Axitinib: Oral tyrosine kinase inhibitor for renal cell carcinoma

Abstract

Axitinib (Inlyta—Pfizer) is the newest oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. This treatment Joins a variety of other tyrosine kinase inhibitors recently approved for the management of renal cell carcinoma such as sunitinib (Sutent—Pfizer), sorafenib (Nexavar—Bayer), and pazopanib (Votrient—GlaxoSmithKline).Axitinib works by inhibiting receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-l, VEGFR-2, and VEGFR-3. These receptors are responsible for pathologic angiogenesis, tumor growth, and cancer progression. Data suggest that axitinib may be more selective for VEGFR-1, −2, and −3 compared with the other agents.Renal cell carcinomaIn 2011, the estimated number of kidney and renal tumors diagnosed in the United States exceeded 60,000, and deaths from renal cancers approached 14,000. Once renal carcinoma is metastatic, median survival is estimated to be about 2 years.The good news is that numerous treatments have come to market in recent years to treat the disease. In addition to the tyrosine kinase inhibitors described above, the monoclonal antibody that targets VEGF-A (bevacizumab [Avastin—Genentech]) and the rapamycin analogs (temsirolimus [Torisel—Pfizer] and everolimus [Afinitor—Novartis]) have all demonstrated efficacy as either first- or second-line treatment options for renal cell carcinoma. Axitinib’s place in therapy is as a second-line treatment option for patients who fail at least one prior therapy.Clinical dataThe safety and effectiveness of axitinib were evaluated in a Phase III open-label, multicenter clinical trial that randomized 723 patients whose disease had progressed on or after treatment with one prior systemic therapy to axitinib (n = 361) or sorafenib (n = 362). Results showed that axitinib significantly extended progression-free survival (hazard ratio 0.67 [95% CI 0.54-0.81], P < 0.0001] with a median progression-free survival of 6.7 months (95% CI 6.3-8.6) compared with 4.7 months (95% CI 4.65.6) for those treated with sorafenib. This represented a 43% improvement in median progression-free survival compared with sorafenib.Adverse events, including numerous serious events (see sidebar), are a concern with axitinib therapy. More than half of patients given axitinib (55%) required dosage modifications or a temporary delay of treatment because of adverse events in clinical trials. The most common events observed in more than 20% of patients in the clinical study were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia (loss of voice), palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, vomiting, asthenia, and constipation. Drug interactions with cytochrome (CYP) 3A4/5 inhibitors and CYP3A4/5 inducers are also a concern with axitinib.Patient counselingEducate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment.Axitinib (Inlyta)Manufacturer: PfizerDrug class: Oral tyrosine kinase inhibitorIndication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapyDosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm. Axitinib (Inlyta—Pfizer) is the newest oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. This treatment Joins a variety of other tyrosine kinase inhibitors recently approved for the management of renal cell carcinoma such as sunitinib (Sutent—Pfizer), sorafenib (Nexavar—Bayer), and pazopanib (Votrient—GlaxoSmithKline). Axitinib works by inhibiting receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-l, VEGFR-2, and VEGFR-3. These receptors are responsible for pathologic angiogenesis, tumor growth, and cancer progression. Data suggest that axitinib may be more selective for VEGFR-1, −2, and −3 compared with the other agents. Renal cell carcinomaIn 2011, the estimated number of kidney and renal tumors diagnosed in the United States exceeded 60,000, and deaths from renal cancers approached 14,000. Once renal carcinoma is metastatic, median survival is estimated to be about 2 years.The good news is that numerous treatments have come to market in recent years to treat the disease. In addition to the tyrosine kinase inhibitors described above, the monoclonal antibody that targets VEGF-A (bevacizumab [Avastin—Genentech]) and the rapamycin analogs (temsirolimus [Torisel—Pfizer] and everolimus [Afinitor—Novartis]) have all demonstrated efficacy as either first- or second-line treatment options for renal cell carcinoma. Axitinib’s place in therapy is as a second-line treatment option for patients who fail at least one prior therapy. In 2011, the estimated number of kidney and renal tumors diagnosed in the United States exceeded 60,000, and deaths from renal cancers approached 14,000. Once renal carcinoma is metastatic, median survival is estimated to be about 2 years. The good news is that numerous treatments have come to market in recent years to treat the disease. In addition to the tyrosine kinase inhibitors described above, the monoclonal antibody that targets VEGF-A (bevacizumab [Avastin—Genentech]) and the rapamycin analogs (temsirolimus [Torisel—Pfizer] and everolimus [Afinitor—Novartis]) have all demonstrated efficacy as either first- or second-line treatment options for renal cell carcinoma. Axitinib’s place in therapy is as a second-line treatment option for patients who fail at least one prior therapy. Clinical dataThe safety and effectiveness of axitinib were evaluated in a Phase III open-label, multicenter clinical trial that randomized 723 patients whose disease had progressed on or after treatment with one prior systemic therapy to axitinib (n = 361) or sorafenib (n = 362). Results showed that axitinib significantly extended progression-free survival (hazard ratio 0.67 [95% CI 0.54-0.81], P < 0.0001] with a median progression-free survival of 6.7 months (95% CI 6.3-8.6) compared with 4.7 months (95% CI 4.65.6) for those treated with sorafenib. This represented a 43% improvement in median progression-free survival compared with sorafenib.Adverse events, including numerous serious events (see sidebar), are a concern with axitinib therapy. More than half of patients given axitinib (55%) required dosage modifications or a temporary delay of treatment because of adverse events in clinical trials. The most common events observed in more than 20% of patients in the clinical study were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia (loss of voice), palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, vomiting, asthenia, and constipation. Drug interactions with cytochrome (CYP) 3A4/5 inhibitors and CYP3A4/5 inducers are also a concern with axitinib.Patient counselingEducate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment.Axitinib (Inlyta)Manufacturer: PfizerDrug class: Oral tyrosine kinase inhibitorIndication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapyDosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm. The safety and effectiveness of axitinib were evaluated in a Phase III open-label, multicenter clinical trial that randomized 723 patients whose disease had progressed on or after treatment with one prior systemic therapy to axitinib (n = 361) or sorafenib (n = 362). Results showed that axitinib significantly extended progression-free survival (hazard ratio 0.67 [95% CI 0.54-0.81], P < 0.0001] with a median progression-free survival of 6.7 months (95% CI 6.3-8.6) compared with 4.7 months (95% CI 4.65.6) for those treated with sorafenib. This represented a 43% improvement in median progression-free survival compared with sorafenib. Adverse events, including numerous serious events (see sidebar), are a concern with axitinib therapy. More than half of patients given axitinib (55%) required dosage modifications or a temporary delay of treatment because of adverse events in clinical trials. The most common events observed in more than 20% of patients in the clinical study were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia (loss of voice), palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, vomiting, asthenia, and constipation. Drug interactions with cytochrome (CYP) 3A4/5 inhibitors and CYP3A4/5 inducers are also a concern with axitinib.Patient counselingEducate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment.Axitinib (Inlyta)Manufacturer: PfizerDrug class: Oral tyrosine kinase inhibitorIndication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapyDosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm. Patient counselingEducate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment.Axitinib (Inlyta)Manufacturer: PfizerDrug class: Oral tyrosine kinase inhibitorIndication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapyDosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm. Patient counselingEducate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment. Educate patients that capsules should be swallowed whole with a full glass of water and doses should be spaced by approximately 12 hours. If doses are missed, patients should not double doses. In terms of adverse events, educate patients on the potential for elevations in blood pressure and the signs and symptoms of arterial and venous thromboembolic events (e.g., chest pain, numbness or weakness on one side). Inform patients about the potential for birth defects in fetuses and the importance of using effective birth control during treatment. Axitinib (Inlyta)Manufacturer: PfizerDrug class: Oral tyrosine kinase inhibitorIndication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapyDosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm. Manufacturer: Pfizer Drug class: Oral tyrosine kinase inhibitor Indication: Treatment of advanced renal cell carcinoma after failure of one prior systemic therapy Dosage: Starting dose is 5 mg twice daily with or without food; doses should be taken approximately 12 hours apart.■Patients who are able to tolerate axitinib for at least 2 consecutive weeks can have their dose increased to 7 mg twice daily for at least 2 weeks and then to 10 mg twice daily.■If dose reductions are needed because of adverse events, reductions to 3 mg twice daily and then 2 mg twice daily are recommended.■Dosage reductions are also recommended for patients receiving strong cytochrome 3A4/5 inhibitors and for those with moderate hepatic impairment. Refer to prescribing information for detailed information on dosage reductions in these situations.Of note: Hypertension and hypertensive crisis can occur with axitinib. Blood pressure should be monitored closely during treatment.■Although rare, arterial thromboembolic events have been reported to occur with axitinib. These events have included transient ischemic attacks, cerebrovascular accidents, myocardial infarctions, and retinal artery occlusion, with some events resulting in death.■Other warnings and precautions for axitinib include venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes and hepatic impairment.■Women of childbearing age should avoid becoming pregnant, as axitinib may cause fetal harm.