Afinitor (everolimus) - 6 indications

Scroll down for information on each indication:

• Renal cell carcinoma; approved 03/01/2009
• Subependymal giant cell astrocytoma associated with tuberous sclerosis; approved 11/01/2010
• Advanced pancreatic neuroendocrine tumors; approved 05/01/2011
• Renal angiomyolipoma associated with tuberous sclerosis complex; approved 04/01/2012
• Hormone receptor-positive, HER2-negative breast cancer; approved 07/01/2012
• Neuroendocrine tumors of gastrointestinal or lung origin; approved 02/01/2016

General Information

Afinitor (everolimus), an inhibitor of mTOR (mammalian target of rapamycin), is an antineoplastic agent.

Afinitor is specifically indicated for the following conditions:

• Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
• Adult and pediatric patients aged 1 year and older with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
• Adults with progressive neuroendocrine tumors of pancreatic origin (PNET).
• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
• Postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.
• Adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.

Afinitor is supplied as a tablet for oral administration. Please scroll down for specific dosing recommendations for each therapeutic indication.

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 and in tuberous sclerosis complex (TSC). 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.

Side Effects

Adverse effects associated with the use of Afinitor for breast cancer, NET and RCC may include, but are not limited to, the following:

• stomatitis
• infections
• rash
• fatigue
• diarrhea
• edema
• abdominal pain
• nausea
• fever
• asthenia
• cough
• headache
• decreased appetite

Adverse reactions associated with the use of Afinitor for TSC-Associated Renal Angiomyolipoma and TSC-Associated SEGA  may include, but are not limited to, the following:

• stomatitis
• respiratory tract infection

Indication 1 - Renal cell carcinoma

approved 03/01/2009

Dosing/Administration

The recommended dosage is 10 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Afinitor for use in adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib was based on the results of a clinical trial. This international, multicenter, randomized, double-blind study enrolled 416 subjects with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. The subjects received Afinitor 10 mg once daily or placebo, both in conjunction with best cupportive care. After documented radiological progression, subjects could be unblinded by the investigator: those randomized to placebo were then able to receive open-label Afinitor 10 mg daily. The primary endpoint was progression-free survival (PFS), documented using RECIST criteria. The median progression-free survival was 4.9 months for Afinitor versus 1.9 months for placebo.

Indication 2 - Subependymal giant cell astrocytoma associated with tuberous sclerosis

approved 11/01/2010

Dosing/Administration

The recommended starting dosage is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Afinitor for SEGA associated with TSC was based on a single study of 28 patients. At six months into the study, nine patients (32 percent) had a greater than 50 percent reduction in space the tumor occupied (tumor volume) of their largest SEGA tumor lesion. The length of time from when a patient's tumor visibly shrank and then remained stable (duration of response) for these nine patients ranged from about three months to two and one-half years with a median of 266 days. Seven of these patients retained the greater than 50 percent reduction in space the tumor occupied at time of last follow up.

Indication 3 - Advanced pancreatic neuroendocrine tumors

approved 05/01/2011

Dosing/Administration

The recommended dosage is 10 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Afinitor for adults with progressive neuroendocrine tumors of pancreatic origin was based on a randomized, double-blind, multi-center trial in 410 subjects with locally advanced or metastatic advanced pancreatic neuroendocrine tumors and disease progression within the prior 12 months. The subjects received either Afinitor 10 mg/day or placebo until disease progression. The primary endpoint was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). 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.

Indication 4 - Renal angiomyolipoma associated with tuberous sclerosis complex

approved 04/01/2012

Dosing/Administration

The recommended dosage is 10 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Afinitor for use in adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery was based on the results of a double-blind, placebo-controlled phase III trial dubbed EXIST-2. The study enrolled 113 adults with renal angiomyolipoma as a feature of TSC and 5 adults with sporadic lymphangioleiomyomatosis. Subjects were randomized 2:1 to be treated with Afinitor 10 mg per day or matching placebo until disease progression or unacceptable toxicity. CT and MRI scans assessed disease levels at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic review of skin lesions were reviewed at baseline and every 12 weeks until treatment discontinuation. The primary efficacy endpoint of angiomyolipoma response rate was evaluated by independent central radiology review and was reached. 42% of the subjects treated with Afinitor experienced an angiomyolipoma response versus 0% of patients in the placebo arm. The time to angiomyolipoma progression was also statistically significantly longer in the Afinitor arm. Of the 97% of subjects with skin lesions, a 26% response rate was seen in subjects treated with Afinitor versus 0% with placebo.

Indication 5 - Breast Cancer

approved 07/01/2012

Dosing/Administration

The recommended dosage is 10 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA approval of Afinitor for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer was based on a randomized, double-blind, multicenter study 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. The subjects were randomized to Afinitor 10 mg/day plus exemestane 25 mg/day (n = 485) or to placebo plus exemestane 25 mg/day (n = 239). The primary endpoint was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. The median progression-free survival at the time of the final PFS analysis was 7.8 and 3.2 months in the Afinitor and placebo arms, respectively [p < 0.0001]. Objective response rate was 12.6% in the Afinitor plus exemestane arm vs. 1.7% 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.

Indication 6 - Neuroendocrine tumors of gastrointestinal or lung origin

approved 02/01/2016

Dosing/Administration

The recommended dosage is 10 mg orally once daily until disease progression or unacceptable toxicity.

Clinical Trial Results

The FDA aproval of Afinitor for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic was based on the RADIANT-4 study. Data showed Afinitor reduced the risk of progression in patients by 52% versus placebo. Afinitor also increased median progression-free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months in the Afinitor arm and 3.9 months in the placebo arm.