Important Safety Information

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, other rapamycin derivatives, or any excipients. There have been reports of noninfectious pneumonitis (including some with…+

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Indication

AFINITOR® (everolimus) Tablets is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease.

AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.

Efficacy

PFS

AFINITOR MORE THAN DOUBLED MEDIAN PFS VS PLACEBO1

RADIANT-3 Kaplan-Meier Graph

AFINITOR® (everolimus) Tablets extended median PFS by more than 6 months (HR=0.35 [95% CI, 0.27-0.45], P<0.001).1

  • 65% reduction in risk of progression regardless of WHO performance status, tumor grade, or prior SSA use1,2

OS was not statistically significantly different between study arms (HR=0.94 [95% CI, 0.73-1.20], P=0.30). Investigator-determined response rate was low (4.8%) in the AFINITOR arm and there were no complete responses.1

Duration of Treatment

 

*Calculation: (365 days/12 months)/7 days in a week=4.35 weeks in the average month.
37 weeks/4.35 weeks=8.51 months for AFINITOR; 16 weeks/4.35 weeks=3.678 months for placebo.

Important Safety Information

There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with fatal outcomes.1

Study Design

RADIANT-3: THE LARGEST (N=410) PHASE 3 TRIAL OF ADVANCED PANCREATIC NET1,2

RADIANT-3 Trial Design

*0 vs 1 and 2.
Yes or no.
Best supportive care (BSC) could include somatostatin analogue therapy.
§Crossover to AFINITOR was allowed upon disease progression.

RADIANT-3 was a large, robust trial2

Objectives2:

  • Primary end point: PFS
  • Secondary end points: Safety, objective response rate (complete response or partial response), response duration, and OS

Key eligibility criteria2:

  • Advanced (unresectable or metastatic) pancreatic NET
  • Disease progression ≤12 months prior to randomization

Abbreviations: mTOR, mammalian target of rapamycin; NET, neuroendocrine tumor; OS, overall survival; PFS, progression-free survival; WHO, World Health Organization.

Patient Population

DIVERSE INCLUSION CRITERIA COUNT

 

RADIANT-3 enrolled patients with a range of characteristics2

DemographicsAFINITOR (n=207)Placebo (n=203)
Prior chemotherapy, % 50 50
Prior somatostatin analogue therapy, % 49 50
Median age, y 58 57
Male, % 53 58
Female, % 47 42

 

Across a range of tumor grades2

Tumor StatusAFINITOR, % (n=207)Placebo, % (n=203)
Well differentiated 82 84
Moderately differentiated 17 15
Unknown 1 1

 

Across WHO performance status2

WHO StatusAFINITOR, % (n=207)Placebo, % (n=203)
0 67 66
1 30 32
2 3 3

 

A range of metastatic sites2

Number of Metastatic SitesAFINITOR, % (n=207)Placebo, % (n=203)
1 25 31
2 41 32
≥3 34 38

 

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016. 2. Yao JC, Shah MH, Ito T, et al; for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523.

Important Safety Information

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Manage noninfectious pneumonitis by dose interruption until symptoms resolve, follow with a dose reduction, and consider the use of corticosteroids. Discontinue AFINITOR if toxicity recurs at grade 3 or for grade 4 cases. For patients who require use of corticosteroids, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment.

PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.  

Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. 

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR.

Impaired Wound Healing: Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period. 

Laboratory Tests and Monitoring: Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function.

Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter.

Drug-Drug Interactions: Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less.

Hepatic Impairment: Exposure to everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. 

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. 

Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential of the potential risk to a fetus and to use effective contraception while using AFINITOR and for 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence ≥30%) were stomatitis (70%), rash (59%), diarrhea (50%), fatigue (45%), edema (39%), abdominal pain (36%), nausea (32%), fever (31%), headache (30%), and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence ≥5%) were stomatitis (7%) and diarrhea (5.5%). Deaths primarily due to adverse events during the double-blind treatment phase occurred in 7 patients taking AFINITOR. 

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥50%, all grades) were: decreased hemoglobin (86%) and bicarbonate (56%); increased fasting glucose (75%), alkaline phosphatase (74%), cholesterol (66%), and aspartate transaminase (56%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were: decreased hemoglobin (15%), lymphocytes (16%), and phosphate (10%), and increased glucose (17%) and alkaline phosphatase (8%).

Please see full Prescribing Information.

Indication

AFINITOR is indicated for the treatment of adults with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced, or metastatic disease.

AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.