Trade names Inlyta MedlinePlus a612017 | AHFS/Drugs.com Monograph Routes of
administration Oral | |
 | ||
License data EU EMA: Inlyta
US FDA: Axitinib Pregnancy
category AU: D
US: D (Evidence of risk) | ||
Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.
Contents
- Renal cell carcinoma
- Clinical trials
- Contraindications
- Adverse effects
- Interactions
- Mechanism of action
- References
It was approved for RCC by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival, though there have been reports of fatal adverse effects.
Renal cell carcinoma
It has received approval for use as a treatment for renal cell carcinoma from US FDA (27 January 2012), EMA (13 September 2012), UK MHRA (3 September 2012) and Australian TGA (26 July 2012) .
Clinical trials
A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer. However, Pfizer reported on January 30, 2009 that Phase III clinical trials of the drug when used in combination with gemcitabine showed no evidence of improved survival rates over treatments using gemcitabine alone for advanced pancreatic cancer and halted the trial.
In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib. In December 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend that US FDA approve axitinib for the second-line treatment of patients with advanced renal cell carcinoma (RCC), based on the results of the Phase III trial comparing axitinib and sorafenib. It has also been trialled in combination with the ALK1 inhibitor dalantercept.
A study published in 2015 showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors like imatinib. This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient's own cells.
Contraindications
The only contraindication to axitinib is hypersensitivity to axitinib.
Cautions include:
Adverse effects
Diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation are the most common side effects occurring in more than 20% of patients.
Interactions
Coadministration with strong CYP3A4/CYP3A5 inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib.
Mechanism of action
Its primary mechanism of action is thought to be Vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours).
It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.
It has also been shown to bind (in a different conformation from the VEGF binding) to the BCR-ABL fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform.