The FDA has approved the oral tyrosine kinase inhibitor ripretinib (Qinlock – Deciphera) for treatment of adults with advanced gastrointestinal stromal tumors (GISTs) who have previously received treatment with ≥3 kinase inhibitors, including imatinib (Gleevec, and generics).

The FDA has approved the oral tyrosine kinase inhibitor avapritinib (Ayvakit – Blueprint Medicines) for treatment of unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) D842V or other PDGFRA exon 18 mutation. Avapritinib is the first drug to be approved for this indication in the US.

The FDA has approved the oral tyrosine kinase inhibitor cabozantinib (Cabometyx – Exelixis) for treatment of patients with advanced renal cell carcinoma previously treated with antiangiogenic therapy. Cabozantinib was first approved in 2012 as Cometriq for treatment of progressive, metastatic medullary thyroid cancer.

Anti-VEGF antibodies, tyrosine kinase inhibitors, and mTOR kinase inhibitors have become the standard of care for treatment of unresectable or metastatic renal cell cancer.1

FDA approval was based on the results of a randomized open-label trial (METEOR) comparing cabozantinib to everolimus in 658 patients with advanced or metastatic renal cell carcinoma that had progressed on antivascular endothelial growth factor receptor (VEGFR) therapy. In patients treated with cabozantinib, median progression-free survival was significantly longer (7.4 vs 3.8 months with everolimus) and the objective response rate was significantly higher (21% vs 5% with everolimus).2Median overall survival was 21.4 months with cabozantinib and 16.5 months with everolimus.3

Common adverse effects of cabozantinib include diarrhea, fatigue, nausea, vomiting, weight loss, palmar-plantar erythrodysesthesia, and hypertension. Serious adverse effects, including GI perforation, hemorrhage, and arterial thromboembolic events, occurred in >60% of patients treated with cabozantinib in the clinical trial.

The recommended dosage of cabozantinib is 60 mg taken once daily without food. Dosage adjustments are required for patients taking strong CYP3A4 inhibitors or inducers concomitantly.4 In patients who experience severe or intolerable adverse effects, reducing the dosage or withholding the drug until improvement occurs is recommended.

1. Axitinib (Inlyta) for advanced renal cell carcinoma. Med Lett Drugs Ther 2012; 54:47.
2. TK Choueiri et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373:1814.
3. TK Choueiri et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016 June 3 (epub).
4. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2016; 58:e46.

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Regorafenib (Stivarga – Bayer), a multikinase inhibitor, has been approved by the FDA for treatment of patients with metastatic colorectal cancer previously treated with multiple other regimens specified in the labeling. It has also been approved for use in treatment-refractory, locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST).

Axitinib (Inlyta – Pfizer), an oral tyrosine kinase inhibitor, has been approved by the FDA for treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. It is the fourth oral tyrosine kinase inhibitor to be approved for treatment of advanced renal cell carcinoma.

Everolimus (Afinitor – Novartis) and pazopanib (Votrient – GlaxoSmithKline), two oral multikinase inhibitors, have been approved by the FDA for treatment of advanced renal cell carcinoma. Sunitinib (Sutent) and sorafenib (Nexavar), two other oral multikinase inhibitors, and temsirolimus (Torisel), an IV multikinase inhibitor, were approved earlier for the same indication.

Temsirolimus (Torisel - Wyeth), an mTOR (mammalian target of rapamycin) kinase inhibitor that is metabolized to sirolimus (rapamycin), has been approved by the FDA for intravenous treatment of advanced renal cell carcinoma.

Sunitinib (Sutent - Pfizer) and sorafenib (Nexavar - Bayer), two oral tyrosine kinase inhibitors, have been approved by the FDA for treatment of advanced renal cell carcinoma (RCC). Sunitinib is also approved for use in patients with gastrointestinal stromal tumor (GIST) who are not responding to or are intolerant of standard therapy with imatinib (Gleevec).