In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On December 1, 2020, pralsetinib (Gavreto) was granted approval by the U.S. Food and Drug Administration (FDA) for treatment of adult and pediatric patients (12 years of age and older) with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy or RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate).^1,2

Supporting Efficacy Data

The approval was supported by findings in the multicenter, multicohort phase I/II ARROW trial (ClinicalTrials.gov identifier NCT03037385) in patients whose tumors had RET gene alterations.² Identification of RET gene alterations was prospectively determined in local laboratories using next-generation sequencing, fluorescence in situ hybridization, or other tests.

The main efficacy outcome measures were overall response rate and response duration assessed by blinded independent review committee using Response Evaluation Criteria in Solid Tumors, v1.1. Among 55 evaluable patients with advanced or metastatic RET-mutant medullary thyroid cancer who received prior cabozantinib or vandetanib, an objective response was observed in 33 (60%, 95% confidence interval [CI] = 46%–73%), with a complete response in 1. The median duration of response was not reached (95% CI = 15.1 months to not estimable), with 79% of responders having a response of at least 6 months. Among 29 patients with RET-mutant medullary thyroid cancer who did not receive prior cabozantinib or vandetanib, an objective response was observed in 19 (66%, 95% CI = 46%–82%), with a complete response in 3. The median duration of response was not reached, with 84% of responders having a response for at least 6 months. Among nine patients with RET fusion–positive thyroid cancer who were radioactive iodine–refractory, an objective response was observed in 8 (89%, 95% CI = 52%–100%). The median duration of response was not reached, with all responders having a response for at least 6 months.

How It Works

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M, and RET M918T). At higher but clinically achievable concentrations, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited antitumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L, and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.

How It Is Used

Patients must be selected for pralsetinib treatment based on the presence of a RET gene fusion in thyroid cancer or a RET gene mutation in medullary thyroid cancer. An FDA-approved test for the detection of RET gene fusion in thyroid cancer and RET gene mutations is not currently available.

The recommended pralsetinib dose in adults and pediatric patients aged ≥ 12 years is 400 mg orally once daily on an empty stomach with no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib. Treatment should be continued until disease progression or unacceptable toxicity. The recommended dose reductions for adverse reactions are sequentially to 300 mg, 200 mg, and 100 mg once daily. Treatment should be discontinued in patients unable to tolerate 100 mg once daily.

Concomitant use of pralsetinib with strong CYP3A inhibitors, combined P-glycoprotein and strong CYP3A inhibitors, and strong CYP3A inducers should be avoided. Prescribing information provides instructions on pralsetinib dose reduction if concomitant use with combined P-glycoprotein and strong CYP3A inhibitors cannot be avoided and pralsetinib dose increase if concomitant use with strong CYP3A inducers cannot be avoided.

Safety Profile

Among the 138 patients with RET-altered thyroid cancer receiving pralsetinib in ARROW, the most common adverse events of any grade (≥ 25%) were musculoskeletal pain, constipation, hypertension, fatigue, diarrhea, and edema. The most common grade 3 or 4 adverse events included hypertension, fatigue, and diarrhea. The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased calcium, and decreased phosphate.

Serious adverse events occurred in 39% of patients, with those occurring in at least 2% of patients consisting of pneumonia, pneumonitis, urinary tract infection, pyrexia, fatigue, diarrhea, dizziness, anemia, hyponatremia, and ascites. Adverse events led to dosage interruption in 67% of patients and to dose reduction in 44%. Adverse events led to permanent discontinuation of treatment in 9% of patients. Fatal adverse events occurred in 2.2% of patients, with the most common being pneumonia in two patients.

Pralsetinib has warnings/precautions for interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor-lysis syndrome, risk of impaired wound healing, and embryofetal toxicity. Treatment should be permanently discontinued for recurrent interstitial lung disease/pneumonitis or grade 3 or 4 interstitial lung disease/pneumonitis. Treatment should not be started in patients with uncontrolled hypertension. Alanine aminotransferase and aspartate aminotransferase levels should be monitored prior to initiating treatment, every 2 weeks during the first 3 months, then monthly thereafter, and as clinically indicated. Treatment should be permanently discontinued for severe or life-threatening hemorrhage. Treatment should be withheld for at least 5 days prior to elective surgery and for at least 2 weeks following major surgery. 

Patients should be advised not to breastfeed while receiving pralsetinib. In pediatric use, open growth plates should be monitored in adolescent patients, and interruption or discontinuation of treatment should be considered if abnormalities occur. 

REFERENCES

1. U.S. Food and Drug Administration: 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. Accessed December 14, 2020.

2. Gavreto (pralsetinib) capsules prescribing information, Blueprint Medicines Corporation, September 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf. Accessed December 14, 2020.