Mechanism of Action

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

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.

Pharmacodynamics

QT/QTc Prolongation Potential

In a randomized, placebo-controlled, crossover study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. There is no indication of a QT/QTc prolonging effect of AFINITOR in single doses up to 50 mg.

Exposure Response Relationships

Markers of protein synthesis show that inhibition of mTOR is complete after a 10 mg daily dose.

In patients with SEGA, higher everolimus trough concentrations appear to be associated with larger reductions in SEGA volume. However, as responses have been observed at trough concentrations as low as 3 ng/mL, once acceptable efficacy has been achieved, additional dose increase may not be necessary.

Pharmacokinetics

Absorption

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 between 5 mg and 10 mg. At 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.

Food effect: In healthy subjects, high fat meals reduced systemic exposure to AFINITOR 10 mg tablet (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile.

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/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

Metabolism

Everolimus is a substrate of CYP3A4 and PgP. 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.

In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.

Excretion

No specific excretion 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. The mean elimination half-life of everolimus is approximately 30 hours.

Patients with Renal Impairment

Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of [14C]-labeled everolimus. In a population pharmacokinetic analysis which included 170 patients with advanced cancer, no significant influence of creatinine clearance (25–178 mL/min) was detected on oral clearance (CL/F) of everolimus [see Use In Specific Populations].

Patients with Hepatic Impairment

The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Compared to normal subjects (N=13), there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in exposure (i.e. AUC) for subjects with mild (Child-Pugh class A, N=6), moderate (Child-Pugh class B, N=9), and severe (Child-Pugh class C, N=6) hepatic impairment, respectively. In another study, the average AUC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in eight subjects with normal hepatic function.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with moderate or mild hepatic impairment, a dose reduction is recommended [see DOSAGE AND ADMINISTRATION].

For SEGA patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B), adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see DOSAGE AND ADMINISTRATION]. For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR should not be used.

Effects of Age and Gender

In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance and patient age or gender.

Ethnicity

Based on a cross-study comparison, Japanese patients (n=6) had on average exposures that were higher than non-Japanese patients receiving the same dose.

Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in Black patients than in Caucasians.

The significance of these differences on the safety and efficacy of everolimus in Japanese or Black patients has not been established.

Dose Proportionality in Patients with SEGA

In patients with SEGA, intra-patient steady-state trough concentrations were dose-proportional at daily doses of 1.5 to 14.6 mg/m² [see DOSAGE AND ADMINISTRATION].

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.

Clinical Studies

Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer

A randomized, double-blind, multicenter study of AFINITOR plus exemestane versus placebo plus exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER 2/neu-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 vs. 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 primary endpoint for the trial was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other endpoints included overall survival (OS), objective response rate (ORR), and safety.

Patients were randomly allocated in a 2:1 ratio to AFINITOR 10 mg/day plus exemestane 25 mg/day (n = 485) or to placebo plus exemestane 25 mg/day (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 median progression-free survival by investigator assessment at the time of the final PFS analysis was 7.8 and 3.2 months in the AFINITOR and placebo arms, respectively [HR = 0.45 (95% CI: 0.38, 0.54), one-sided log-rank p < 0.0001] (see Table 12 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.

Objective response rate was 12.6% (95% CI: 9.8, 15.9) in the AFINITOR plus exemestane arm vs. 1.7% (95% CI: 0.5, 4.2) in the placebo plus exemestane arm. There were 3 complete responses (0.6%) and 58 partial responses (12.0%) in the AFINITOR plus exemestane arm. There were no complete responses and 4 partial responses (1.7%) in the placebo plus exemestane arm.

The overall survival results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted [HR=0.77 (95% CI: 0.57, 1.04)].

Table 12: Progression-free Survival Results

Figure 1: Kaplan-Meier Progression-free Survival Curves (Investigator Radiological Review)

Advanced Neuroendocrine Tumors

Locally Advanced or Metastatic Advanced Pancreatic Neuroendocrine Tumors (PNET):

A randomized, double-blind, multi-center trial of AFINITOR plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with locally advanced or metastatic advanced pancreatic neuroendocrine tumors (PNET) and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes/no) and by WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The primary endpoint for the trial was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). After documented radiological progression, patients could be unblinded by the investigator; those randomized to placebo were then able to receive open-label AFINITOR. Other endpoints included safety, objective response rate [ORR (complete response (CR) or partial response (PR)], response duration, and overall survival.

Patients were randomized 1:1 to receive either AFINITOR 10mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 79% Caucasian). Crossover from placebo to open-label AFINITOR occurred in 73% (148/203) of patients.

The trial demonstrated a statistically significant improvement in PFS (median 11.0 months versus 4.6 months), resulting in a 65% risk reduction in investigator-determined PFS (HR 0.35; 95%CI: 0.27 to 0.45; p < 0.001) (see Table 13 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 below in Table 13.

Table 13: Progression-free Survival Results

Figure 2: Kaplan-Meier Investigator-Determined Progression-free Survival Curves

Investigator-determined response rate was low (4.8%) in the AFINITOR arm and there were no complete responses. The overall survival results are not yet mature and no statistically significant treatment-related difference in OS was noted [HR=1.05 (95% CI: 0.71 to 1.55)].

Locally Advanced or Metastatic Carcinoid Tumors

In a randomized, double-blind, multi-center trial in 429 patients with carcinoid tumors, AFINITOR plus depot octreotide (Sandostatin LAR®) was compared to placebo plus depot octreotide. After documented radiological progression, patients could be unblinded by the investigator: those randomized to placebo were then able to receive open-label AFINITOR plus depot octreotide. The study did not meet the primary efficacy endpoint (PFS) and the OS interim analysis numerically favored the placebo plus depot octreotide arm. Therefore, the use of AFINITOR in patients with carcinoid tumors remains investigational.

Advanced Renal Cell Carcinoma

An international, multi-center, randomized, double-blind trial comparing AFINITOR 10 mg daily and placebo, both in conjunction with best supportive care, 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 [see REFERENCES].

Progression-free survival (PFS), documented using Response Evaluation Criteria in Solid Tumors (RECIST) was assessed via a blinded, independent, central radiologic review. After documented radiological progression, patients could be unblinded by the investigator: those randomized to placebo were then able to receive open-label AFINITOR 10 mg daily.

In total, 416 patients were randomized 2:1 to receive AFINITOR (n=277) or placebo (n=139). Demographics were well balanced between the two arms (median age 61 years; 77% male, 88% Caucasian, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).

AFINITOR was superior to placebo for PFS (see Table 14 and Figure 3). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final overall survival (OS) results yield a hazard ratio of 0.90 (95% CI: 0.71 to 1.14), with no statistically significant difference between the two treatment groups. Planned crossover from placebo due to disease progression to open label AFINITOR occurred in 111 of the 139 patients (79.9%) and may have confounded the OS benefit.

Table 14: Efficacy Results by Central Radiologic Review

Figure 3: Kaplan-Meier Progression-free Survival Curves

Renal Angiomyolipoma with Tuberous Sclerosis Complex

A randomized (2:1), double-blind, placebo-controlled trial 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 daily oral AFINITOR 10 mg or matching placebo 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. Analyses of efficacy outcome measures were limited to the blinded treatment period which ended 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/no).

Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo. The median age was 31 years (range 18 to 61 years), 34% were male, and 89% were Caucasian. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least one 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 (range 9 to 1612 cm³) and 120 cm³ (range 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 (range 0.7 to 24.8 months).

The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients; there were 33 (41.8%) patients with angiomyolipoma responses in the AFINITOR arm as compared to none in the placebo arm. Results are displayed in Table 15. The median response duration is 5.3+ months (range 2.3+ to 19.6+ months).

Table 15: Angiomyolipoma Response

There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. 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).

Skin lesion response rates were assessed by local investigators in 77 patients in the AFINITOR arm and 37 patients in the placebo arm 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%-99% skin lesions, considering all skin lesions, durable for at least eight weeks (Physician's Global Assessment of Clinical Condition).

Subependymal Giant Cell Astrocytoma

An open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. Serial radiological evidence of SEGA growth was required for entry. Change in SEGA volume at the end of the core 6-month treatment phase was assessed via an independent central radiology review. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34), 61% male, 86% Caucasian. Four patients had surgical resection of their SEGA lesions with subsequent re-growth prior to receiving AFINITOR treatment. After the core treatment phase, patients could continue to receive AFINITOR treatment as part of an extension treatment phase where SEGA volume was assessed every 6 months. The median duration of treatment was 24.4 months (range 4.7-37.3 months).

At 6 months, 9 out of 28 patients (32%, 95% CI: 16% to 52%) had a ≥ 50% reduction in the tumor volume of their largest SEGA lesion. Duration of response for these 9 patients ranged from 97 to 946 days with a median of 266 days. Seven of these 9 patients had an ongoing volumetric reduction of ≥ 50% at the data cutoff.

Three of 4 patients who had prior surgery experienced a ≥ 50% reduction in the tumor volume of their largest SEGA lesion. One of these three patients responded by month 6. No patient developed new lesions.

Last reviewed on RxList: 8/2/2012
This monograph has been modified to include the generic and brand name in many instances.