Axitinib is a second-generation tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; the drug is an antineoplastic agent.1, 2, 8, 9, 10, 16
First-line Therapy in Patients with Advanced Renal Cell Carcinoma
Axitinib is used in combination with avelumab or pembrolizumab for the first-line treatment of advanced renal cell carcinoma.1 Axitinib also has been used as monotherapy for the first-line treatment of metastatic renal cell carcinoma† .25
Combination Therapy with Avelumab
Axitinib is used in combination with avelumab for the first-line treatment of advanced renal cell carcinoma.1 Efficacy of axitinib in combination with avelumab was demonstrated in the open-label, randomized, controlled trial (JAVELIN Renal 101) in 886 patients with previously untreated advanced renal cell carcinoma with clear cell histology regardless of tumor PD-L1 expression (intent-to-treat [ITT] population).1, 21 Patients with an autoimmune disease or conditions requiring systemic immunosuppression were excluded.1 The median age of patients was 61 years; 75% were male, 75% were white, and an Eastern Cooperative Oncology Group (ECOG) performance status score was 0 or 1 in 63 or 37% of patients, respectively.1 The International Metastatic Renal Cell Carcinoma Database (IMDC) risk group status was favorable, intermediate, or poor in 21, 62, or 16% of patients, respectively.1 Patients were randomized to receive axitinib in combination with avelumab or sunitinib monotherapy until disease progression or unacceptable toxicity.1 Patients randomized to axitinib received a dosage of 5 mg orally twice daily in combination with avelumab 10 mg/kg administered by IV infusion every 2 weeks; the dosage of axitinib was increased to 7 mg twice daily, followed by an increase to 10 mg twice daily if tolerated.1 Patients randomized to sunitinib received a dosage of 50 mg orally once daily for 4 consecutive weeks followed by 2 weeks without therapy.1
The primary measures of efficacy were progression-free survival and overall survival in patients with PD-L1-positive tumors.1 In the first interim analysis, progression-free survival was substantially prolonged in patients treated with axitinib in combination with avelumab compared with those treated with sunitinib.1 Among patients with PD-L1-positive tumors, median progression-free survival was 13.8 months in patients treated with axitinib in combination with avelumab and 7.2 months in those treated with sunitinib.21 In the overall study population, median progression-free survival was 13.8 months in patients treated with axitinib in combination with avelumab and 8.4 months in those treated with sunitinib.1, 21 At a median follow-up of 19 months, overall survival had not been reached.1 In the overall study population and cohort of patients with PD-L1-positive tumors, progression-free survival benefit was maintained in patients receiving axitinib in combination with avelumab at the time of the second interim analysis.22
Combination Therapy with Pembrolizumab
Axitinib is used for the first-line treatment of advanced renal cell carcinoma in combination with pembrolizumab.1 50 Efficacy of axitinib in combination with pembrolizumab was investigated in the open-label, randomized, controlled trial (KEYNOTE-426) in 861 patients who had not received systemic therapy for advanced renal cell carcinoma.1, 23 Patients were enrolled regardless of PD-L1 tumor expression status.1 Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were excluded.1 Patients were randomized to receive axitinib in combination with pembrolizumab or sunitinib monotherapy.1 Axitinib and sunitinib were continued until disease progression or unacceptable toxicity occurred.1 Pembrolizumab was continued for up to 24 months or until disease progression or unacceptable toxicity occurred.1 Patients randomized to axitinib received a dosage of 5 mg orally twice daily in combination with pembrolizumab 200 mg IV every 3 weeks; the dosage of axitinib was increased to 7 mg twice daily, followed by an increase to 10 mg twice daily if the initial 5 mg dosage was tolerated for 2 consecutive cycles.1 Patients randomized to sunitinib received a dosage of 50 mg orally once daily for 4 consecutive weeks followed by 2 weeks without therapy.1 The median age of patients enrolled in the study was 62 years; 73% were male, 79% were white, 20% were Asian, and 80% of patients had a baseline Karnofsky performance status of 90-100.1 IMDC risk group status was favorable, intermediate, or poor in 31, 56, or 13% of patients, respectively.1
The primary measures of efficacy were overall survival and progression-free survival.1 At a median follow-up duration of 12.8 months, overall survival was substantially prolonged in patients treated with axitinib in combination with pembrolizumab compared with those treated with sunitinib.1 An updated analysis was conducted at the time of 418 observed deaths; patients treated with axitinib in combination with pembrolizumab were reported to have an overall survival of 45.7 months compared with 40.1 months in those treated with sunitinib.1 Median progression-free survival was prolonged (15.1 versus 11 months) and objective response rate was higher (59 versus 36%) in patients treated with axitinib in combination with pembrolizumab compared with those treated with sunitinib.1 Consistent results were observed across prespecified subgroups, IMDC risk categories and PD-L1 tumor expression status.1
Long-term follow-up of the KEYNOTE-426 study demonstrated continued clinical benefit in patients treated with axitinib in combination with pembrolizumab compared with those treated with sunitinib.24 At a median duration of follow-up of 30.6 months, median progression-free survival was 15.4 or 11.1 months in patients treated with axitinib in combination with pembrolizumab compared with those treated with sunitinib; at the time of analysis, median overall survival had not been reached in patients treated with axitinib in combination with pembrolizumab.24
Second-line Therapy in Patients with Advanced Renal Cell Carcinoma
Axitinib is used as monotherapy for the treatment of advanced renal cell carcinoma following failure of one prior systemic therapy.1, 2, 3, 13 Efficacy of axitinib as a single agent for second-line treatment of advanced renal cell carcinoma is based principally on the results of a randomized, open-label, multicenter, phase 3 study (AXIS) in adults whose disease progressed during or following treatment with one prior systemic therapy (i.e., sunitinib-, bevacizumab plus interferon alfa-, temsirolimus-, or cytokine-based therapy).1, 2 In the AXIS study, 723 patients were randomized in a 1:1 ratio to receive either axitinib (5 mg orally twice daily initially with dosage adjustment as needed) or sorafenib (400 mg orally twice daily initially with dosage adjustment as needed).1, 2 Patients were treated until disease progression, unacceptable toxicity, death, or withdrawal of patient consent.2 The primary end point of this study was progression-free survival; secondary endpoints included overall survival, objective response rate, duration of response, and time to deterioration.1, 2 The median age of patients enrolled in the study was 61 years; enrolled patients had received one prior therapy for their disease, including regimens consisting of sunitinib (54% of patients), cytokines (35%), bevacizumab (8%), and temsirolimus (3%).1, 2 The majority of enrolled patients (99%) had clear-cell carcinoma histology.1
Patients receiving axitinib in the AXIS study had a substantially longer median progression-free survival than those receiving sorafenib (6.7 versus 4.7 months).1, 2 In the patients treated with axitinib, median progression-free survival was longer in those who had previously been treated with a cytokine (12.1 months) than in those previously treated with sunitinib (4.8 months).1, 2 Improved progression-free survival was observed in the axitinib-treated patients regardless of their Memorial Sloan-Kettering Cancer Center (MSKCC) risk category, gender, age, or region.2 Patients receiving axitinib also had higher objective response rates (19 versus 9%) with a median response duration of 11 months for those receiving axitinib and 10.6 months for those receiving sorafenib; there were no complete responses in the axitinib treatment group.1, 2 Median overall survival was 20.1 months with axitinib and 19.2 months with sorafenib, which was not a statistically significant difference.1 Treatment was discontinued because of adverse effects in 4% of patients receiving axitinib compared with 8% of those receiving sorafenib.2
Use of axitinib also was investigated in an open-label, multicenter, phase 2 study in 62 adults with sorafenib-refractory metastatic renal cell carcinoma whose disease had progressed following at least one prior systemic therapy.13 All patients enrolled in this study had undergone nephrectomy and approximately 95% of patients had clear-cell and/or mixed histology.13 All patients received axitinib at an initial dosage of 5 mg orally twice daily with subsequent dosage adjustments based on tolerability.13 Most patients (74.2%) in this study were treated with at least 2 prior systemic therapies.13 In addition, 85.5% received sorafenib as the only or final treatment before beginning axitinib therapy.13 The primary end point of this study was objective response rate.13 The objective response rate with axitinib therapy was 22.6% with a median response duration of 17.5 months; there were no complete responses.13 At a median follow-up of 22.7 months, the study revealed a median progression-free survival of 7.4 months and median overall survival of 13.6 months with axitinib therapy.13
Prognosis is generally poor in patients with metastatic RCC, including those who have undergone complete tumor resection.51 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced RCC; however, relapsed or refractory RCC eventually develops in most patients.52 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have generally become a standard for the treatment of advanced RCC.53 A limited number of randomized controlled trials have compared sunitinib with other treatment options for advanced renal cell carcinoma (e.g., pembrolizumab plus axitinib,20 avelumab plus axitinib,21 atezolizumab plus bevacizumab,22 nivolumab plus ipilimumab,23 nivolumab plus cabozantinib,24 or lenvatinib plus pembrolizumab.25 In clinical trials, combination chemotherapy resulted in longer progression-free survival compared with sunitinib alone in patients with previously untreated advanced renal cell carcinoma.20, 21, 22, 23, 24, 25
Some experts also state that subsequent monotherapy with a tyrosine kinase inhibitor (e.g., sunitinib, pazopanib) may be offered as an alternative to programmed death 1 (PD-1) inhibitor-based combinations in the first-line setting when immune checkpoint therapy is contraindicated or not available or as a second-line option following disease progression during immune checkpoint inhibitor-based therapy.54
Axitinib has also been used in the treatment of advanced thyroid cancer†.26
Dispensing and Administration Precautions
Axitinib is administered orally twice daily (in doses given approximately 12 hours apart).1 The drug may be given without regard to meals.1 Axitinib tablets should be swallowed whole with a full glass of water;1, 3 the tablets should not be crushed or split.1, 3
If a dose of axitinib is missed or vomited, patients should not double the dosage or take extra doses.1 The next dose should be taken at the regularly scheduled time.1
For patients unable to swallow tablets in clinical trials, axitinib tablets have been dissolved (without crushing) in 15 mL of USP-grade water in an amber-colored syringe and administered through a nasogastric tube; use of tap or bottled water was avoided.3 The nasogastric tube should be flushed with 15 mL of USP-grade water prior to and following administration of the dose.3 The prepared dose should not be exposed to direct light and should be prepared just prior to administration.3
Procedures for proper handling of antineoplastic drugs should be followed when preparing doses of axitinib for nasogastric administration.3
Store axitinib tablets at 20-25ºC; excursions permitted between 15-30ºC.1
First-line Therapy: Combination Therapy with Avelumab
For the first-line treatment of advanced renal cell carcinoma in adults, the recommended initial dosage of axitinib is 5 mg twice daily (12 hours apart) in combination with avelumab (800 mg by IV infusion over 60 minutes every 2 weeks) until disease progression or unacceptable toxicity.1 In the principal efficacy study, patients received axitinib for a median duration of 9 months.21 When used in combination with avelumab, increases of axitinib dosage above the initial 5 mg dosage may be considered at intervals of 2 weeks or longer.1 Consult the Full Prescribing Information for recommended avelumab dosing.1
During the course of therapy, patients who tolerate axitinib for at least 2 consecutive weeks without adverse effects greater than grade 2, are normotensive, and are not receiving antihypertensive agents may have their axitinib dosage increased.1 When a dosage increase from 5 mg twice daily is recommended, the dosage may be increased to 7 mg twice daily, and then further increased to 10 mg twice daily using the same criteria.1
First-line Therapy: Combination Therapy with Pembrolizumab
For the first-line treatment of advanced renal cell carcinoma in adults, the recommended initial dosage of axitinib is 5 mg twice daily (12 hours apart) in combination with pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks administered as an IV infusion over 30 minutes) until disease progression or unacceptable toxicity.1 In the principal efficacy study, patients received axitinib for a median duration of 10.4 months.23 When used in combination with pembrolizumab, increases of axitinib dosage above the initial 5 mg dosage may be considered at intervals of 6 weeks or longer.1 Consult the Full Prescribing Information for recommended pembrolizumab dosing.1
During the course of therapy, patients who tolerate axitinib for at least 2 consecutive weeks without adverse effects greater than grade 2, are normotensive, and are not receiving antihypertensive agents may have their axitinib dosage increased.1 When a dosage increase from 5 mg twice daily is recommended, the dosage may be increased to 7 mg twice daily, and then further increased to 10 mg twice daily using the same criteria.1
Second-line Therapy: Monotherapy
For the treatment of advanced renal cell carcinoma in adults, the recommended initial dosage of axitinib is 5 mg twice daily (12 hours apart).1 In the principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.2 Patients in this study received axitinib for a median duration of 6.4 months.2
During the course of therapy, patients who tolerate axitinib for at least 2 consecutive weeks without adverse effects greater than grade 2, are normotensive, and are not receiving antihypertensive agents may have their axitinib dosage increased.1 When a dosage increase from 5 mg twice daily is recommended, the dosage may be increased to 7 mg twice daily, and then further increased to 10 mg twice daily using the same criteria.1
Dosage Modification for Toxicity
Adjustment of axitinib dosage is recommended based on individual safety and tolerability.1 Recommended dosage reductions for adverse reactions are provided in Table 1.1
Dosage Reduction Level | Recommended Dosage |
|---|---|
First dose reduction | 3 mg twice daily |
Second dose reduction | 2 mg twice daily |
If systolic blood pressure (SBP) >150 mmHg or diastolic blood pressure (DBP) >100 mmHg despite antihypertensive therapy, reduce the dosage by one level.1 If SBP >160 mmHg or DBP >105 mmHg, withhold axitinib until blood pressure <150/100 mmHg; then resume at a reduced dosage.1
For grade 4 hypertension or hypertensive crisis, permanently discontinue axitinib.1
For grade 3 or 4 hemorrhage, withhold axitinib until resolution to grade 0 or 1 or baseline.1 Resume at either a reduced dosage or discontinue axitinib, depending on the severity and persistence of the adverse reaction.1
For asymptomatic cardiomyopathy (left ventricular ejection fraction >20% but <50% below baseline or below the lower limit of normal if baseline was not obtained), withhold axitinib until resolution to grade 0 or 1 or baseline; then resume at a reduced dosage.1
For clinically manifested congestive heart failure, discontinue axitinib permanently.1
The safety of resumption of axitinib after resolution of any grade of wound healing has not been established.1 For any grade of impaired wound healing, either resume at a reduced dosage or discontinue, depending on the severity and persistence of the adverse reaction.1
Reversible Posterior Leukoencephalopathy Syndrome
For any grade of reversible posterior leukoencephalopathy syndrome, discontinue axitinib permanently.1
For patients with ≥2 grams of proteinuria over 24 hours, withhold axitinib until resolution to <2 grams of proteinuria over 24 hours.1 Then resume axitinib at a reduced dosage.1
For any other grade 3 adverse reactions, reduce dosage by one level.1 For any other grade 4 reactions, withhold axitinib until resolution to grade 2, then resume at a reduced dosage.1
Combination therapy with avelumab or pembrolizumab : If elevations in ALT or AST concentrations are at least 3 times the upper limit of normal (ULN), but less than 10 times the ULN without concurrent total bilirubin concentration at least 2 times the ULN, withhold both axitinib and avelumab or pembrolizumab until hepatotoxicity resolves to grade 1 or less.1 Consider rechallenge with axitinib and/or avelumab or pembrolizumab; if rechallenging with axitinib, consider dosage reduction per Table 1.1 If ALT or AST concentrations increase to more than 3 times the ULN with concurrent total bilirubin concentration at least 2 times the ULN or ALT or AST at least 10 times the ULN, permanently discontinue both axitinib and avelumab or pembrolizumab.1
Combination therapy with avelumab or pembrolizumab : If grade 1 or 2 diarrhea occurs, initiate treatment with symptomatic medications.1 For grade 3 diarrhea, interrupt axitinib and initiate symptomatic medications.1 If diarrhea is controlled, axitinib may be resumed at either the same dosage or reduced by one dosage level.1 For grade 4 diarrhea, withhold axitinib until resolution to grade <2, then restart axitinib at a dosage reduced by one level.1
Combination therapy with avelumab: For grade 3 or 4 major adverse cardiac events (MACE), permanently discontinue axitinib.1
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of axitinib with drugs that are potent inhibitors of cytochrome P-450 (CYP) isoenzymes 3A4 or 3A5 should be avoided .1, 6 If concomitant use of a potent CYP3A4/5 inhibitor cannot be avoided, the manufacturer recommends reducing the axitinib dosage by approximately 50% (i.e., one half).1 This dosage is predicted to adjust the AUC of axitinib to the range observed in the absence of CYP3A4/5 inhibitors.1 However, there are no clinical studies to date evaluating this reduced dosage in patients concomitantly receiving potent CYP3A4/5 inhibitors.1 Subsequent increases or decreases in axitinib dosage may be made based on individual safety and tolerability.1 If concurrent administration of the potent inhibitor is discontinued, the axitinib dosage should be returned (after 3-5 elimination half-lives of the CYP3A4/5 inhibitor) to the dosage used prior to initiation of the potent CYP3A4/5 inhibitor.1
Dosage adjustment is not necessary in patients with mild preexisting hepatic impairment (Child-Pugh class A).1 In patients with moderate preexisting hepatic impairment (Child-Pugh class B), the initial dosage of axitinib should be reduced by approximately 50% (i.e., to 2.5 mg twice daily); subsequent dosage may be increased or decreased based on individual safety and tolerability.1 Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1
Initial dosage adjustment is not necessary in patients with mild to severe preexisting renal impairment (creatinine clearance of 15 to less than 89 mL/minute).1 Axitinib should be used with caution in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1
No dosage adjustment is necessary in geriatric patients.1
None.1
Hypertension and Hypertensive Crisis
In the AXIS clinical trial evaluating axitinib and sorafenib for advanced renal cell carcinoma, hypertension was reported in 40% (grade 3 or 4 in 16%) of patients receiving axitinib compared with 29% (grade 3 or 4 in 11%) of those receiving sorafenib.1, 2 Hypertensive crisis was reported in less than 1% of patients receiving axitinib compared with none of those receiving sorafenib.1 Median time to development of hypertension (systolic blood pressure exceeding 150 mm Hg or diastolic blood pressure exceeding 100 mm Hg) was within the first month of axitinib therapy, and blood pressure increases were observed as early as 4 days after initiating the drug.1 Hypertension necessitated discontinuance of therapy in less than 1% of axitinib-treated patients.1
Blood pressure should be well controlled prior to initiating axitinib therapy.1 Patients should be monitored for the development of hypertension during therapy and treated as needed with standard antihypertensive therapy.1 Axitinib-associated hypertension usually responds well to antihypertensive treatment.9, 8, 14 Temporarily interrupt axitinib treatment and then reduce the dosage or permanently discontinue therapy depending on severity of hypertension.1 Permanently discontinue therapy if grade 4 hypertension or hypertensive crisis occurs.1
Arterial Thromboembolic Events
Arterial thromboembolic events, including fatal cases, have been reported in axitinib-treated patients.1 In the phase 3 clinical study, grade 3 or 4 arterial thromboembolic events were reported in 1% of patients receiving axitinib and 1% of those receiving sorafenib.1 Fatal cerebrovascular accident occurred in less than 1% of patients receiving axitinib compared with none of those receiving sorafenib.1 In clinical trials, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 2% of axitinib-treated patients, including 2 deaths secondary to cerebrovascular accident.1 Axitinib has not been evaluated in patients who had an arterial thromboembolic event within the previous 12 months.1
The manufacturer states that axitinib should be used with caution in patients who are at risk for, or have a history of, arterial thromboembolic events.1 Axitinib should be permanently discontinued if an arterial thromboembolic event occurs during treatment.1
Venous thromboembolic events (VTE), including fatal cases, have been reported in axitinib-treated patients in clinical trials.1 In the phase 3 clinical study, VTE occurred in 3% of patients receiving axitinib and 1% of patients receiving sorafenib.1 Grade 3 or 4 VTE (including pulmonary embolism [PE], deep-vein thrombosis [DVT], retinal vein occlusion, and retinal vein thrombosis) were reported in 3% of patients receiving axitinib and 1% of those receiving sorafenib.1 Fatal PE occurred in less than 1% of patients receiving axitinib compared with none of those receiving sorafenib.1 Axitinib has not been evaluated in patients who had a VTE within the previous 6 months.1 In clinical trials with axitinib, VTE was reported in 3% of patients, including 2 deaths secondary to PE.1
Monitor patients for signs and symptoms of VTE and PE.1 If symptoms occur, withhold axitinib and then resume at the same dose or discontinue permanently based on the severity of the VTE event.1
In the phase 3 clinical trial (AXIS), hemorrhagic events were reported in 16 and 18% of patients receiving axitinib and sorafenib, respectively.1 Grade 3 or 4 hemorrhagic events (including cerebral hemorrhage, hematuria, hemoptysis, lower GI hemorrhage, and melena) were reported in 1% of axitinib-treated patients compared with 3% of those receiving sorafenib.1 Fatal hemorrhage occurred in less than 1% of patients receiving axitinib (gastric hemorrhage) and in 1% of those receiving sorafenib.1
Axitinib has not been evaluated in patients with evidence of untreated brain metastasis or recent, active GI bleeding; the manufacturer states that axitinib should not be used in such patients.1 If hemorrhagic events occur, withhold axitinib therapy and then reduce the dosage or discontinue based on severity and persistence of hemorrhage.1
In a clinical trial of axitinib for the treatment of patients with renal cell carcinoma, cardiac failure was reported in 6 of 359 patients (2%) receiving axitinib and 3 of 355 patients (1%) receiving sorafenib.1 Grade 3 or 4 cardiac failure was observed in 2 of the patients receiving axitinib and in 1 patient receiving sorafenib.1 Fatal cardiac failure was reported in 2 patients receiving axitinib and in 1 patient receiving sorafenib.1
Monitor for signs or symptoms of cardiac failure during axitinib therapy.1 Management of cardiac failure may require reduction of dosage, or interuption or permanent discontinuation of axitinib.1
GI Perforation and Fistula Formation
GI perforation occurred in less than 1% of patients receiving axitinib and none of those receiving sorafenib in the phase 3 trial.1 In clinical trials with axitinib, GI perforation and fistula formation were each reported in approximately 1% of patients; one death from GI perforation also was reported.1
Axitinib should be used with caution in patients at risk for GI perforation or fistula.1 Patients receiving the drug should be monitored for symptoms of GI perforation and fistula formation periodically during treatment.1
Thyroid dysfunction (hypothyroidism or hyperthyroidism), which may require thyroid hormone replacement therapy, commonly occurs during treatment with certain tyrosine kinase inhibitors, including axitinib.1, 14, 18, 19, 20 In the phase 3 clinical study, hypothyroidism was reported in 19 and 8% of patients receiving axitinib and sorafenib, respectively; hyperthyroidism occurred at a similar rate (1%) between the 2 treatment groups.1 In patients with baseline thyrotropin (thyroid-stimulating hormone, TSH) concentrations of less than 5 microunits/mL, elevations in thyrotropin concentration to 10 microunits/mL or greater occurred in 32% of patients receiving axitinib and 11% of those receiving sorafenib.1
Baseline thyroid function should be assessed prior to initiation of axitinib therapy and then monitored periodically during treatment.1 Hypothyroidism and hyperthyroidism should be treated according to standard medical practice to maintain a euthyroid state.1
Inhibitors of vascular endothelial growth factor receptor (VEGFR) may impair wound healing;1 therefore, axitinib may impair wound healing.1
Axitinib should be discontinued for at least 2 days prior to elective surgery and for at least 2 weeks following major surgery and until adequate wound healing has occurred.1 Resume axitinib at a reduced dosage or discontinue based on severity and persistence of the impaired wound healing.1 Safety of resuming axitinib after resolution of wound healing complications has not been established.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients receiving axitinib.1 This complication occurred in one patient (less than 1%) treated with axitinib in the phase 3 clinical study; 2 additional cases of RPLS have been reported in other clinical trials with the drug.1 RPLS is a neurologic disorder that may manifest with headache, seizures, lethargy, confusion, blindness, and other visual and neurologic disturbances.1 Mild to severe hypertension may also be present.1 Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.1
Axitinib should be permanently discontinued in patients who develop signs or symptoms of RPLS.1 The safety of reinitiating axitinib therapy in patients previously experiencing RPLS is not known.1
Proteinuria was reported in 11% (grade 3 in 3%) of patients receiving axitinib compared with 7% (grade 3 in 2%) of those receiving sorafenib in the phase 3 clinical trial for renal cell carcinoma.1 The manufacturer recommends that patients be evaluated for proteinuria prior to initiation of axitinib therapy and monitored for proteinuria periodically during treatment with the drug.1 In patients who develop moderate to severe proteinuria, withhold axitinib treatment and then reduce the dosage.1
In the phase 3 clinical trial, elevations in serum concentrations of alanine aminotransferase (ALT [SGPT]) occurred in 22% of patients receiving axitinib or sorafenib, with grade 3 or 4 elevations reported in less than 1% of patients receiving axitinib.1 Serum aminotransferase (ALT and AST [SGOT]) and bilirubin concentrations should be monitored prior to initiation of, and periodically during, monotherapy with axitinib.1 More frequent monitoring of liver function should be considered when axitinib is used in combination with avelumab or pembrolizumab than as a single agent.1 If abnormalities in liver function tests occur, interrupt axitinib and avelumab or pembrolizumab therapy and consider administering systemic corticosteroid therapy as clinically indicated.1
Axitinib in combination with avelumab or pembrolizumab can cause hepatotoxicity with higher than expected frequencies of grade 3 or 4 ALT or AST elevations.1 Monitor liver enzymes before initiation of therapy and periodically throughout treatment.1 More frequent monitoring of liver function should be considered when axitinib is used in combination with avelumab or pembrolizumab.1 For elevated liver enzymes, interrupt or permanently discontinue axitinib and avelumab or pembrolizumab, and administer corticosteroids as needed.1
Grade 3 and 4 elevations in ALT or AST concentrations were reported in 9 or 7%, respectively, of patients receiving axitinib in combination with avelumab.1 Elevated ALT concentrations (at least 3 times the upper limit of normal [ULN]) resolved to grade 1 or less in 92% of patients receiving axitinib in combination with avelumab.1 Among patients who were rechallenged with either avelumab, axitinib, or both, elevated concentrations of ALT (at least 3 times the ULN) was not observed in patients receiving avelumab, but did occur in 6 patients receiving axitinib and 15 patients receiving both avelumab and axitinib.1 Recurrence of ALT ≥3 ULN occurred in 22 (88%) patients, with subsequent recovering to Grade 0-1.1 Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with grade 3 or 4 immune-mediated hepatitis.1 Hepatotoxicity led to permanent discontinuation in 7% and immune-mediated hepatitis led to permanent discontinuation of either avelumab or axitinib in 5% of patients.1 Treatment with corticosteroids was required in 34 patients and one patient required a non-steroidal immunosuppressant; resolution of hepatitis occurred in 31 of the 35 patients at the time of data analysis.1
Grade 3 and 4 elevations in ALT or AST concentrations were reported in 20 or 13%, respectively, of patients receiving axitinib in combination with pembrolizumab.1 Among patients who experienced increased concentrations of ALT, 59% received systemic corticosteroids.1 Elevated ALT concentrations (at least 3 times the ULN) resolved to grade 1 or less in 94% of patients.1 Among patients rechallenged with either pembrolizumab, axitinib, or both, elevated concentrations of ALT (at least 3 times the ULN) were observed in one patient receiving pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both pembrolizumab and axitinib.1 All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.1
Major Adverse Cardiovascular Events
Axitinib in combination with avelumab can cause severe and fatal cardiovascular events.1 Consider baseline and periodic evaluations of left ventricular ejection fraction (LVEF).1 Monitor for signs and symptoms of cardiovascular events, and optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia.1 Permanently discontinue axitinib and avelumab if grade 3 or 4 cardiovascular events occur.1
Major adverse cardiovascular events occurred in 7% of patients with advanced renal cell carcinoma treated with axitinib in combination with avelumab compared to 3.4% treated with sunitinib in a randomized trial (JAVELIN Renal 101).1 These events included death due to cardiac events, grade 3 or 4 myocardial infarction, and grade 3 or 4 congestive heart failure.1 The median time to onset of a major adverse cardiovascular event was 4.2 months.1
Fetal/Neonatal Morbidity and Mortality
Axitinib may cause fetal harm in humans based on its mechanism of action; the drug has been shown to be teratogenic, embryotoxic, and fetotoxic in animals.1 There are no adequate and well-controlled studies in pregnant women.1 Pregnancy should be avoided during therapy.1 If axitinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
When axitinib is used in combination with avelumab or pembrolizumab, the usual cautions, precautions, and contraindications associated with avelumab and pembrolizumab must be considered in addition to those associated with axitinib.1
Based on findings in animals, axitinib may impair fertility in females and males of reproductive potential.1
Axitinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
There are no available human data to inform the drug-associated risk.1
It is not known whether axitinib is distributed into human milk.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1 Because of the potential for adverse reactions to axitinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Advise females of reproductive potential of the potential risk to the fetus.1 Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with axitinib and for 1 week after the last dose.1
Safety and efficacy of axitinib have not been established in pediatric patients younger than 18 years of age.1 The pharmacokinetics of axitinib also have not been studied in pediatric patients.1
Toxicities in bone (e.g., thickened growth plates) and teeth (e.g., abnormalities in growing incisor teeth, including dental caries, malocclusions, broken and/or missing teeth) have been observed in immature animals receiving oral axitinib for one month or longer.1 Other toxicities of potential concern in pediatric patients have not been evaluated to date in juvenile animal studies.1
In controlled clinical studies evaluating axitinib in patients with renal cell carcinoma either as a single agent or in combination with avelumab or pembrolizumab, 34-40% of patients were 65 years of age or older.1 Although no overall differences in safety and efficacy were observed between patients 65 years of age or older and younger patients, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.1
Following a single dose of axitinib, systemic exposure of the drug in patients with mild hepatic impairment (Child-Pugh class A) was similar to that in individuals with normal hepatic function.1 However, systemic exposure of axitinib was increased in individuals with moderate hepatic impairment (Child-Pugh class B) compared with individuals with normal hepatic function.1 Initial dosage reduction is therefore recommended in patients with moderate hepatic impairment.1 Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) to date.1
A dedicated renal impairment trial for axitinib has not been conducted to date.1 Population pharmacokinetic analyses indicate that preexisting mild to severe renal impairment does not substantially alter the pharmacokinetics of axitinib.1 However, data in patients with end-stage renal disease are very limited, and axitinib should therefore be used with caution in such patients.1
Adverse effects occurring in 20% or more of patients receiving axitinib in combination with avelumab for first-line treatment of advanced renal cell carcinoma were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia (hand-foot syndrome), dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.1
Adverse effects occurring in 20% or more of patients receiving axitinib in combination with pembrolizumab for first-line treatment of advanced renal cell carcinoma were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia (hand-foot syndrome), nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.1
Adverse effects occurring in 20% or more of patients receiving axitinib for the second-line treatment of advanced renal cell carcinoma in the randomized trial were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, vomiting, asthenia, and constipation.1, 2, 13
Axitinib is metabolized principally by the cytochrome P-450 (CYP) isoenzyme 3A4/5 and, to a lesser extent, by CYP1A2, CYP2C19, and uridine diphosphate-glucurosyltransferase (UGT) 1A1 in vitro.1, 6
In vitro studies demonstrate that axitinib has the potential to inhibit CYP isoenzymes 1A2 and 2C8.1
In vitro studies indicate that axitinib does not inhibit CYP2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or UGT1A1 at therapeutic plasma concentrations.1
Axitinib inhibits P-glycoprotein (P-gp) in vitro; however, the drug is not expected to inhibit P-gp at therapeutic plasma concentrations.1
Axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5 in human hepatocytes in vitro.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant administration of axitinib with potent inhibitors of CYP3A4/5 may result in increased plasma concentrations of axitinib.1, 6 When the potent CYP3A4/5 inhibitor ketoconazole (400 mg once daily for 7 days) was administered concomitantly with axitinib (single 5-mg dose) in healthy individuals, mean peak plasma concentrations and systemic exposure of axitinib increased by approximately 1.5- and twofold, respectively.1, 6
Concomitant use of axitinib with potent CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided, and selection of an alternative drug with no or minimal CYP3A4/5 inhibition potential is recommended.1, 6 If concomitant use with a potent CYP3A4/5 inhibitor cannot be avoided, the manufacturer recommends reducing the axitinib dosage by approximately 50%; subsequent axitinib dosages may be increased or decreased based on individual safety and tolerability.1 If concomitant use of the potent CYP3A4/5 inhibitor is discontinued, the axitinib dosage should be returned (after 3-5 elimination half-lives of the CYP3A4/5 inhibitor) to the dosage used prior to initiation of the potent CYP3A4/5 inhibitor.1
Concomitant administration of axitinib with inducers of CYP3A4/5 may result in decreased plasma concentrations of axitinib.1 When the potent CYP3A4/5 inducer rifampin (600 mg once daily for 9 days) was administered concomitantly with axitinib (single 5-mg dose), mean peak plasma concentrations and systemic exposure of axitinib decreased by 71 and 79%, respectively.1, 7 When the potent CYP3A4/5 inducer phenytoin was administered concomitantly with axitinib in one patient, peak plasma concentrations and systemic exposure of axitinib decreased approximately tenfold.9
Concomitant use of axitinib with potent CYP3A4/5 inducers (e.g., carbamazepine, dexamethasone, rifabutin, rifampin, rifapentine, phenobarbital, phenytoin, St. John's wort [ Hypericum perforatum ]) should be avoided, and selection of an alternative drug with no or minimal CYP3A4/5 induction potential is recommended.1 Concomitant use of axitinib with moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) also should be avoided if possible.1
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies indicate that axitinib has the potential to inhibit CYP isoenzymes 1A2 and 2C8.1 However, when the CYP2C8 substrate paclitaxel was administered concomitantly with axitinib, plasma concentrations of paclitaxel were unchanged.1
Drugs Affecting Gastric Acidity
Because the aqueous solubility of axitinib is dependent on pH, drugs that increase the pH of the upper GI tract (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) may potentially decrease the solubility of axitinib and subsequently reduce its bioavailability.1, 9 However, when the proton-pump inhibitor rabeprazole (20 mg once daily) was administered concomitantly with axitinib, the peak plasma concentration of axitinib was decreased and changes in systemic exposure of axitinib were not considered clinically important.1, 9 The manufacturer states that dosage adjustment is not necessary when axitinib is administered concurrently with drugs affecting gastric acidity, including antacids and proton-pump inhibitors.1
Concomitant administration of axitinib and bevacizumab in combination with FOLFIRI (irinotecan/fluorouracil/leucovorin) or FOLFOX (oxaliplatin/fluorouracil/leucovorin) did not substantially alter the pharmacokinetics of axitinib or the other antineoplastic agents.11
Concurrent administration of axitinib and a standard regimen of paclitaxel plus carboplatin did not substantially affect the pharmacokinetics of axitinib or the other antineoplastic agents.12
Concomitant administration of axitinib and gemcitabine plus cisplatin did not substantially affect the pharmacokinetics of axitinib, gemcitabine, or cisplatin.12
Grapefruit products are CYP3A4/5 inhibitors and should be avoided during axitinib therapy because of the potential for increased plasma axitinib concentrations.1
Because warfarin is a substrate of CYP1A2, axitinib may increase plasma warfarin concentrations; however, this potential interaction has not been systematically evaluated to date and its clinical importance is unclear.1, 3 Pending further accumulation of data, clinicians should consider that hemorrhagic events have been reported in some patients receiving axitinib therapy alone.1
Axitinib is a selective, second-generation inhibitor of receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; the drug is an antineoplastic agent.1, 2, 3, 8, 9, 10, 16 Chemically, axitinib is a substituted indazole derivative.8, 14 Receptor tyrosine kinases (TKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cancer cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1, 8, 10 Axitinib potently and selectively inhibits VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations.1, 2, 3, 8, 9, 10 The VEGFR signaling pathway plays an important role in the pathogenesis and progression of several types of tumors since it is a pivotal mediator of tumor angiogenesis; the pathway also regulates tumor growth and metastatic spread.1, 8, 10 Axitinib appears to be 50-450 times more potent at blocking VEGFR receptors than first-generation VEGFR inhibitors (e.g., sorafenib, sunitinib, pazopanib).2, 13, 14, 16 Axitinib exhibits eightfold to tenfold lower inhibitory activity against platelet-derived growth factor receptor beta (PDGFR-β) and stem cell factor receptor (c-Kit);10, 15 the drug also has minimal inhibitory effects on other receptor kinases, including colony stimulating factor receptor type 1 (CSF-1R), fms-like tyrosine kinase 3 (Flt-3), fibroblast growth factor receptor (FGFR)-1, ret proto-oncogene (RET), epidermal growth factor receptor (EGFR), and met proto-oncogene encoding hepatocyte growth factor (c-MET).8, 10, 16 Axitinib has been shown to inhibit VEGF-mediated endothelial cell proliferation and survival in vitro and in mice.1 The drug has also demonstrated inhibition of tumor growth and VEGFR-2 phosphorylation in mice bearing tumor xenografts.1
Following oral administration, axitinib is readily absorbed with peak plasma concentrations occurring within 2.5-4.1 hours.1, 8 When axitinib is administered orally twice daily, accumulation of the drug is approximately 1.4-fold higher compared with administration of a single dose.1 At steady state, axitinib exhibits approximately linear pharmacokinetics within a dosage range of 1-20 mg.1, 8 Steady-state concentrations of the drug are expected within 2-3 days.1 Axitinib is metabolized in the liver principally by cytochrome P-450 (CYP) 3A4/5 and, to a lesser extent, by CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyl transferase (UGT) 1A1.1, 8 Axitinib is highly bound (more than 99%) to plasma proteins.1 The elimination half-life of axitinib ranges from 2.5-6.1 hours.1 Following oral administration of a radiolabeled dose of axitinib, approximately 41% of the dose is recovered in the feces (mainly as unchanged drug) and approximately 23% of the dose is recovered in urine (mainly as carboxylic acid and sulfoxide metabolites).1 In vitro, the sulfoxide and N -glucuronide metabolites are more than 400 times less potent against VEGFR-2 compared with axitinib.1 Use of axitinib in combination with avelumab or pembrolizumab does not appear to substantially affect exposure of axitinib, avelumab, or pembrolizumab or the clearance of avelumab compared to each of these agents alone.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Axitinib can only be obtained through designated specialty pharmacies.4 Contact manufacturer for specific availability information.4
1. Pfizer Labs. Inlyta® (axitinib) tablets prescribing information. New York, NY: 2022 Sept. [Web]
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3. Pfizer Inc. New York, NY: Personal communication.
4. Pfizer Inc. Specialty pharmacy distribution network for IBRANCE® (palbociclib), INLYTA® (axitinib), XALKORI® (crizotinib), BOSULIF® (bosutinib), and SUTENT® (sunitinib malate) New York, NY. Accessed 2021 Nov 13 [Web]
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