring this promising treatment to patients as expeditiously as possible.”

RET fusions are identified in approximately 10% to 20% of patients with papillary thyroid cancer and approximately 90% of MTC cases. Standard treatments have demonstrated limited efficacy in patients with solid tumors that harbor these fusions. Pralsetinib is a highly specific RET inhibitor that was designed to potently inhibit RET fusions and mutations, including predicted resistance mutations.

The RET inhibitor was found to induce responses in several patients with difficult-to-treat RET fusion—positive solid tumors, according to recent data from the phase 1/2 ARROW trial (NCT03037385) presented during the 2020 ASCO Virtual Scientific Program.2

The first-in-human phase 2 trial examined the safety and efficacy of the RET inhibitor in cohorts of patients with RET fusion—positive NSCLC, RET mutation–positive MTC, and patients with other RET fusion–positive solid tumors. To be eligible for enrollment, patients had to have an advanced solid tumor harboring RET alterations without any other driver mutations. Patients received 400 mg of oral pralsetinib once daily. The primary end points of the phase 2 portion of the trial was centrally reviewed ORR via RECIST v1.1 criteria and safety.

Results showed that in 11 patients with RET fusion—positive thyroid cancer, the ORR was 91% (95% CI, 59%-100%); this was comprised entirely of partial responses (PRs). The remaining patient achieved stable disease (SD; 9%). The disease control rate (DCR) reported with the agent in this patient population was 100% (95% CI, 72-100).

“Most of these patients had papillary thyroid cancer and pralsetinib is active in these patients regardless of the fusion partner,” lead study investigator Vivek Subbiah, MD, an associate professor in the Department of Investigational Cancer Therapeutics of the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center said during a presentation at the meeting. Treatment duration was also found to be prolonged, with 7 patients were still on the therapy.

In the presentation, Subbiah shared a case of a man aged 66 years who had poorly differentiated thyroid cancer that harbored a RET fusion and had not received any previous treatment. After having received pralsetinib, the patient achieved a deep and durable PR of 18 months, as well as a 94% shrinkage of target lesions. Throughout the course of treatment with the agent, thyroglobulin antibodies decreased from 1411 IU/mL to <1 IU/mL and the patient achieved complete clearance of NCOA4-RET fusion circulating tumor DNA.

Additionally, in 12 patients with RET fusion—positive solid tumors, the ORR with pralsetinib was 50% (95% CI, 21%-79%), again comprised of all PRs. A total of 5 patients also experienced SD, which led to a DCR of 92% (95% CI, 62%-100%). Again, responses were reported regardless of fusion partner; they were also experienced by heavily pretreated patients. Of note, all 3 patients with pancreatic adenocarcinoma and both patients with cholangiocarcinoma achieved a PR with the treatment. At the time of the report, 6 patients in the subgroup were still receiving treatment.

With regard to safety, the majority of adverse events (AEs) reported were grade 1 or 2, and the most commonly reported treatment-related AEs included anemia (33%), increased AST (33%), reduced white blood cell count (33%), hypertension (30%), increased ALT (26%), hyperphosphatemia (19%), and neutropenia (19%). Notably, no patients discontinued treatment with the agent because of treatment-related AEs.

In May 2020, the United States and European marketing applications for pralsetinib as a treatment for patients with locally advanced or metastatic RET fusion—positive NSCLC were accepted by the FDA and validated by the European Medicines agency, respectively.


1. Blueprint Medicines announces submission of new drug application to FDA for pralsetinib for the treatment of advanced RET mutant and RET fusion—positive thyroid cancers. News release. Blueprint Medicines. July 1, 2020. Accessed July 1, 2020. bit.ly/3ip9QZB.

2. Subbiah V, Hu MI, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. J Clin Oncol. 2020;38(suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109