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BAVENCIO® (avelumab) and INLYTA® (axitinib) safety and tolerability profile

BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies.

  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions

  • Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment 

  • In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection 

  • Institute medical management promptly, including specialty consultation as appropriate

No dose reduction for BAVENCIO is recommended. For immune-mediated adverse reactions, withhold or permanently discontinue BAVENCIO depending on severityIn general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions

  • Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids

  • In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade ≤1

  • Upon improvement to Grade ≤1, initiate corticosteroid taper and continue to taper over ≥1 month

    Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy

    Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in subsequent sections

BAVENCIO can cause immune-mediated pneumonitis.

  • Withhold BAVENCIO for Grade 2, and permanently discontinue for Grade 3 or Grade 4 pneumonitis

  • Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%), and Grade 2 (0.6%) adverse reactions

  • Systemic corticosteroids were required in all (21/21) patients with pneumonitis

BAVENCIO can cause immune-mediated colitis.

  • The primary component of immune-mediated colitis consisted of diarrhea

  • Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies

  • Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 colitis

  • Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions

  • Systemic corticosteroids were required in all (26/26) patients with colitis

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis.

  • Withhold or permanently discontinue BAVENCIO based on tumor involvement of the liver and severity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation

  • Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% (16/1738) of patients, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions

  • Systemic corticosteroids were required in all (16/16) patients with hepatitis

BAVENCIO can cause primary or secondary immune-mediated adrenal insufficiency.

  • For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated

  • Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity

  • Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients, including Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions

  • Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency

BAVENCIO can cause immune-mediated hypophysitis.

  • Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects

  • Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated

  • Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity

  • Immune-mediated pituitary disorders occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction

BAVENCIO can cause immune-mediated thyroid disorders.

  • Thyroiditis can present with or without endocrinopathy

  • Hypothyroidism can follow hyperthyroidism

  • Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated

  • Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity

  • Thyroiditis occurred in 0.2% (4/1738) of patients, including Grade 2 (0.1%) adverse reactions

  • Hyperthyroidism occurred in 0.4% (7/1738) of patients, including Grade 2 (0.3%) adverse reactions

  • Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism

  • Hypothyroidism occurred in 5% (90/1738) of patients, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions.

  • Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism

BAVENCIO can cause immune-mediated type I diabetes mellitus, which can present with diabetic ketoacidosis.

  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes

  • Initiate treatment with insulin as clinically indicated

  • Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity

  • Immune-mediated type I diabetes mellitus occurred in 0.1% (2/1738) of patients, including Grade 3 (0.1%) adverse reactions

BAVENCIO can cause immune-mediated nephritis with renal dysfunction.

  • Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 increased blood creatinine

  • Immune-mediated nephritis with renal dysfunction occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. Systemic corticosteroids were required in this patient

BAVENCIO can cause immune-mediated dermatologic adverse reactions, including rash or dermatitis.

  • Exfoliative dermatitis including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies

  • Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes

  • Withhold BAVENCIO for suspected and permanently discontinue for confirmed SJS, TEN, or DRESS

  • Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions

  • Systemic corticosteroids were required in 29% (26/90) of patients with dermatologic adverse reactions

BAVENCIO can result in other immune-mediated adverse reactions.

  • Other clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies

  • For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4

  • For neurological toxicities, withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4

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 Grade 1 or Grade 2 infusion-related reactions

  • Permanently discontinue BAVENCIO for Grade 3 or Grade 4 infusion-related reactions

  • Infusion-related reactions occurred in 25% of patients, including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions

  • Eleven (92%) of the 12 patients with Grade ≥3 reactions were treated with intravenous corticosteroids

Fatal and other serious complications of allogeneic hematopoietic stem cell transplantation (HSCT) can occur in patients who receive HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.

  • Follow patients closely for evidence of transplant-related complications and intervene promptly

  • Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT

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

  • Permanently 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 in a randomized trial

  • 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

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

INLYTA in combination with BAVENCIO 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 BAVENCIO, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity

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

  • Consider baseline and periodic evaluations of left ventricular ejection fraction and monitor for signs and symptoms of cardiovascular events
  • Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia
  • Discontinue INLYTA and BAVENCIO for Grade 3 or 4 cardiovascular events

INLYTA can cause fetal harm.

  • Advise patients of the potential risk to the fetus and to use effective contraception

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%)
  • Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with BAVENCIO in combination with INLYTA. Patients received premedication with an antihistamine and acetaminophen prior to each infusion
  • An oral prednisone dose equivalent to ≥40 mg daily was administered for an immune-mediated adverse reaction to 11% (48) of patients treated with BAVENCIO in combination with INLYTA

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

Adverse reactions (≥20%) in patients receiving BAVENCIO in combination with INLYTA

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

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

Hepatotoxicity 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.

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

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

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

#Musculoskeletal 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.

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

††Dyspnea 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

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

Selected laboratory abnormalities worsening from baseline occurring in ≥20% of patients receiving BAVENCIO + INLYTA

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*Each 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.

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

Discontinuation rates due to adverse reactions

  • 22% of patients permanently discontinued treatment with either BAVENCIO (avelumab) or INLYTA (axitinib) due to adverse reactions
  • 8% of patients permanently discontinued both BAVENCIO + INLYTA due to adverse reactions compared to 13.4% with sunitinib1
  • 19% of patients permanently discontinued treatment with BAVENCIO alone due to adverse reactions
  • 13% of patients permanently discontinued treatment with INLYTA alone due to adverse reactions
  • 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 and reductions due to adverse reactions

  • 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
    • BAVENCIO was interrupted in 50% of patients
    • INLYTA was interrupted in 66% of patients 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%)

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.