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Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner.
Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis.
Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.
Pharmacodynamics: Exposure-Response Relationship: In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration.
Cardiac Electrophysiology: In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.
Clinical Studies: Hormone Receptor-Positive, HER2-Negative Breast Cancer: A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of AFINITOR in combination with exemestane vs. placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes versus no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR).
Patients were randomized 2:1 to AFINITOR 10 mg orally once daily in combination with exemestane 25 mg once daily (n = 485) or to placebo in combination with exemestane 25 mg orally once daily (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to AFINITOR at the time of disease progression.
The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 1 and Figure 1). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.
ORR was higher in the AFINITOR in combination with exemestane arm vs. the placebo in combination with exemestane arm (Table 1). There were 3 complete responses (0.6%) and 58 partial responses (12%) in the AFINITOR arm. There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm.
After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)]. (See Table 1 and Figure 1.)
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Click on icon to see table/diagram/imageNeuroendocrine Tumors (NET): Pancreatic Neuroendocrine Tumors (PNET): A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of AFINITOR in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes vs. no) and WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The major efficacy outcome was PFS evaluated by RECIST. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included ORR, response duration, and OS.
Patients were randomized 1:1 to receive either AFINITOR 10 mg once daily (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58 years, 55% male, 79% White). Of the 203 patients randomized to BSC, 172 patients (85%) received AFINITOR following documented radiologic progression.
The trial demonstrated a statistically significant improvement in PFS (Table 2 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown as follows in Table 2. (See Table 2 and Figure 2.)
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Click on icon to see table/diagram/imageInvestigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses. OS was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30].
NET of Gastrointestinal (GI) or Lung Origin: A randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of AFINITOR in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin. The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. Patients were randomized 2:1 to receive either AFINITOR 10 mg once daily or placebo, and stratified by prior somatostatin analog use (yes vs. no), tumor origin and WHO performance status (0 vs. 1). The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST. Additional efficacy outcome measures were OS and ORR.
A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm. The median age was 63 years (22 to 86 years); 47% were male; 76% were White; 74% had WHO performance status of 0 and 26% had WHO performance status of 1. The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).
The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 3 and Figure 3). The final OS analysis did not show a statistically significant difference between those patients who received AFINITOR or placebo (HR = 0.90 [95% CI: 0.66, 1.24]). (See Table 3 and Figure 3.)
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Click on icon to see table/diagram/imageLack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors: The safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, AFINITOR in combination with long-acting octreotide (Sandostatin LAR) was compared to placebo in combination with long-acting octreotide. After documented radiological progression, patients on the placebo arm could receive AFINITOR; of those randomized to placebo, 67% received open-label AFINITOR in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm.
Renal Cell Carcinoma (RCC): An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing AFINITOR 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included OS.
In total, 416 patients were randomized 2:1 to receive AFINITOR (n = 277) or placebo (n = 139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% White, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).
AFINITOR was superior to placebo for PFS (Table 4 and Figure 4). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label AFINITOR occurred in 80% of the 139 patients and may have confounded the OS benefit. (See Table 4 and Figure 4.)
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Click on icon to see table/diagram/imageTuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma: A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received AFINITOR 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).
Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were White. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (9 to 1612 cm3) and 120 cm3 (3 to 4520 cm3) in the AFINITOR and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis.
The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients (Table 5). The median response duration was 5.3+ months (2.3+ to 19.6+ months).
There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001). (See Table 5).
Click on icon to see table/diagram/imageSkin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the AFINITOR arm (26% vs. 0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition).
Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR. The median duration of AFINITOR treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period. No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.
Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA): EXIST-1: A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter. The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).
Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were White. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm3 (0.18 to 25.15 cm3) and 1.30 cm3 (0.32 to 9.75 cm3) in the AFINITOR and placebo arms, respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis.
The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 6). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months).
With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention. (See Table 6.)
Click on icon to see table/diagram/imagePatients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR treatment and follow-up was 3.9 years (0.2 to 4.9 years).
By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study.
Study 2485: Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m2/orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study.
A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% White.
At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years).
By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on AFINITOR. Nine additional patients were identified as having a ≥ 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR, including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.
Pharmacokinetics: Absorption: After administration of AFINITOR in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.
In patients with TSC-associated SEGA, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.
Effect of Food: In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to AFINITOR 10 mg (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and Cmax by 42%.
In healthy subjects who received 9 mg of AFINITOR DISPERSIBLE, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%.
Relative Bioavailability: The AUCinf of everolimus was equivalent between AFINITOR DISPERSIBLE and AFINITOR; the Cmax of everolimus in the AFINITOR DISPERSIBLE dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration.
Distribution: The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
Elimination: The mean elimination half-life of everolimus is approximately 30 hours.
Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.
Specific Populations: No relationship was apparent between oral clearance and age or sex in patients with cancer.
Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.
Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage & Administration, Precautions].
Pediatric Patients: In patients with TSC-associated SEGA, the mean Cmin values normalized to mg/m2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to body surface area was higher in pediatric patients as compared to adults.
Race or Ethnicity: Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in Black patients than in White patients.
Drug Interaction Studies: Effect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when AFINITOR was coadministered with: ketoconazole (a P-gp and strong CYP3A4 inhibitor) - Cmax and AUC increased by 3.9- and 15-fold, respectively; erythromycin (a P-gp and moderate CYP3A4 inhibitor) - Cmax and AUC increased by 2- and 4.4-fold, respectively; verapamil (a P-gp and moderate CYP3A4 inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.
Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of AFINITOR with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and Cmax by 58% compared to AFINITOR alone [see Dosage & Administration].
Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).
The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with AFINITOR resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC0-inf.
The coadministration of AFINITOR with exemestane increased exemestane Cmin by 45% and C2h by 64%; however, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.
The coadministration of AFINITOR with long acting octreotide increased octreotide Cmin by approximately 50%.
Effect of Everolimus on Antiepileptic drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam's metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily.
Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m2/day, approximately 255-fold the recommended dose of AFINITOR 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA, based on the body surface area), administered as 2 doses, 24 hours apart.
Based on non-clinical findings, AFINITOR may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng·hr/mL and 414 ng·hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng·hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%.
Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.
Animal Toxicology and/or Pharmacology: In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.
