Safety & Tolerability Profile

INLYTA® (axitinib) + pembrolizumab for 1st-Line Treatment of Advanced RCC

Summary of warnings and precautions​​​​​​​

Adverse reactions

KEYNOTE-426: A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (safety population N=854)

The safety data described here reflect exposure to INLYTA® (axitinib) in combination with pembrolizumab in 854 patients who were randomized to receive either INLYTA + pembrolizumab (n=429) or sunitinib (n=425) in the KEYNOTE-426 trial

  • Fatal adverse reactions (ARs) occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab
    • ​​​​​​​​​​​​​​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
  • Serious ARs occurred in 40% of patients receiving INLYTA in combination with pembrolizumab
    • Serious ARs in ≥1% of patients receiving INLYTA in combination with pembrolizumab included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%)
  • 27% of patients treated with INLYTA in combination with pembrolizumab received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated AR
  • Permanent discontinuation due to an AR of either INLYTA or pembrolizumab occurred in 31% of patients
    • The majority (69%) of patients in KEYNOTE-426 did not discontinue INLYTA or pembrolizumab due to an AR
    • 13% discontinued pembrolizumab only, 13% discontinued INLYTA only, and 8% discontinued both drugs
  • The most common ARs (>1%) resulting in permanent discontinuation of INLYTA, pembrolizumab, or the combination were:
    • Hepatotoxicity (13%)
    • Diarrhea/colitis (1.9%)
    • Acute kidney injury (1.6%)
    • Cerebrovascular accident (1.2%)
  • Dose interruptions or reductions due to an AR, excluding temporary interruptions of pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving pembrolizumab in combination with axitinib
    • This includes interruption of pembrolizumab in 50% of patients. INLYTA was interrupted in 64% of patients and dose-reduced in 22% of patients
  • The most common ARs (>10%) resulting in either interruption or reduction of INLYTA were:
    • ​​​​​​​Hepatotoxicity (21%)
    • Diarrhea (19%)
    • Hypertension (18%)
  • The most common ARs (>10%) resulting in interruption of pembrolizumab were:
    • ​​​​​​​Hepatotoxicity (14%)
    • Diarrhea (11%)
  • AR management may have helped patients remain on therapy
    • ​​​​​​​Remind patients to communicate any ARs they have as soon as possible
    • If necessary, the dose of INLYTA can be increased or decreased based on individual safety and tolerability

Adverse reactions occurring in ≥20% of patients receiving INLYTA® (axitinib) + pembrolizumab

*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic.
Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension.
§Includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased.
||Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash.

The most common ARs (>10%) resulting in either interruption or reduction of INLYTA® (axitinib) are hepatotoxicity, diarrhea, and hypertension

NOTE: For suspected immune-mediated ARs, refer to the full Prescribing Information for pembrolizumab

Hepatotoxicity

  • Hepatotoxicity (all grades) occurred in 39% of patients taking INLYTA in combination with pembrolizumab
  • Grade 3/4 hepatotoxicity occurred in 20% of patients taking INLYTA in combination with pembrolizumab
  • Hepatotoxicity led to a dose interruption or reduction of INLYTA in 21% of patients, and to a dose interruption of pembrolizumab in 14% of patients
  • Hepatotoxicity led to a permanent discontinuation of INLYTA, pembrolizumab, or the combination in 13% of patients

Diarrhea

  • Diarrhea (all grades) occurred in 56% of patients taking INLYTA in combination with pembrolizumab
  • Grade 3/4 diarrhea occurred in 11% of patients taking INLYTA in combination with pembrolizumab
  • Diarrhea led to a dose interruption or reduction of INLYTA in 19% of patients, and to a dose interruption of pembrolizumab in 11% of patients
  • Diarrhea led to a permanent discontinuation of INLYTA, pembrolizumab, or the combination in 1.9% of patients

Hypertension

  • Hypertension (all grades) occurred in 48% of patients taking INLYTA in combination with pembrolizumab
  • Grade 3/4 hypertension occurred in 24% of patients taking INLYTA in combination with pembrolizumab
  • Hypertension led to a dose interruption or reduction of INLYTA in 18% of patients

If necessary, the dose of INLYTA may be increased or decreased based on individual safety and tolerability. See dosing and titration.
​​​​​​​

Laboratory abnormalities

KEYNOTE-426: A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (safety population N=854)

Laboratory abnormalities worsened from baseline occurring in ≥20% of patients receiving INLYTA® (axitinib) + pembrolizumab

*Each test incidence is based on the number of patients who had both baseline and at least 1 on-study laboratory measurement available: pembrolizumab/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients).
Graded per NCI CTCAE v4.03.
Corrected for albumin.
§Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.


​​​​​​​Reference

  1.     1.  US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Published June 2010. Accessed July 23, 2021. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

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INLYTA + pembrolizumab for 
1st-Line Treatment of Advanced RCC

  • Overview
  • Efficacy Measures: OS, PFS, & ORR 
  • Safety & Tolerability Profile 
  • Dosing
  • Therapy Management Strategies 
  • MOAs - INLYTA and pembrolizumab ​​​​​​​
  • NCCN Recommendation
  • Publications
  • Health Care Provider Videos  
  • Professional Resources

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EFFICACY MEASURES

OS, PFS, & ORR

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THERAPY MANAGEMENT STRATEGIES

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PATIENT FINANCIAL SUPPORT 
& RESOURCES

PFIZER ONCOLOGY TOGETHER™, 
CO-PAY CARD, & RESOURCES

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Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

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.

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. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

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 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. 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 treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with 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 used for monotherapy. Consider withholding INLYTA and/or pembrolizumab, initiating corticosteroid therapy, and/or permanently discontinuing 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%), nausea (28% vs 32%), constipation (21% vs 15%), hypothyroidism (35% vs 32%), decreased appetite (30% vs 29%), palmar-plantar erythrodysesthesia (28% vs 40%), stomatitis/mucosal inflammation (27% vs 41%), rash (25% vs 21%), dysphonia (25% vs 3.3%), and cough (21% vs 14%).

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%).

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.

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.​​​​​​​