Everolimus (Afinitor)

Approved for renal cancer after the failure of sunitinib or sorafenib.

Doubles progression free survival after failure of sunitinib or sorafenib.

Inhibits m-TOR through allosteric binding to mTORC1.

Its target is mTOR is a serine-threonine kinase involved in the control and proliferation, cell growth and apoptosis through modulation of the cell cycle progression.

Approved for treatment of kidney tumors not requiring immediate surgery in patients with tuberous sclerosis.

It is indicated for the treatment of hormone receptor positive HER2 negative advanced breast cancer in combination with exemestane in postmenopausal women without symptomatic visceral disease after recurrence or progression after treatment with a nonsteroidal aromatase inhibitor.

Everolimus Tablets available Seizures in Tuberous Sclerosis

Approval for everolimus tablets for oral suspension for the treatment of pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Approved for renal angiomyolipomas , a benign tumor of the kidney, in patients with the tuberous sclerosis complex.

Inhibits mTOR and can correct the specific molecular defect that causes the tuberous sclerosis complex.

Targets both tumor cells and blood vessel cells.

Has immunosuppressive properties and may predispose patients to infections.

Used in posttransplant patients for immunosuppression.

May cause oral ulcerations.

Mucositis is induced by local inflammation from the targeted therapy.

SWISH trial explored prophylactic use of dexamethasone mouthwash to prevent the occurrence of everolimus oral mucositis and is presently the standard of care.

Oral ulceration is the most frequently occurring adverse reaction.

Maybe associated with elevations of serum creatinine, glucose, blood lipids, triglycerides and reductions in hemoglobin, lymphocytes, platelets and neutrophils.

Reports of association with noninfectious pneumonitis, infections, and renal failure.

Everolimus induced pneumonia occurs in nearly 1/4 of patients.

Delays wound healing and increases the occurrence of wound related complications.

Should not be used in patients who have received live vaccines.

Most adverse reactions include stomatitis, infections, asthenia, fatigue, cough and diarrhea.

Daily use of a steroid-based mouthwash was shown to decrease the incidence and severity of stomatitis in women treated with Everolimus plus Aromasin for their advanced breast cancer.

10 mg/day doses are the most opimal regarding m-TOR inhibition.

Everolimus is efficacious in carcinoid tumors (Yu et al).

Single agent 10 mg/day phase II study in pretreated metastatic breast cancer patients indicated a 12% response rate (Ellard SL et al).

In a phase 3 trial Breast Cancer Trials of Oral Everolimus ( BOLERO-2) 724 postmenopausal patients with metastatic breast cancer hormonally receptive positive and with progressive disease while receiving aromatase inhibitors anastrozole or letrozole, treated with exemestane plus everolimus resulted in a median progressive free survival of 7.4 months, compared with 3.2 months among those treated with exemestane plus placebo.

BOLERO-2 trial of women with advanced hormone resistant estrogen receptor positive breast cancer treated with everolimus and the aromatase inhibitor exemestane found at increased progression free survival from a median of 2.8 months with exemestane alone to 6.9 months for the combination with a 64% reduction in risk of progression or death.

The objective response rates were 12.6% and 1.7% in the everolimus and placebo arms, respectively.

In women with hormone receptor positive disease and advanced breast cancer with recurrence within 12 months of adjuvant therapy, everolimus plus exemestane improved median progression free survival 11.5 compared to 4.1 months with placebo plus exemestane (Rugo HS et al)

The most common adverse reactions, with an incidence ≥ 30%, in patients receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite.

Dose int2242uptions or reductions were necessary in 63% of patients on the everolimus arm compared to 14% on the placebo arm.

The recommended dose and schedule for everolimus is 10 mg orally each day.

The addition of this agent to paclitaxel and trastuzumab in patients with trastuzumab refractory, HER2 positive patients with metastatic breast cancer was associated with a high response rate and suggested m-TOR inhibition can delay or reverse trastuzumab resistance by the PI3K/AKT/m-TOR pathways.

In preclinical models use with aromatase inhibitors results in synergistic inhibition of the proliferation and induction of apoptosis.

Everolimus combined with letrozole as neoadjuvant therapy as a higher response rate in estrogen receptor positive breast cancer patients in letrozole alone (Basegla J et al).

BOLERO-2 study- The Breast Cancer Trials of Oral Everolimus-2 study evaluated the efficacy and safety of combining everolimus and exemestane in patients with ER positive breast cancer refractory to aromatase inhibitors: improvement in progression free survival was noted.

It is suggested that mTOR inhibition could reverse resistance endocrine therapy.

Everolimus, a derivative of rapamycin, can disrupt neuroendocrine tumor cell growth, its proliferation and can prolong progression free survival from 4.6 months to 11 months in patients with pancreatic neuroendocrine tumors.

Autocrine activation of the mTOR signaling pathway that is mediated via insulin-like growth factor has beenimplicated in the proliferation of pancreatic neuroendocrine tumors.

In RADIANT-2 everolimus vs. placebo, both with octreoditde in patients with carcinoid and neuroendocrine tumors and was associated with a 5.1 month improvement in median progression free survival.

RAD001 in Advanced Neuroendocrine Tumor third trial (RADIANT-3) studied 10 mg per day of everolimus in patients with pancreatic neuroendocrine tumors: associated with prolonged progression free survival with a low rate of severe adverse events.

RADIANT-4 study treatment with everolimus associated with improved progression-free survival in progressive lung or gastrointestinal neuroendocrine tumors.

In the phase III RADIANT-4 trial in patients with either gastrointestinal neuroendocrine tumors or neuroendocrine tumors of unknown primary origin experienced a 40% or more decrease in the risk of disease progression when treated with Everiolimus.

Everiolimus improved progression free survival in patients with GI neuroendocrine tumors when compared with placebo, and 6.1 months when compared with placebo in patients with neuroendocrine tumors of unknown origin.follow

May cause non-infectious pneumonitis with fatal outcome.

Can increase creatinine, glucose, lipids, triglycerides and decrease hemoglobin, lymphocytes, neutrophils and platelets.

Associated with angioedema at 6.8% when treating with an ACE inhibitor.

May be associated with acute pancreatitis and hypertriglycerdemia.

In HER2 negative breast cancer study the incidence of deaths of any cause within 28 days of the last Afinitor dose and adverse reactions leading to permanent treatment discontinuation is greater in patients greater than 65 years of age.

Adding fulvestrant to everolimus in postmenopausal women with advanced breast cancer results in a progression free survival of 10.4 months versus 5.1 months for fulvestrant alone.

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