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AiM Advise. Identify. Manage.

Take AIM through a targeted treatment strategy to optimize therapy

Support patients on AFINITOR treatment through patient education, proactive planning, and established AE management strategies

In the BOLERO-2 study

  • The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and reversible1,2
  • 100% of patients were initiated at the 10-mg dose of AFINITOR3
  • 38% of patients did not require a dose interruption and/or reduction4
  • Median dose intensity of AFINITOR was 8.6 mg/day with once-daily oral administration4

Visit and assessment schedule from BOLERO-21

"Visit and assessment schedule from BOLERO-2"
  • Prompt follow-up allows for early identification and management of AEs4

For more information about how to identify and manage specific AEs, please use the tool below.

ADVISE

Educate patients on the potential benefits and risks of AFINITOR

  • Patients with advanced HR+, HER2-negative breast cancer in the BOLERO-2 trial were initiated at the 10-mg dose of AFINITOR plus exemestane and demonstrated more than double the median PFS vs placebo plus exemestane3
  • Both investigator (7.8 months vs 3.2 months median PFS) and independent (11.0 months vs 4.1 months median PFS) reviews confirmed the magnitude of benefit of AFINITOR plus exemestane vs placebo plus exemestane3
  • All pre-specified patient subgroups in BOLERO-2 derived benefit compared with placebo plus exemestane3
  • AFINITOR offers once-daily oral administration taken either consistently with or consistently without food3
    • Median dose intensity of AFINITOR in BOLERO-2 was 8.6 mg/day4
  • Early identification, careful monitoring, and timely management of AEs in the oncology setting are important4
  • Encourage patients to proactively communicate with their doctor and/or healthcare team at the earliest sign of an AE
  • The most common all-grade adverse events (incidence ≥20%, among those with at least 2% incidence of grade 3/4 events, irrespective of causality) were stomatitis (60%), fatigue (38%), diarrhea (36%), dyspnea (23%), and anemia (22%)2
  • The most common grade 3/4 adverse events (incidence ≥5%, irrespective of causality) were stomatitis (8%), anemia (8%), gamma-glutamyltransferase increase (7%), hyperglycemia (6%), and dyspnea (5%)2
  • The most frequently (≥2%) reported serious adverse events in patients receiving AFINITOR plus exemestane therapy were pneumonitis (3%), dyspnea (3%), and pneumonia (2%)2

STOMATITIS

IDENTIFY

  • mTOR inhibitor–associated stomatitis is distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation5
  • In the BOLERO-2 study, the majority of stomatitis events were grade ≤2 and were generally reversible1
  • In the BOLERO-2 study, more than 33% of events grade ≥2 occurred within the first 2 weeks after treatment initiation4
  • In patients receiving AFINITOR plus exemestane in the BOLERO-2 study, 97% of patients with grade ≥3 stomatitis saw resolution to grade ≤1 after a median of 3.1 weeks following dose interruption/reduction, and 82% saw complete resolution after a median of 7.4 weeks4
  • Stomatitis mostly occurs within the first 8 weeks of treatment3
STOMATITIS GRADATION6
Grade 1 Asymptomatic or mild symptoms; intervention not indicated
Grade 2 Moderate pain; not interfering with oral intake; modified diet indicated
Grade 3 Severe pain; interfering with oral intake
Grade 4 Life-threatening consequences; urgent intervention indicated
 

Typical presentation of varying grades of stomatitis observed during clinical examination

 

GRADE 1

Identification

Grade 1 Stomatitis

 
Reprinted with permission from ELSEVIER, A261.7
 

GRADE 2

Identification

Grade 2 Stomatitis

 
Reprinted with permission from ELSEVIER, A261.8
 

GRADE 3

Identification

Grade 3 Stomatitis

 
Reprinted with permission from ELSEVIER, 105.7
 

GRADE 4

Identification

Grade 4 Stomatitis

 
Reprinted with permission from ELSEVIER, 105.7
 

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Identification

Grade 1 Stomatitis

Grade 2 Stomatitis

Grade 3 Stomatitis

Grade 4 Stomatitis

 
Reprinted with permission from ELSEVIER, A261.7
Reprinted with permission from ELSEVIER, A261.8
Reprinted with permission from ELSEVIER, 105.7
Reprinted with permission from ELSEVIER, 105.7

Tell your patients to

  • Look out for mouth ulcers, pain, discomfort, or open sores
  • Avoid products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives3

MANAGE

Manage therapy with established strategies

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage stomatitis.3

GRADE 1

FIRST OCCURRENCE

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

UPON RECURRENCE

GRADE 2

FIRST OCCURRENCE

  1. Temporary AFINITOR dose interruption until recovery to grade ≤1

  2. Reinitiate treatment at same dose

UPON RECURRENCE

  1. Interrupt AFINITOR until grade ≤1  

     

  2. Reinitiate at  5 mg daily

     

GRADE 3

FIRST OCCURRENCE

  1. Temporary AFINITOR dose interruption until recovery to
    grade ≤1

  2. Reinitiate treatment at 5 mg daily

UPON RECURRENCE

GRADE 4

FIRST OCCURRENCE

DISCONTINUE TREATMENT

UPON RECURRENCE

ADVERSE EVENT

FIRST OCCURRENCE

UPON RECURRENCE

GRADE 1

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

GRADE 2

  1. Temporary AFINITOR dose interruption until recovery to grade ≤1

  2. Reinitiate treatment at same dose

  1. Interrupt AFINITOR until grade ≤1  

     

  2. Reinitiate at  5 mg daily

     

GRADE 3

  1. Temporary AFINITOR dose interruption until recovery to
    grade ≤1

  2. Reinitiate treatment at 5 mg daily

GRADE 4

DISCONTINUE TREATMENT

If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.3

Tips to further manage AFINITOR treatment3

  • Management of stomatitis may include prophylactic and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as a mouthwash. However, products containing alcohol, hydrogen peroxide, iodine, and thyme derivatives should be avoided, as they may exacerbate the condition
  • Monitoring for and treatment of fungal infection is recommended, especially in patients being treated with steroid-based medications
  • Antifungal agents should not be used unless fungal infection has been diagnosed

NONINFECTIOUS PNEUMONITIS

IDENTIFY

In the BOLERO-2 study

  • The majority of noninfectious pneumonitis events were grade ≤2 and were generally reversible1,2
  • Approximately 25% of events grade ≥2 occurred within the first 12 weeks after treatment initiation4
  • 80% of patients with grade 3 noninfectious pneumonitis experienced resolution to grade ≤1 after a median of 3.8 weeks, typically following dose interruption or reduction4
  • Complete resolution of grade ≥3 pneumonitis was reported in 75% of patients after a median of 5.4 weeks, typically following dose interruption or reduction4
NONINFECTIOUS PNEUMONITIS GRADATION6
Grade 1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 Symptomatic; medical intervention indicated; limiting instrumental ADL
Grade 3 Severe symptoms; limiting self-care ADL; oxygen indicated
Grade 4 Life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation)
  • Appropriate multidisciplinary differential diagnosis to exclude alternative causes (such as infection) is required to diagnose noninfectious pneumonitis3

Radiological scans of chest suggestive of noninfectious pneumonitis9

Radiological scan of chest suggestive of noninfectious pneumonitis
Slight increase in markings in addition to metastases.
Image courtesy of Memorial Sloan-Kettering Cancer Center, New York, NY.
Radiological scan of chest suggestive of noninfectious pneumonitis
Stable metastatic nodules but increased interstitial markings with septal thickening.
Reprinted with permission from Wolters Kluwer Health. White DA, Schwartz LH, Dimitrijevic S, et al. Characterization of pneumonitis in patients with advanced non-small cell lung cancer treated with everolimus (RAD001). J Thorac Oncol. 2009;4:1357-1363.
Reprinted with permission of the American Thoracic Society. Copyright © 2014 American Thoracic Society.

Tell your patients to promptly report any new or worsening respiratory symptoms, such as3

  • Hypoxia, pleural effusion, cough, or dyspnea

Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be ruled out in the differential diagnosis of noninfectious pneumonitis.

MANAGE

Manage therapy with established strategies3

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage noninfectious pneumonitis.

GRADE 1

FIRST OCCURRENCE

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

UPON RECURRENCE

GRADE 2

FIRST OCCURRENCE

  1. Consider interruption of AFINITOR therapy until symptoms improve to grade ≤1

  2. Reinitiate treatment at  5 mg daily.
    Discontinue treatment if failure to recover within 4 weeks

UPON RECURRENCE

GRADE 3

FIRST OCCURRENCE

  1. Interrupt treatment until symptoms resolve to grade ≤1

  2. Consider reinitiating treatment at 5 mg daily

UPON RECURRENCE

  1. If toxicity recurs at grade 3,
    consider discontinuation

     

GRADE 4

FIRST OCCURRENCE

DISCONTINUE TREATMENT

UPON RECURRENCE

ADVERSE EVENT

FIRST OCCURRENCE

UPON RECURRENCE

GRADE 1

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

GRADE 2

  1. Consider interruption of AFINITOR therapy until symptoms improve to grade ≤1

  2. Reinitiate treatment at  5 mg daily.
    Discontinue treatment if failure to recover within 4 weeks

GRADE 3

  1. Interrupt treatment until symptoms resolve to grade ≤1

  2. Consider reinitiating treatment at 5 mg daily

  1. If toxicity recurs at grade 3,
    consider discontinuation

     

GRADE 4

DISCONTINUE TREATMENT

If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.3

Tips to further manage AFINITOR treatment3

Grades 2/3:

  • If symptoms are moderate (grade 2) or severe (grade 3), the use of corticosteroids may be indicated until clinical symptoms resolve
  • For patients who require use of corticosteroids for treatment of noninfectious pneumonitis, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered

INFECTIONS

IDENTIFY & MANAGE

Manage therapy with established strategies3

  • While taking AFINITOR, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR
  • If a diagnosis of invasive systemic fungal infection is made, the AFINITOR treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy

RASH

IDENTIFY

ACNEIFORM RASH GRADATION6
Grade 1 Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness
Grade 2 Papules and/or pustules covering 10%-30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL
Grade 3 Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated
Grade 4 Papules and/or pustules covering any percentage of BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-threatening consequences

 

MACULOPAPULAR RASH GRADATION6
Grade 1 Macules/papules covering <10% BSA with or without symptoms (eg, pruritus, burning, tightness)
Grade 2 Macules/papules covering 10%-30% BSA with or without symptoms (eg, pruritus, burning, tightness); limiting instrumental ADL
Grade 3 Macules/papules covering >30% BSA with or without associated symptoms; limiting self-care ADL
Grade 4 -

MANAGE

Manage therapy with established strategies3

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage rash.

GRADE 1

FIRST OCCURRENCE

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

UPON RECURRENCE

GRADE 2

FIRST OCCURRENCE

  1. If toxicity is tolerable, no dose adjustment required. If toxicity becomes intolerable, temporary dose interruption until recovery to grade ≤1

  2. Reinitiate treatment at same dose

UPON RECURRENCE

  1. If toxicity recurs at grade 2, interrupt treatment until recovery to grade ≤1 

  2. Reinitiate treatment at 5 mg daily

GRADE 3

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤1

  2. Consider reinitiating treatment at  5 mg daily

UPON RECURRENCE

  1. If toxicity recurs at grade 3, consider discontinuation

GRADE 4

FIRST OCCURRENCE

DISCONTINUE TREATMENT

UPON RECURRENCE

ADVERSE EVENT

FIRST OCCURRENCE

UPON RECURRENCE

GRADE 1

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

GRADE 2

  1. If toxicity is tolerable, no dose adjustment required. If toxicity becomes intolerable, temporary dose interruption until recovery to grade ≤1

  2. Reinitiate treatment at same dose

  1. If toxicity recurs at grade 2, interrupt treatment until recovery to grade ≤1 

  2. Reinitiate treatment at 5 mg daily

GRADE 3

  1. Temporary dose interruption until recovery to grade ≤1

  2. Consider reinitiating treatment at  5 mg daily

  1. If toxicity recurs at grade 3, consider discontinuation

GRADE 4

DISCONTINUE TREATMENT

METABOLIC EVENTS

IDENTIFY

  • Monitor fasting blood glucose and lipid levels at the start of therapy and periodically thereafter3
METABOLIC EVENTS GRADATION6
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Grade 1 metabolic event lab values Grade 1 metabolic event lab values Grade 3 metabolic event lab values Grade 4 metabolic event lab values
 

Hypertriglyceridemia

 

Hypercholesterolemia

 

Hyperglycemia

MANAGE

Manage therapy with established strategies3

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage metabolic events.

ADVERSE EVENT

GRADE 1

FIRST OCCURRENCE

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be
lower than 5 mg daily

UPON RECURRENCE

GRADE 2

FIRST OCCURRENCE

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

UPON RECURRENCE

GRADE 3

FIRST OCCURRENCE

  1. Temporary dose interruption

  2. Reinitiate treatment at  5 mg daily

UPON RECURRENCE

GRADE 4

FIRST OCCURRENCE

DISCONTINUE TREATMENT

UPON RECURRENCE

ADVERSE EVENT

FIRST OCCURRENCE

UPON RECURRENCE

GRADE 1

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be
lower than 5 mg daily

GRADE 2

Dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily

GRADE 3

  1. Temporary dose interruption

  2. Reinitiate treatment at  5 mg daily

GRADE 4

DISCONTINUE TREATMENT

HEMATOLOGIC TOXICITIES

IDENTIFY

Hematologic toxicity gradation6
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Grade 1 hematologic toxicities lab values Grade 2 hematologic toxicities lab values Grade 3 hematologic toxicities lab values Grade 4 hematologic toxicities lab values
 

Neutropenia

 

Thrombocytopenia

Febrile neutropenia6

  • Grade 3: ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour
  • Grade 4: Life-threatening consequences; urgent intervention indicated

MANAGE

Manage therapy with established strategies3

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage neutropenia and thrombocytopenia.

ADVERSE EVENT

Grade 1

ADVERSE EVENT

Neutropenia


Thrombocytopenia

FIRST OCCURRENCE

Dose adjustment is usually not required.If dose reduction is required,
the recommended dose is 5 mg daily and must not be lower than
5 mg daily

UPON RECURRENCE

Grade 2

ADVERSE EVENT

Neutropenia

FIRST OCCURRENCE

No dose adjustment required

UPON RECURRENCE

ADVERSE EVENT

Thrombocytopenia

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 x 109/L)

  2. Reinitiate treatment at same dose

UPON RECURRENCE

Grade 3

ADVERSE EVENT

Neutropenia

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1 x 109/L)

  2. Reinitiate treatment at same dose

UPON RECURRENCE

ADVERSE EVENT

Febrile neutropenia

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1.25 x 109/L) and no fever

  2. Reinitiate treatment at 5 mg daily

UPON RECURRENCE

ADVERSE EVENT

Thrombocytopenia

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 x 109/L)

  2. Reinitiate treatment at 5 mg daily

UPON RECURRENCE

GRADE 4

ADVERSE EVENT

Neutropenia 

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1 × 109/L)

  2. Reinitiate treatment at 5 mg daily

UPON RECURRENCE

ADVERSE EVENT

Febrile neutropenia

FIRST OCCURRENCE

DISCONTINUE TREATMENT

UPON RECURRENCE

ADVERSE EVENT

Thrombocytopenia

FIRST OCCURRENCE

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 × 109/L)

  2. Reinitiate treatment at 5 mg daily

UPON RECURRENCE

ADVERSE EVENT

FIRST OCCURRENCE

UPON RECURRENCE

Grade 1

Neutropenia


Thrombocytopenia

Dose adjustment is usually not required.If dose reduction is required,
the recommended dose is 5 mg daily and must not be lower than
5 mg daily

Grade 2

Neutropenia

No dose adjustment required

Thrombocytopenia

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 x 109/L)

  2. Reinitiate treatment at same dose

Grade 3

Neutropenia

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1 x 109/L)

  2. Reinitiate treatment at same dose

Febrile neutropenia

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1.25 x 109/L) and no fever

  2. Reinitiate treatment at 5 mg daily

Thrombocytopenia

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 x 109/L)

  2. Reinitiate treatment at 5 mg daily

GRADE 4

Neutropenia 

  1. Temporary dose interruption until recovery to grade ≤2
    (≥1 × 109/L)

  2. Reinitiate treatment at 5 mg daily

Febrile neutropenia

DISCONTINUE TREATMENT

Thrombocytopenia

  1. Temporary dose interruption until recovery to grade ≤1
    (≥75 × 109/L)

  2. Reinitiate treatment at 5 mg daily

If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.3

The medical judgment of the treating physicians should guide all treatment decisions.

Abbreviations:
aBC, advanced breast cancer; ADL, activities of daily living; AE, adverse event; ANC, absolute neutrophil count; BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; BSA, body surface area; FGV, fasting glucose value; HR+, hormone receptor-positive; IV, intravenous; LLN, lower limit of normal; mTOR, mammalian target of rapamycin; PFS, progression-free survival; ULN, upper limit of normal.
References:
1. Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870-884.
2. Data on file. Novartis Pharma AG; 2017.
3. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2017.
4. Rugo HS, Pritchard KI, Gnant M, et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25(4):808-815.
5. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010;116(1):210-215.
6. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v4.03.
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published June 14, 2010.
Accessed January 5, 2018.
7. de Oliveira MA, Martins e Martins F, Wang Q, et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011;47(10):998-1003.
8. Ferté C, Paci A, Zizi M, et al. Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur J Cancer. 2011;47(15):2249-2255.
9. White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010;182(3):396-403.