FDA Approval Summary: Pralsetinib for the Treatment of Lung and Thyroid Cancers With RET Gene Mutations or Fusions

Abstract

The FDA granted accelerated approval for pralsetinib on September 4, 2020 for non–small cell lung cancer (NSCLC) and December 1, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion–positive NSCLC, (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was based on the results of a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385), demonstrating substantial overall response rates (ORR) and durable responses in patients with RET-altered tumors. ORRs within the approved patient populations ranged from 57% [95% confidence interval (CI), 46–68] in patients with RET fusion–positive NSCLC previously treated with platinum chemotherapy to 89% (95% CI, 52–100) in patients with RET fusion–positive thyroid cancer, with response duration of at least 6 months in most responders. The product label includes warnings and precautions for pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity. This article summarizes the major considerations during FDA review leading to the approval of pralsetinib.

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

“…Finally, the refined ligand library and the target protein molecule were optimized using the OPLS_2005 force field [ 24 ]. The pralsetinib was considered as a control for our analysis as it is an only RET-specific inhibitor that is approved by the Food and Drug Administration (FDA) in the recent time [ 25 , 26 ].…”

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

“…Since therapeutic molecules targeting RET rearrangements have been recently approved by the FDA and EMA, it is now mandatory to look for these genomic alterations in advanced NS-NSCLC (Figure 2, lower panel), as recommended by international guidelines. [75][76][77][78][79][80] Depending on the patient population and on the technique for detection, fusions in RET have been identified in 1%-2.8% of NSCLC Caucasian patients and unto 9% of patients in series of Asians. 81 They occur in F I G U R E 2 Show cases of NTRK (upper panel) and RET (lower panel) fusions.…”

RET signaling pathway and RET inhibitors in human cancer

“…Additionally, pralsetinib showed robust intracranial activity in 78% (7/9) of NSCLC patients with CNS metastases and mitigated progression of new CNS lesions, suggesting that pralsetinib crosses the BBB to act on brain metastases ( 274 ). Pralsetinib was granted accelerated approval by the FDA in 2020 for adults with metastatic RET fusion-positive NSCLC, and patients with metastatic RET-mutant MTC that may or may not be radioactive iodine-refractory ( 275 ). While pralsetinib is well-tolerated in patients included within the ARROW clinical trial, a recent report characterized leptomeningeal progression in a NSCLC patient despite durable extracranial response to pralsetinib, though this patient exhibited clinical CNS response following selpercatinib treatment ( 276 ), suggesting that selpercatinib may improve on the intracranial therapeutic efficacy of pralsetinib.…”