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HomeFirst-line Advanced RCCFirst-line Advanced RCCOverviewEfficacy Measures: OS, PFS, & ORRSafety & Tolerability ProfileDosingTherapy Management StrategiesMOAs – INLYTA and pembrolizumabNCCN Recommendation  PublicationsProfessional ResourcesSecond-line Advanced RCCSecond-line Advanced RCCOverviewEfficacy Measures: PFS, ORR, OS, & Subset AnalysesSafety & Tolerability ProfilePatient Characteristics & Treatment ConsiderationsOral DosingVEGFR Pathway & INLYTA® (axitinib) MOANCCN Recommendation  Patient Support and ResourcesPatient Support and ResourcesPfizer Oncology TogetherEventsMaterials
Prescribing InformationIndicationsPatient Site
Patient Characteristics & Treatment ConsiderationsINLYTA® (axitinib) for 2nd-Line Treatment of Advanced RCCEfficacy measures: PFS, ORR, OS

From the AXIS trial: an open-label, phase 3 trial in metastatic RCC following one prior systemic therapy (N=723)*

From AXIS, a multicenter, open-label, phase 3 trial of 723 patients with metastatic RCC (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen [54%, 3%, 8%, and 35% of patients in each of the treatment arms, respectively]). Patients were randomized 1:1 to either INLYTA 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362), with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc., New York, NY.Tolerability considerations
  • 9% of patients discontinued INLYTA® (axitinib) (n=34/359) due to AEs vs 13% of patients with sorafenib (n=46/355)
  • Overall, 61% of patients receiving INLYTA discontinued treatment vs 71% receiving sorafenib1
    • In both study groups, the most common reasons for discontinuation included disease progression or relapse and AEs
  • Fewer patients receiving INLYTA had dose modifications or temporary delay of treatment due to AEs compared with patients receiving sorafenib (55% vs 62%, respectively)
From AXIS, a multicenter, open-label, phase 3 trial of 723 patients with metastatic RCC (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen [54%, 3%, 8%, and 35% of patients in each of the treatment arms, respectively]). Patients were randomized 1:1 to either INLYTA 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362), with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2MOST COMMON ADVERSE EVENTS

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

  • Data from the study indicate that long-term treatment with INLYTA (≥2 years) was not associated with unanticipated AEs; some AEs increased over time (proteinuria, increased blood creatinine, and peripheral edema)3
  • It is important to evaluate and manage risk factors for myocardial infarction and increased amylase3
  • In the AXIS trial, the median duration of treatment was 6.4 months (range 0.03-22.0) and 5 months (range 0.03-20.1) for INLYTA and sorafenib, respectively
From a retrospective study that analyzed pooled data from 5 clinical trials (phase 3 and phase 2), including AXIS, in patients (N=672) with previously treated mRCC. In one study, patients may have received one or more previous systemic treatments; the remaining 4 trials examined patients who had received one previous 1st-line regimen.3
  • 68% of patients maintained their starting dose and 12% increased from their starting dose​​​​​​​​​​
From a retrospective, observational, cohort study (N=1175) using the Specialty Pharmacy Data Mart, an IMS®-managed database containing data from a limited distribution network of 22 specialty pharmacies (regional and national) that dispense INLYTA, for first prescriptions dispensed between May 2012 and April 2013. 659/1175, or 56% of patients, were prescribed INLYTA after one prior systemic therapy. For these patients, the mean daily dose of INLYTA over treatment duration was 10.3 mg.4

Study limitations4

  • Data from medical and pharmacy claims have inherent limitations: Claims data are collected for billing and reimbursement purposes rather than research objectives—causality cannot be inferred
  • Clinical outcomes (such as survival) were not addressed
For further study limitations, please see MacLean E, Cisar L, Mehle K, Eremina D, Quigley JM. Real-world axitinib use in the United States: a retrospective study using linked datasets. J Manag Care Spec Pharm. 2016;22(6):723-732u.References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc., New York, NY. 3. Rini BI, Escudier B, Hariharan S, et al. Long-term safety with axitinib in previously treated patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015;13(6):540-547. 4. MacLean E, Cisar L, Mehle K, Eremina D, Quigley JM. Real-world axitinib use in the United States: a retrospective study using linked datasets. J Manag Care Spec Pharm. 2016;22(6):723-732u.After 1st-line cytokine-based immunotherapy (IL-2 or IFN-α)

From the AXIS trial: an open-label, phase 3 trial in mRCC following one prior systemic therapy (N=723)*

PRIMARY ENDPOINT: PROGRESSION-FREE SURVIVAL (PFS) IN THE OVERALL STUDY POPULATIONSUBGROUP ANALYSES

INLYTA nearly doubled median PFS (mPFS) after progression on 1st-line cytokine-based immunotherapy (IL-2 or IFN-α)

Improvement in PFS among patients previously treated with cytokine-based immunotherapy (IL-2 or IFN-α): from a prespecified subset analysis of the phase 3 AXIS trial1
  • 35% of patients in the AXIS trial had previously been treated with IL-2 or IFN-α
    • Prior therapies for other patients in the trial contained sunitinib (54%), bevacizumab (8%), or temsirolimus (3%)​​​​​​​​​​​​
  • The cytokine-based immunotherapies IL-2 and IFN-α were the most common 1st-line immunotherapies used at the time of the AXIS trial, for which registration concluded in 2010
INLYTA prolonged mPFS after progression on sunitinib

In another prespecified subset analysis of the phase 3 AXIS trial, INLYTA prolonged mPFS after progression on sunitinib

  • 4.8 months mPFS (95% CI: 4.5, 6.4) with INLYTA (n=194) vs 3.4 months (95% CI: 2.8, 4.7) with sorafenib (n=195) (HR=0.74 [95% CI: 0.57, 0.96]); P value is not included because there was no adjustment for multiple testing
From AXIS, a multicenter, open-label, phase 3 trial of 723 patients with metastatic RCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen [54%, 3%, 8%, and 35% of patients in each of the treatment arms, respectively]). Patients were randomized 1:1 to either INLYTA 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362), with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included objective response rate, overall survival, and safety and tolerability.1,2References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc., New York, NY.Risk status

DISTRIBUTION OF PATIENTS BY RISK STATUS IN THE PHASE 3 AXIS TRIAL1*

  • 45% of patients in the AXIS trial had an ECOG performance status of 1; 55% had an ECOG performance status of 0
From AXIS, a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen [54%, 3%, 8%, and 35% of patients in each of the treatment arms, respectively]). Patients were randomized 1:1 to either INLYTA® (axitinib) 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362), with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc., New York, NY.Sites of metastases  

THE AXIS TRIAL INCLUDED PATIENTS WITH A VARIETY OF METASTATIC SITES AT BASELINE1

  • Additional sites in patients receiving INLYTA (vs sorafenib) included pleural effusion (5.0% vs 5.0%), ascites (0.6% vs 1.4%), pancreas (2.2% vs 2.8%), spleen (3.9% vs 2.8%), pelvis (3.0% vs 1.1%), peritoneum (7.2% vs 8.3%), and other (38.5% vs 35.9%)
Reference: 1. Data on file. Pfizer Inc., New York, NY.Short half-life
  • INLYTA® (axitinib) has a short half-life of 2.5 to 6.1 hours
  • Based on the plasma half-life, steady state for INLYTA is expected within 2 to 3 days
Reference: 1. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23(24):5474-5483.No fasting requirement 
  • INLYTA® (axitinib) may be taken with or without food
  • Patients should not eat grapefruit, drink grapefruit juice, or take St John's wort while taking INLYTA
Oral dosing  ORAL ADMINISTRATION AND DOSING 
  • INLYTA® (axitinib) may be taken with or without food
  • Patients should not eat grapefruit, drink grapefruit juice, or take St. John's wort while taking INLYTA
  • Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided
  • Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers
Dosing recommendations
  • The recommended starting dose of INLYTA is 5 mg twice daily
  • For patients with moderate hepatic impairment (Child-Pugh class B) or those concomitantly receiving a strong CYP3A4/5 inhibitor, reduce the starting dose by approximately half
  • Dose adjustments can be made based on individual safety and tolerability
  • Administer doses approximately 12 hours apart
  • Swallow whole with a glass of water
  • May be taken with or without food
Dose titration
  • Management of some AEs may require temporary interruption or permanent discontinuation and/or dose reduction.
If a dose reduction from the starting dose is required:
  • Reduce dose to 3 mg twice daily
  • Reduce dose to 2 mg twice daily if additional dose reduction is required
Dose increase criteria:
  • Patients tolerate INLYTA for at least 2 consecutive weeks with no AEs >grade 2 and are normotensive without hypertension medication
  • Dose may be increased to 7 mg twice daily if patients meet dose increase criteria at the starting dose
  • Dose may be further increased to 10 mg twice daily if patients meet the dose increase criteria at the 7-mg dose
 Efficacy Measures

OS, PFS, & ORR

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WARNINGS, PRECAUTIONS, & ADVERSE REACTIONS

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INDICATIONSINLYTA® (axitinib) in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.
Important Safety Information

Hypertension including hypertensive crisis has been observed. Ensure that blood pressure is well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. Withhold and then dose reduce INLYTA or permanently discontinue based on severity of hypertension.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for, or who have a history of, these events. Permanently discontinue INLYTA if an arterial thromboembolic event occurs during treatment. Monitor for signs and symptoms of VTE and pulmonary embolism. Withhold INLYTA and then resume at same dose or permanently discontinue based on severity of VTE.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. Withhold and then dose reduce INLYTA or discontinue based on severity and persistence of hemorrhage.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require dose reduction, dose interruption or permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.

INLYTA has the potential to adversely affect wound healing. Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer INLYTA for at least 2 weeks following major surgery and until adequate wound healing. Resume INLYTA at a reduced dose or discontinue based on severity and persistence of the impaired wound healing. The safety of resuming INLYTA after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue INLYTA.

Proteinuria has been observed. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, withhold and then dose reduce INLYTA.

Liver enzyme elevation has occurred during treatment with INLYTA as a single agent. INLYTA in combination with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grades 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. Withhold INLYTA and/or pembrolizumab, initiate corticosteroid therapy as needed, and/or permanently discontinue the combination for severe or life-threatening hepatotoxicity.

For patients with moderate hepatic impairment, the starting dose of INLYTA should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

INLYTA can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. When INLYTA is used in combination with pembrolizumab, refer to the full Prescribing Information of pembrolizumab for pregnancy and contraception information.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose of INLYTA. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Fatal adverse reactions (ARs) occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism, and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.

The most common (≥20%) ARs (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were diarrhea (56% vs 45%), fatigue/asthenia (52% vs 51%), hypertension (48% vs 48%), hepatotoxicity (39% vs 25%), hypothyroidism (35% vs 32%), decreased appetite (30% vs 29%), palmar-plantar erythrodysesthesia (28% vs 40%), nausea (28% vs 32%), stomatitis/mucosal inflammation (27% vs 41%), dysphonia (25% vs 3.3%), rash (25% vs 21%), cough (21% vs 14%), and constipation (21% vs 15%).

The most common (≥20%) Grade 3/4 ARs (vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were hypertension (24% vs 20%) and hepatotoxicity (20% vs 4.9%).

The most common (≥20%) lab abnormalities (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC included hyperglycemia (62% vs 54%), increased ALT (60% vs 44%), increased AST (57% vs 56%), increased creatinine (43% vs 40%), hyponatremia (35% vs 29%), hyperkalemia (34% vs 22%), hypoalbuminemia (32% vs 34%), hypercalcemia (27% vs 15%), hypophosphatemia (26% vs 49%), increased alkaline phosphatase (26% vs 30%), hypocalcemia (22% vs 29%), increased blood bilirubin (22% vs 21%), prolonged activated partial thromboplastin time (22% vs 14%), lymphopenia (33% vs 46%), anemia (29% vs 65%), and thrombocytopenia (27% vs 78%).

The most common (≥20%) ARs (all grades, vs sorafenib) in patients receiving INLYTA as second-line treatment for advanced RCC were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), palmar-plantar erythrodysesthesia syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) Grade 3/4 ARs (vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

The most common (≥20%) lab abnormalities (all grades, vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%).

IndicationS

INLYTA® (axitinib) in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.

Please see full Prescribing Information for INLYTA.