By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the second highly selective and potent kinase inhibitor for a specific form of non-small cell lung cancer (NSCLC). Pralsetinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and oncogenic RET fusions and mutations.1 The agency granted the drug priority review and breakthrough therapy designation. The FDA based its designations on the overall response rate and duration of response data from a Phase I/II study. Continued approval may be contingent on demonstration of clinical benefit. Pralsetinib is distributed as Gavreto.

INDICATIONS

Pralsetinib should be prescribed to treat adults with metastatic RET, fusion-positive NSCLC.1 There is an FDA-approved test to detect RET mutation.

DOSAGE

The recommended dose is 400 mg (4 × 100 mg capsules) once daily on an empty stomach.1 The patient should not consume food at least two hours before or at least one hour after taking pralsetinib. Continue prescribing the drug until the patient records unacceptable toxicity levels or the disease progresses. Modify or reduce the dose if there are adverse reactions (e.g., pneumonitis, hypertension, hepatotoxicity, hemorrhagic events) and for concomitant use with P-glycoprotein and strong CYP3A inhibitors or inducers.1 Pralsetinib is available as 100 mg capsules.

POTENTIAL ADVANTAGES

Pralsetinib showed response (i.e., tumor shrinkage) in both previously treated and treatment-naïve patients as well as those with central nervous system metastasis.1 In contrast to selpercatinib, pralsetinib does not carry a warning for QT interval prolongation.

POTENTIAL DISADVANTAGES

Pralsetinib can cause severe, life-threatening, and fatal interstitial lung disease/pneumonitis, with a frequency of 10% overall (2.7% with grade 3-4; 0.5% fatal).1 Other serious adverse events can include hypertension (14% grade 3), increase in AST/ALT (5-6% grade 3 or 4), hemorrhagic events (2.5% grade ≥ 3), and potential for embryo-fetal toxicity. It also can impair wound healing because of inhibition of the vascular endothelial growth factor signaling pathway.1 Dose interruption caused by adverse reactions occurred in 60% of patients, dose reduction in 36%, and permanent discontinuation in 15%.1 The most frequently reported adverse reactions (> 30%) were fatigue, constipation, musculoskeletal pain, and laboratory abnormalities (higher AST, ALT, creatinine, alkaline phosphate levels; lower hemoglobin, lymphocytes, neutrophils levels.)1 Unlike selpercatinib, pralsetinib is not approved for RET mutant medullary thyroid or RET fusion-positive thyroid cancer.

COMMENTS

The efficacy of pralsetinib was evaluated in an open-label, nonrandomized clinical trial that included subjects with RET fusion-positive metastatic NSCLC.1 The subjects were enrolled into two cohorts: those who had progressed on platinum-based chemotherapy and those who were treatment-naïve. Subjects with asymptomatic central nervous system metastasis (including those with stable or decreasing steroid use within two weeks before study entry) were enrolled. The primary efficacy outcomes were overall response rate (ORR) and duration of response (DOR). These tumor-centric criteria (i.e., improved, stabilized, or worse) were based on imaging (e.g., CT, MRI) and assessed by a blinded, independent, central review. In the treatment-experienced cohort (n = 87), ORR was 57% (52% partial response). Eighty percent had DOR ≥ 6 months. For the treatment-naïve cohort (n = 27), ORR was 70% (11% complete response, 59% partial response). Fifty-eight percent had DOR ≥ 6 months.

CLINICAL IMPLICATIONS

RET is a transmembrane receptor protein-tyrosine kinase (proto-oncogene) required for normal tissue development and maturation. The RET rearrangement (i.e., chromosomal rearrangement/mutation) gene has been associated with 1-2% of NSCLC, particularly in patients who never smoked (or in those who smoked lightly and developed lung adenocarcinoma) and patients who are younger.2-5 Currently, the National Comprehensive Cancer Network guidelines (Version 8.2020) lists both selpercatinib and pralsetinib as “preferred” therapy when RET rearrangement is detected before first-line systemic therapy or after completion of first-line systemic therapy (if discovered during therapy). Pralsetinib may offer an advantage to patients at risk of QTc prolongation. The cost for a 30-day supply of pralsetinib is $19,243 vs. $20,600 for selpercatinib.

REFERENCES

  1. Blueprint Medicines Corporation. Gavreto prescribing information. September 2020.
  2. Zhang Q, Xu C, Wang W, et al. Comparison of rearranged during transfection (RET) gene rearrangements in primary versus metastatic non-small cell lung cancer (NSCLC). Med Sci Monit 2018;24:8207-8212.
  3. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry. J Clin Oncol 2017;1:1403-1410.
  4. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2017;13:27-45.
  5. Stinchcombe TE. Current management of RET rearranged non-small cell lung cancer. Ther Adv Med Oncol 2020;12:1-11.