What is ripretinib?
Ripretinib is an oral tyrosine kinase inhibitor that primarily works by inhibiting KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor A (PDGFRA) kinase signaling. Ripretinib also inhibits other kinases, including PDGFRB, TIE2, VEGFR2, and BRAF.
How does ripretinib work?
Ripretinib binds to both wild-type and mutant forms of KIT and PDGFRA. This potently inhibits activation of kinases across KIT and PDGFRA known to drive disease progression and drug resistance in gastrointestinal stromal tumor (GIST).
What is this approved for?
Ripretinib was granted accelerated approval and breakthrough therapy designation by the FDA for use in adults with advanced GIST who have received treatment with three or more kinase inhibitors, including imatinib.
What is the basis for this approval?
Ripretinib was approved based on the results of the INVICTUS (NCT03353753) trial. This was a randomized, double-blind, placebo-controlled trial in 129 GIST patients previously treated with imatinib, sunitinib, and regorafenib. Patients were randomized to either ripretinib 150 mg orally once daily or placebo in 28-day cycles. The primary outcome of progression-free survival showed a median of 6.3 months in the ripretinib arm compared to 1 month in the placebo arm (HR: 0.15, p < 0.0001). This was a statistically significant reduction of the risk of disease progression or death by 85 percent in the ripretinib arm compared to placebo (J Clin Oncol 2020;38(suppl)abstract11539).
How do you administer ripretinib?
Ripretinib is available as a 50 mg tablet and administered orally at a dose of 150 mg once daily. Tablets should be swallowed whole and can be taken with or without food.
Are there any pre-medications needed?
Ripretinib has minimal to low emetic risk. No routine pre-medications are recommended.
What are the common side effects associated with ripretinib (> or =20%)?
The most common adverse events were alopecia (52%), nausea (39%), abdominal pain (36%), constipation (34%), myalgia (32%), decreased appetite (27%), palmar-plantar erythrodysesthesia (21%), and vomiting (21%).
What are the uncommon side effects associated with ripretinib (less than 20%)?
Headache (19%), weight loss, (19%), arthralgia (18%), peripheral edema (17%), muscle spasms (15%), hypertension (14%), dyspnea (13%), dry skin (13%), asthenia (13%), pruritus (11%), and stomatitis (11%) were seen in studies. Rare but serious adverse effects include primary cutaneous malignancies, cardiac ischemic events, and embryo-fetal toxicity.
Are there any important drug interactions I should be aware of?
Ripretinib is primarily metabolized by CYP3A4. Coadministration with CYP3A4 inhibitors may result in an increased exposure to ripretinib and these patients should be monitored more frequently for adverse effects. Coadministration with a strong CYP3A4 inducer should be avoided due to the potential to decrease ripretinib exposure.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments are needed in patients with mild hepatic dysfunction; however, patients with moderate-to-severe hepatic function have not been evaluated in clinical trials. No dose adjustments are necessary for those with mild or moderate renal dysfunction.
What should my patients know about ripretinib?
* Patients should be advised to withhold ripretinib at least 1 week prior to elective surgery and continue holding for at least 2 weeks following major surgery or until adequate wound healing.
* Patients should use sun protection while taking ripretinib to decrease the risk of skin cancers.
* Pregnancy should be avoided due to the risk for embryo-fetal toxicity and both men and women should use effective contraception during treatment and at least 1 week following the last dose of ripritinib.
* Breastfeeding should be avoided during treatment and at least 1 week after the last dose.
What else should I know about ripretinib?
In a pooled safety analysis, squamous cell carcinoma and melanoma occurred in 7 percent and 0.9 percent of the patients who received ripretinib, respectively. In addition, ripretinib resulted in decreased ejection fraction in 1.7 percent of patients.
What useful links are available regarding ripretinib?
* https://www.decipheraaccesspoint.com/
Any ongoing clinical trials related to ripretinib?
Ripretinib is also being studied in phase I clinical trials in patients with advanced systemic mastocytosis and other advanced cancers, such as melanoma, germ cell, non-small cell lung carcinoma, etc. More information is available about these trials at http://clinicaltrials.gov.
SASHA HAARBERG, PHARMD, is Clinical Oncology Pharmacist at the Siteman Cancer Center and Washington University School of Medicine, St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.
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