Gavreto From Blueprint Medicines Corporation
RET fusions and mutations drive many types of cancer.
The FDA has approved GAVRETO (pralsetinib) from Blueprint Medicines Corporation for the treatment of metastatic RET fusion–positive non–small cell lung cancer (NSCLC) as detected by an agency-approved test, advanced or metastatic RET-mutant medullary thyroid cancer (MTC) requiring systemic therapy, and advanced or metastatic RET fusion–positive thyroid cancer requiring systemic therapy in patients who are radioactive iodine refractory.1 RET fusions and mutations drive many types of cancer. Approximately 1% to 2% of patients with NSCLC and 10% to 20% of patients with papillary thyroid cancer cases have RET fusion–positive tumors, and approximately 90% of patients with advanced MTC harbor RET mutations.2 Gavreto received an accelerated approval based on the overall response rate and duration of response. Its continued approval may be contingent upon additional confirmatory trials.1
PHARMACOLOGY AND PHARMACOKINETICS
Gavreto is a kinase inhibitor of wild-type RET and oncogenic RET fusions and mutations. After a single oral dose, the median time to peak concentration is 2 to 4 hours. Gavreto reaches steady-state concentrations after 3 to 5 days of treatment. Gavreto displays a mean elimination half-life of 15.7 hours after a single dose and 20 hours after multiple doses.1
DOSAGE AND ADMINISTRATION
The recommended dosage of Gavreto is 400 mg orally once daily on an empty stomach. Counsel patients to avoid food consumption for at least 2 hours before and at least 1 hour after their doses. Only patients with a gene mutation or RET gene fusion should receive treatment with Gavreto. When used for NSCLC, Gavreto is approved for adult patients only. When used for MTC or thyroid cancer, it is approved for patients 12 years and older. Gavreto is supplied as 100-mg capsules.1
The phase 1/2 ARROW clinical trial evaluated Gavreto in patients with RET fusion–positive metastatic NSCLC. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR). In 87 patients previously treated with platinum chemotherapy, the ORR was 57% with a 5.7% complete response rate, and the median DOR was not estimable. In 27 treatment-naive patients who were ineligible for platinum-based chemotherapy, the ORR was 70%, with an 11% complete response rate, and the median DOR was 9 months.1,3
The ARROW trial also evaluated Gavreto in patients with RET-mutant MTC and RET fusion–positive metastatic thyroid cancer. In 55 patients with RET-mutant metastatic MTC who were previously treated with cabozantinib, vandetanib, or both, the ORR was 60%, and the median DOR was not reached. In 29 patients with RET-mutant advanced MTC who were cabozantinib and vandetanib treatment- naive, the ORR was 66%, and the median DOR was not reached. In 9 patients with RET fusion–positive metastatic thyroid cancer, the ORR was 89%, and the median DOR was not reached.1,2
CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS
There are no contraindications to treatment with Gavreto.
Fatal, life-threatening, or severe interstitial lung disease or pneumonitis can occur in patients using Gavreto, which may require dose reduction or permanent or temporary discontinuation of treatment. Patients with uncontrolled hypertension should have their blood pressure (BP) controlled prior to beginning Gavreto. BP should be checked after 1 week of treatment and at least monthly during treatment. Subsequent hypertensive episodes may warrant the medication to be permanently discontinued, reduced, or withheld. Because serious hepatic adverse reactions have occurred, alanine aminotransferase and aspartate aminotransferase should be monitored before beginning Gavreto, every 2 weeks during the first 3 months, and monthly thereafter. Hepatoxicity may require discontinuation or dose reduction of Gavreto. Tumor lysis syndrome has been reported in patients with medullary thyroid carcinoma who used Gavreto. Gavreto should be permanently discontinued in patients with a life-threatening or severe hemorrhage. Gavreto should not be used for at least 5 days prior to elective surgery and for at least 2 weeks after major surgery. The medication can cause fetal harm. Women of reproductive potential should use an effective nonhormonal contraceptive during treatment and for 2 weeks after their last dose. Gavreto should not be used during breastfeeding.
Concomitant use of Gavreto with strong CYP3A inhibitors should be avoided.
Gavreto should not be used concurrently with combined P-glycoprotein and strong CYP3A inhibitors, but if this combination cannot be avoided, the dose of Gavreto should be reduced. Coadministration of Gavreto with strong CYP3A inducers should be avoided, but if this is not possible, the dose of Gavreto should be increased.
The most common adverse reactions are constipation, diarrhea, fatigue, hypertension, and musculoskeletal pain.
Monica Holmberg, PharmD, BCPS, is a pharmacist and Pharmacy Times contributor.
1. Gavreto. Prescribing information. Blueprint Medicines Corporation; 2020. Accessed December 7, 2020. https://www.blueprintmedicines.com/uspi/GAVRETO.pdf
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 Corporation. December 1, 2020. Accessed December 7, 2020. http://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-fda-approval-gavretotm-0
3. Blueprint Medicines announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Blueprint Medicines Corporation. September 4, 2020. Accessed December 7, 2020.