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Safety and tolerability profile for BAVENCIO® (avelumab) and INLYTA® (axitinib)

Summary of BAVENCIO warnings and precautions

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases.

  • Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging
  • Administer corticosteroids for Grade 2 or greater pneumonitis
  • Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis
  • Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases.

  • Monitor patients for abnormal liver tests prior to and periodically during treatment
  • Administer corticosteroids for Grade 2 or greater hepatitis
  • Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis
  • Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3

BAVENCIO in combination with INLYTA can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation.

  • Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy
  • Withhold BAVENCIO and INLYTA for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity
  • Administer corticosteroids as needed
  • In patients treated with BAVENCIO in combination with INLYTA, Grade 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4

BAVENCIO can cause immune-mediated colitis.

  • Monitor patients for signs and symptoms of colitis
  • Administer corticosteroids for Grade 2 or greater colitis
  • Withhold BAVENCIO for moderate or severe (Grade 2 or 3) colitis until resolution
  • Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO
  • Immune-mediated colitis occurred in 1.5% of patients, including 7 (0.4%) with Grade 3

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

  • Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate
    • Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency 
    • Adrenal insufficiency occurred in 0.5% of patients, including one (0.1%) with Grade 3
  • Thyroid disorders can occur at any time during treatment
    • Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation
    • Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management
    • Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders
    • Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3
  • Type 1 diabetes mellitus including diabetic ketoacidosis
    • Monitor patients for hyperglycemia or other signs and symptoms of diabetes
    • Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved
    • Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia

BAVENCIO can cause immune-mediated nephritis and renal dysfunction.

  • Monitor patients for elevated serum creatinine prior to and periodically during treatment
  • Administer corticosteroids for Grade 2 or greater nephritis
  • Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower
  • Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis
  • Immune-mediated nephritis occurred in 0.1% of patients

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation.

  • For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes
  • Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate
  • Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper
  • Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction
  • The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with INLYTA: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response

BAVENCIO can cause
severe or life-threatening 
infusion-related reactions.

  • Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions
  • Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria
  • Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions
  • Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions
  • Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3

BAVENCIO in combination with INLYTA can cause major adverse cardiovascular events (MACE) including severe and fatal events.

  • Consider baseline and periodic evaluations of left ventricular ejection fraction 
  • Monitor for signs and symptoms of cardiovascular events
  • Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia 
  • Discontinue BAVENCIO and INLYTA for Grade 3-4 cardiovascular events 
  • MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with INLYTA compared to 3.4% treated with sunitinib
  • These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%)

BAVENCIO can cause fetal harm when administered to a pregnant woman.

  • Advise patients of the potential risk to a fetus including the risk of fetal death
  • Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO
  • It is not known whether BAVENCIO is excreted in human milk
  • Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants

Summary of INLYTA warnings and precautions

Hypertension including hypertensive crisis has been observed with INLYTA.

  • 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 with INLYTA and can be fatal.

  • Use with caution in patients who are at increased risk or who have a history of these events

Hemorrhagic events, including fatal events, have been reported with INLYTA.

  • 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 with INLYTA 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 with INLYTA.

  • 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 with INLYTA.

  • Monitor thyroid function before initiation of and periodically throughout treatment

Wound healing complications

  • No formal studies of the effect of INLYTA on wound healing have been conducted
  • Stop INLYTA at least 24 hours prior to scheduled surgery

Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed with INLYTA.

  • If signs or symptoms occur, permanently discontinue treatment

Proteinuria has been observed with INLYTA.

  • Monitor for proteinuria before initiation of, and periodically throughout, treatment
  • For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment

Liver enzyme elevation has been observed during treatment with INLYTA.

  • Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment

Hepatic impairment

  • For patients with moderate hepatic impairment, the starting dose 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 during treatment

In the JAVELIN Renal 101 Trial–a Phase 3, randomized, open-label, multicenter study (N=873)1

  • Fatal adverse reactions occurred in 1.8% of patients receiving BAVENCIO in combination with INLYTA. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%)
  • Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with INLYTA. Serious adverse reactions in ­≥1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), and pneumonia (1.2%)
  • Forty-eight (11%) of patients treated with BAVENCIO in combination with INLYTA received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction  

Adverse reactions (≥20%) in patients receiving BAVENCIO in combination with INLYTA
(JAVELIN Renal 101 Trial)*

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Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03 (NCI CTCAE v4).

*The trial was not designed to demonstrate a statistically significance differences in the incidence of adverse reactions between BAVENCIO in combination with INLYTA and sunitinib.

1Diarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis.

2Mucositis is a composite term that includes mucosal inflammation and stomatitis.

3Hepatotoxicity is a composite term that includes ALT increased, AST increased, autoimmune hepatitis, bilirubin conjugated, bilirubin conjugated increased, 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 disorder, liver injury, and transaminases increased.

4Abdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower.

5Fatigue is a composite term that includes fatigue and asthenia.

6Hypertension is a composite term that includes hypertension and hypertensive crisis.

7Musculoskeletal pain is a composite term that includes musculoskeletal pain, musculoskeletal chest pain, myalgia, back pain, bone pain, musculoskeletal discomfort, neck pain, spinal pain, and pain in extremity.

8Rash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular.

9Dyspnea is a composite term that includes dyspnea, dyspnea exertional, and dyspnea at rest.

  • Other clinically important adverse reactions that occurred in less than 20% of the patients in the JAVELIN Renal 101 Trial included arthralgia, weight decreased, and chills
  • Patients received premedication with an antihistamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with BAVENCIO in combination with INLYTA

 

Selected laboratory abnormalities worsening from baseline occurring in ≥20% of patients receiving BAVENCIO in combination with INLYTA (JAVELIN Renal 101 Trial)*

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*The trial was not designed to demonstrate a statistically significant difference in the incidence of laboratory abnormalities between BAVENCIO in combination with INLYTA and sunitinib.

1Each test incidence is based on the number of patients who had both baseline and at least 1 on-study laboratory measurement available:
the BAVENCIO-in-combination-with-INLYTA group (range: 413 to 428 patients) and  the sunitinib group (range: 405 to 433 patients).

Reference: 1. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med.
2019;380(12):1103-1115.

Discontinuations, dose interruptions, and dose reductions due to adverse reactions from the JAVELIN Renal 101 Trial

  • Permanent discontinuation due to an adverse reaction of either BAVENCIO or INLYTA occurred in 22% of patients: 19% BAVENCIO only, 13% INLYTA only, and 8% both drugs
  • The most common adverse reactions (>1%) resulting in permanent discontinuation of BAVENCIO or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%) 
  • Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 76% of patients receiving BAVENCIO in combination with INLYTA. This includes interruption of BAVENCIO in 50% of patients. INLYTA was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (>10%) resulting in interruption of BAVENCIO was diarrhea (10%) and the most common adverse reactions resulting in either interruption or dose reduction of INLYTA were diarrhea (19%), hypertension (18%), palmar-plantar erythrodysesthesia (18%), and hepatotoxicity (10%)