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AiM Advise. Identify. Manage.

Take AIM through a targeted treatment strategy to optimize therapy

Optimize AFINITOR's benefit through patient education, proactive planning, and established management strategies

In the BOLERO-2 study

  • The majority of AEs were mild to moderate in severity (grade 1/2), generally manageable, and reversible1-3
  • 100% of patients were initiated at the 10-mg dose of AFINITOR1
  • 38% of patients did not require a dose interruption and/or reduction
  • Median dose intensity of AFINITOR was 8.6 mg/day with once-daily oral administration3

Visit and assessment schedule from BOLERO-21

Visit and assessment schedule from BOLERO-2
  • Prompt follow-up allows for early identification and management of AEs2

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

ADVISE

Capitalize on AFINITOR's benefit through patient education

  • 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 without deterioration of QoL vs placebo plus exemestane4
  • Both investigator (7.8 months vs 3.2 months PFS) and independent (11.0 months vs 4.1 months PFS) reviews confirmed the magnitude of benefit of AFINITOR plus exemestane vs placebo plus exemestane4
  • All pre-specified patient subgroups in BOLERO-2 derived benefit compared to placebo plus exemestane4
  • AFINITOR offers once-daily oral administration4
    • Median dose intensity of AFINITOR in BOLERO-2 was 8.6 mg/day3
  • Early identification, careful monitoring, and timely management of AEs in the oncology setting are important to help patients maximize their time on treatment3
  • Encourage patients to proactively communicate with their doctor and/or healthcare team at the earliest sign of an AE

STOMATITIS

IDENTIFY

  • mTOR inhibitor–associated stomatitis is distinct from conventional chemotherapy-induced mucositis in both its pathophysiology and clinical presentation5
  • In BOLERO-2, more than one-third of grade ≥2 events occurred within 2 weeks3

CLINICAL PRESENTATION OF STOMATITIS6

 

GRADE 1

Presentation: clinical exam

Erythema of the mucosa

Presentation: functional/ symptomatic

Minimal symptoms, normal diet

 
 

GRADE 2

Presentation: clinical exam

Patchy ulcerations or pseudomembranes

Presentation: functional/ symptomatic

Symptomatic but can eat and swallow, modified diet

 
 

GRADE 3

Presentation: clinical exam

Confluent ulcerations or pseudomembranes, bleeding with minor trauma

Presentation: functional/ symptomatic

Symptomatic and unable to adequately aliment or hydrate orally

 
 

GRADE 4

Presentation: clinical exam

Tissue necrosis, significant spontaneous bleeding, life-threatening consequences

Presentation: functional/ symptomatic

Symptoms associated with life-threatening consequences

 
 

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Presentation: clinical exam

Erythema of the mucosa

Patchy ulcerations or pseudomembranes

Confluent ulcerations or pseudomembranes, bleeding with minor trauma

Tissue necrosis, significant spontaneous bleeding, life-threatening consequences

Presentation: functional/ symptomatic

Minimal symptoms, normal diet

Symptomatic but can eat and swallow, modified diet

Symptomatic and unable to adequately aliment or hydrate orally

Symptoms associated with life-threatening consequences

 

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 derivatives

MANAGE

Manage therapy with established strategies

Use the guidelines below when considering modifications of the AFINITOR 10-mg dose to manage stomatitis.3,4

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.9

Tips to optimize AFINITOR treatment9

In cases of stomatitis, topical treatments are recommended, but mouthwashes containing alcohol, peroxide, iodine, and thyme derivatives should be avoided.

NONINFECTIOUS PNEUMONITIS

IDENTIFY

  • Noninfectious pneumonitis should be investigated in patients with nonspecific respiratory signs2,4
    • Pulmonary function tests, radiographic imaging, bronchoscopy, and bronchoalveolar lavage can be used to evaluate2
  • In BOLERO-2, approximately one-quarter of grade ≥2 symptomatic events occurred within 12 weeks of treatment initiation3

GRADING OF NONINFECTIOUS PNEUMONITIS6

 

GRADE 1

Presentation

Asymptomatic, radiographic findings only

 
 

GRADE 2

Presentation

Symptomatic,* not interfering with ADL

 
 

GRADE 3

Presentation

Symptomatic,* interfering with ADL, oxygen indicated

 
 

GRADE 4

Presentation

Life-threatening, ventilator support indicated

 
 

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Presentation

Asymptomatic, radiographic findings only

Symptomatic,* not interfering with ADL

Symptomatic,* interfering with ADL, oxygen indicated

Life-threatening, ventilator support indicated

*Symptoms include hypoxia, pleural effusion, cough, or dyspnea.4
  • Appropriate multidisciplinary differential diagnosis to exclude alternative causes (such as infection) is required to diagnose noninfectious pneumonitis10

Radiological scans of chest suggestive of noninfectious pneumonitis11

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 A, Schwartz L, 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. Cite: Author(s)/Year/Title/Journal Title/Volume/Pages. Official Journal of the American Thoracic Society.

Tell your patients to promptly report any new or worsening respiratory symptoms, such as4:

  • Hypoxia, pleural effusion, cough, or dyspnea

MANAGE

Manage therapy with established strategies3,4

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.9

Tips to optimize AFINITOR treatment4

Grades 2/3:

  • Rule out infection and consider treatment with corticosteroids until symptoms improve to
    grade <1

INFECTIONS*

IDENTIFY

CLINICAL PRESENTATION AND IDENTIFICATION: CTCAE v3.0 USED IN THE BOLERO-2 CLINICAL TRIAL6

 

GRADE 1

Presentation

Asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated

 
 

GRADE 2

Presentation

Localized or moderate intervention indicated

 
 

GRADE 3

Presentation

Severe, IV antibiotic, antifungal, or antiviral intervention indicated, disabling

 
 

GRADE 4

Presentation

Life-threatening consequences

 
 

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Presentation

Asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated

Localized or moderate intervention indicated

Severe, IV antibiotic, antifungal, or antiviral intervention indicated, disabling

Life-threatening consequences

MANAGE

Manage therapy with established strategies3

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

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

*Includes all reactions within the "infections and infestations" system organ class including (common) pneumonia and (uncommon) herpes zoster, sepsis, and isolated cases of opportunistic infections (eg, aspergillosis, candidiasis, and hepatitis B).4

RASH

IDENTIFY

  • Presents as rash and pain on palms of hands or soles of feet, skin exfoliation, erythema, pimples, acne, or skin lesions6

CLINICAL PRESENTATION AND IDENTIFICATION: CTCAE v3.0 USED IN THE BOLERO-2 CLINICAL TRIAL6

 

GRADE 1

Presentation

Macular or papular eruption or erythema without associated symptoms

 
 

GRADE 2

Presentation

Macular or papular eruption or erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering <50% of BSA

 
 

GRADE 3

Presentation

Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation covering ≥50% BSA

 
 

GRADE 4

Presentation

Generalized exfoliative, ulcerative, or bullous dermatitis 

 
 

GRADE 1

GRADE 2

GRADE 3

GRADE 4

Presentation

Macular or papular eruption or erythema without associated symptoms

Macular or papular eruption or erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering <50% of BSA

Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation covering ≥50% BSA

Generalized exfoliative, ulcerative, or bullous dermatitis 

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

    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

    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 thereafter4
METABOLIC EVENTS LAB VALUES: CTCAE V3.0 USED IN THE BOLERO-2 CLINICAL TRIAL6
GRADE 1 GRADE 2 GRADE 3 GRADE 4
 

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

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

No dose adjustment required

GRADE 3

  1. Temporary dose interruption

  2. Reinitiate treatment at  5 mg daily

GRADE 4

DISCONTINUE TREATMENT

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

No dose adjustment required

GRADE 3

  1. Temporary dose interruption

  2. Reinitiate treatment at  5 mg daily

GRADE 4

DISCONTINUE TREATMENT

HEMATOLOGIC TOXICITIES

IDENTIFY

HEMATOLOGIC TOXICITIES LAB VALUES: CTCAE V3.0 USED IN THE BOLERO-2 CLINICAL TRIAL6
GRADE 1 GRADE 2 GRADE 3 GRADE 4
 

Neutropenia

 

Thrombocytopenia

Febrile neutropenia6

  • Grade 3: ANC ‹1.0 x 109/L with a temperature of ≥38.5°C
  • Grade 4: Life-threatening consequences (eg, septic shock, hypotension, acidosis, necrosis)

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

.

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

.

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.

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; CTCAE, Common Terminology Criteria for Adverse Events; FGV, fasting glucose value; HR+, hormone receptor-positive; LLN, lower limit of normal; mTOR, mammalian target of rapamycin; PFS, progression-free survival; QoL, quality of life; 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. Rugo HS, Gnant M, Gerberth M, et al. Everolimus-related adverse events: safety insights from BOLERO-2. Poster presented at: St. Gallen International Breast Cancer Conference; March 13-16, 2013; St. Gallen, Switzerland. Poster 274.
  3. 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.
  4. AFINITOR [summary of product characteristics]. Novartis Pharma AG; 2016.
  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) v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Published August 09, 2006. Accessed July 14, 2014.
  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. Ferte 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. Grünwald V, Weikert S, Pavel ME, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie. 2013;36(5):295-302.
  10. Aapro M, Andre F, Blackwell K, et al. Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Ann Oncol. 2014;25(4):763-773.
  11. 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.