Mammalian target of rapamycin

Everolimus treatment of abdominal lymphangioleiomyoma in five women with sporadic lymphangioleiomyomatosis.

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Abstract

Objective: Lymphangioleiomyomatosis (LAM) is a rare systemic disease of young women arising from mutations in the tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. This disrupts the mammalian target of rapamycin (mTOR) pathway, affecting cellular proliferation and growth. mTOR inhibitors are a promising novel therapy in LAM. The mTOR inhibitor sirolimus is reported to produce resolution of lymphatic abnormalities in LAM, but the efficiacy of the mTOR inhibitor everolimus has not been assessed. We aimed to examine the efficacy of everolimus on lymphatic abnormalities in LAM.

Design, setting and participants: Open-label treatment of five patients with sporadic LAM (sLAM) and abdominopelvic and lung involvement at the outpatient LAM clinic of a tertiary city teaching hospital. Clinical data were collected during treatment of the women and included regular clinical reviews, everolimus levels, lung function and computed tomography assessment before and after 6 months of everolimus treatment.

Main outcome measures: Symptoms and level of resolution of lymphangioleiomyomas.

Results: All five women experienced significant shrinkage or complete resolution of the lymphangioleiomyomas during treatment. In one woman, cessation of everolimus resulted in recurrence of symptoms. Adverse events were compatible with the known side-effect profile of everolimus, but overall the drug was well tolerated.

Conclusions: This is the first report to suggest that everolimus has efficacy in the treatment of lymphangioleiomyoma and chylous ascites in sLAM.

Discussion

Although LAM frequently presents with respiratory symptoms, abdominal involvement occurs in up to 70% of cases,14 with abdominal lymphangioleiomyomas in 16% of cases.2 Women may present with abdominal pain and swelling, and refractory chylous ascites, or with non-specific signs such as infertility or perimenstrual abdominal discomfort.4Treatment is generally unsatisfactory, with medical therapies ineffective, and repeated abdominocentesis resulting in fluid reaccumulation, protein loss and potential infection.

The use of mTOR therapy in LAM is a targeted approach to an abnormality arising from a genetic mutation affecting multiple systems. The 2011 MILES trial showed that treatment with sirolimus in LAM was associated with a slower decline in lung function, improvement in quality of life and shrinkage of renal AMLs, but abdominal LAM was not the focus of that trial.3 To date, single-case reports and one observational series have documented regression of abdominal lymphangioleiomyomas with sirolimus or temsirolimus treatment,6–9,11 but there are no reports on everolimus. Our case series suggests that the efficacy of mTOR inhibitors extends to everolimus, and that this has good effect on abdominal LAM, which has been very difficult to treat in the past. Previous studies have shown that mTOR inhibitor treatment needs to be continued in TSC, but longitudinal data in LAM are limited.3,7 This is the first study to report everolimus treatment for LAM for several years, with all five women continuing on everolimus therapy. This is significant because the efficacy of mTOR inhibitors appears to rely on sustained therapy.3,11

Everolimus is a derivative of sirolimus and has a very similar side-effect profile. It has a shorter elimination half-life (about 30 hours) and greater relative bioavailability, compared with sirolimus.15 We used a lower dose of everolimus than the dose of sirolimus that was used in the MILES trial. The everolimus dose we used was consistent with the lower range of doses used in lung transplantation in our centre, with the aim of producing fewer side effects. Overall, everolimus was well tolerated and side effects, although significant, were within its described profile.

In summary, all women with sLAM showed a good response to treatment, with disappearance or shrinkage of abdominal lymphangioleiomyomas in four of five of cases, and clinical resolution of the lymphangioleiomyoma in the fifth. Abdominal symptoms resolved. Cessation of the therapy in one patient resulted in recurrence of ascites, and reinstitution of treatment resulted in resolution again. This is similar to the MILES trial, in which continued treatment was required.3 We suggest that everolimus treatment may be an effective long-term therapy for lymphangioleiomyomas and chylous ascites, which requires further evaluation in an appropriately designed controlled trial.

Source: MJA

 

 

 

 

Everolimus Improves Progression-Free Survival.

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Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.

Now, O’Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.

The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.

The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.

Source: Journal Watch Oncology and Hematology

 

 

Novartis drug Afinitor® significantly extended time without disease progression in women with HER2 positive advanced breast cancer.

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  • nova
  • Everolimus plus trastuzumab and vinorelbine met primary endpoint of extending PFS compared to placebo plus trastuzumab and vinorelbine after prior therapy[1]
  • Results of Phase III trial, BOLERO-3, first to show potential benefit of everolimus in HER2 positive advanced breast cancer, an aggressive form of the disease[1]
  • Detailed data will be presented at the upcoming ASCO Annual Meeting and shared with regulatory authorities worldwide

Results of a pivotal Phase III trial in women with HER2 positive (HER2+) advanced breast cancer showed that Afinitor® (everolimus) tablets in combination with trastuzumab (Herceptin®*) and vinorelbine significantly extended progression-free survival (PFS) after prior therapy when compared to treatment with placebo plus trastuzumab and vinorelbine,meeting the study’s primary endpoint[1].

Efficacy and safety data from the BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) trial were assessed as part of a prospectively planned analysis. These results will be presented on June 2 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois[2], as well as at future medical congresses, and shared with regulatory authorities worldwide.

“We are encouraged by the BOLERO-3 results and are committed to helping improve treatment options for the HER2 positive patient population where there remains an unmet need,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “Everolimus works differently than any currently available treatment for HER2 positive breast cancer, and these results support its potential expanded role in advanced breast cancer.”

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[3]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Data confirm that blocking mTOR is a proven approach to maximize the benefit of existing advanced breast cancer treatments[4].

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor[1]. The specific indications vary by country[1]. HR+/HER2 negative advanced breast cancer is the most common form of the disease[5]. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[6].

*Herceptin® is a registered trademark of Genentech, Inc.

Study design

BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1]. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m2 IV and weekly trastuzumab 2 mg/kg IV following loading dose of 4 mg/kg[1].

The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics[1].

About advanced breast cancer

Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[7]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[7].

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4]. Eighty percent of advanced breast cancer is either hormone receptor-positive (HR+) and/or human epidermal growth factor receptor-2 positive (HER2 positive)[1],[8].

HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[1]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[9].

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells[1],[10]. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer[1].

About Afinitor® (everolimus)

Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive,HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 95 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite, infections (including upper respiratory tract infection), low level of red blood cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of extremities or other parts of the body, nose bleeds, itching, vomiting, high level of blood cholesterol, headache, high level of blood sugar, cough, spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding or bruising, low white blood cells (a type of blood cell that fights infection), and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung or legs, and menstruation disorders such as absence of periods have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Source: Novartis newsletter

Genome Sequencing of One Patient’s Tumor Could Lead to New Treatment Options for Some Bladder Cancer Patients.

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In mapping the entire genome of a tumor from a patient with advanced bladder cancer, researchers at Memorial Sloan-Kettering have uncovered a genetic weakness that could potentially be targeted with an existing drug. Published in the journal Science on August 21, the findings could lead to new and potent therapies for a subset of patients with the disease.

In addition, the investigators hope that their study might encourage more research on cases in which a cancer drug is shown to work in a small number of patients but further investigation has not been pursued because the treatment was found to be ineffective in the majority of patients.

The findings were made after an early-stage clinical trial in which Memorial Sloan-Kettering physicians treated advanced bladder cancer patients with everolimus (Afinitor®), a targeted therapy already used in the treatment of kidney cancer, among other cancer types. While the drug did not help the vast majority of patients enrolled in the trial, the doctors were encouraged by the outcome of one patient – a 73-year-old woman – whose condition radically improved.

“Her response is absolutely remarkable,” affirms physician-scientist David B. Solit, of Memorial Sloan-Kettering’s Human Oncology and Pathogenesis Program, who led the study. “Most impressively, more than two years after starting the treatment, she continues to do well on everolimus, and all signs of her disease are gone.”

By comparison, the health of the other patients on the trial typically worsened two to three months into the study.

Focusing on the Exceptional Case

It is not uncommon for a new cancer drug to have mixed results when tested in patients. One or several trial participants may have good outcomes while others receive no benefit from the treatment. “When favorable responses are seen in only a small fraction of patients, the therapy is often deemed ineffective, and further research studies are not pursued,” says Dr. Solit.

In particular, the investigators noted in their report, cases where only a single patient does remarkably well in a trial have traditionally been “dismissed as failing to provide meaningful clinical evidence” of benefit.

But according to the researchers the findings of the everolimus study suggest that trials in which a drug appears to be successful in only one or several exceptional cases might in fact warrant further scrutiny. In determining the underlying reason why one patient in the largely negative everolimus trial had responded favorably to the drug, the researchers gained new insights about how this therapy could be used to its full advantage to benefit a small subset of bladder cancer patients.

Combing through the Genome

Everolimus works by targeting a cellular process called the mTOR pathway, which often goes awry in cancer cells. Although the researchers did not know why the drug had worked so well for one patient in the study, they hypothesized that a genetic abnormality in the patient’s tumor might be altering this pathway, making her cancer cells vulnerable to the therapy.

Initially, they tested samples of the patient’s tumor for a number of known gene changes. “We didn’t find any of these ‘usual suspects,’” Dr. Solit says. “There are thousands of genes that may be disrupted in cancer. Identifying the mutation that caused her disease to respond so profoundly to everolimus was like looking for a needle in a haystack.”

However, more-powerful technologies for whole-genome sequencing have recently become available, allowing scientists to determine the entire DNA sequence of a tumor or blood sample within weeks or days. As Dr. Solit puts it, “we are now able to discover new mutations by taking the entire haystack apart.”

Using this method, the investigators found that the woman’s tumor carried a mutation in a gene called TSC1, which is known to be involved in the mTOR pathway. “All of a sudden, it made perfect sense that her disease would be so sensitive to everolimus,” says Dr. Solit.

Incremental Progress

Dr. Solit and his colleagues were then able to confirm that mutations in the TSC1 gene were linked to a tumor’s sensitivity to everolimus by analyzing additional tumor tissue from patients in the trial. They found that three other patients whose tumors had partly shrunk in response to the drug also had a mutation in TSC1, while the participants whose disease had not improved did not have this genetic change.

“This tells us that everolimus might be an option for the minority of bladder cancer patients whose tumors have TSC1 mutations, even though the drug was not effective in most patients with this disease,” explains Dr. Solit. The researchers are now planning a new clinical trial in which the drug will be offered only to patients whose cancer cells test positive for TSC1 mutations. He estimates that such mutations are likely to be present in approximately one out of ten people with bladder cancer.

“Over time,” he adds, “as other mutations are found that can be targeted therapeutically, we believe that doctors will be able to offer more-effective treatments to a growing number of patients.”

Source: Source: MCKCC

 

 

Novartis drug Votubia® recommended by CHMP for EU approval to treat patients with non-cancerous kidney tumors associated with TSC.

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  • Votubia (everolimus) would be the first non-surgical treatment option in the EU for kidney tumors associated with tuberous sclerosis complex (TSC)[1]
  • Kidney tumors, or renal angiomyolipomas, affect up to 80% of patients with TSC and growing tumors may lead to life-threatening complications[2]

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Votubia® (everolimus) tablets* for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC) who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery. Votubia would be the first medication available in the European Union (EU) for these patients[1].

“Today’s positive CHMP opinion for Votubia is important for patients in the EU with TSC, as renal angiomyolipoma is among the most difficult-to-treat manifestations of this debilitating disease,” said Hervé Hoppenot, President, Novartis Oncology. “There remain many unmet medical needs in TSC, and Novartis is committed to understanding and improving the lives of people affected by this rare disease through clinical research, education and collaboration with the global TSC community.”

In the EU, the European Commission generally follows the recommendations of the CHMP and delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 27 EU member states plus Iceland and Norway. In Europe, everolimus has orphan drug designation for TSC. Orphan drugs are those that treat a condition which affects no more than five in 10,000 people in the EU[3].

The CHMP positive opinion is based on data from the Phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial, which found that 42% of patients on everolimus experienced an angiomyolipoma response versus 0% of patients in the placebo arm (p<0.0001). The evidence is based on analysis of change in sum of angiomyolipoma volume. Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (p<0.0001). Among the 97% of patients with skin lesions, one of the key concerns for the majority of patients with TSC, a 26% response rate was seen with everolimus versus 0% with placebo (p=0.0002)[4].

Everolimus works by inhibiting mTOR, a protein implicated in many tumor-causing pathways[2],[5]. TSC is caused by defects in the TSC1 and/or TSC2 genes[2]. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism[5],[6]. According to preclinical studies, by inhibiting mTOR activity in this signaling pathway, everolimus reduces cell proliferation and blood vessel growth[1],[5].

About Renal Angiomyolipomas
Up to 80% of patients with TSC – a genetic disorder affecting approximately one to two million people worldwide that may cause non-cancerous tumors to form in many organs – will develop renal angiomyolipomas. Typical symptom onset occurs between the ages of 15 and 30 and prevalence increases with age. Over time, these tumors may grow large enough to cause severe internal bleeding, require emergency surgical interventions, such as embolization and nephrectomy, or lead to kidney failure[2]. The tumors can be difficult to manage as they are often multiple and form in both kidneys at the same time[1],[2]. In the EU, approximately 7,000 TSC patients have large growing AML tumors (> 3 cm) at risk of bleeding[7],[8],[9].

About EXIST-2
EXIST-2 is the first double-blind, randomized, placebo-controlled, international, multicenter Phase III study for the treatment of patients with renal angiomyolipoma associated with TSC. Trial patients (median age=31, range 18-61) were randomized 2:1 to receive either everolimus (n=79) or placebo (n=39) at a daily dose of 10 mg. The median duration of blinded study treatment was 48 weeks in the everolimus arm and 45 weeks in the placebo arm[4].

In the study, 42% of patients on everolimus (33 of 79; 95% confidence interval [CI] 30.8-53.4) experienced an angiomyolipoma response versus 0% on placebo (0 of 39; 95% CI 0.0-9.0; p<0.0001), defined as a 50% or greater reduction in the sum of angiomyolipoma volume relative to baseline, the absence of new tumor growth at least 1 cm in longest diameter, absence of kidney volume increase of 20% or greater and no renal angiomyolipoma-related bleeding of Grade 2 or higher[4].

Everolimus demonstrated superiority to placebo for both supportive efficacy outcomes measured: time to angiomyolipoma progression and skin lesion response rate. There were three patients in the everolimus arm and eight patients in the placebo arm with documented angiomyolipoma progression by central radiologic review. The time to angiomyolipoma progression was statistically significantly longer in patients on everolimus (hazard ratio [HR] 0.08, 95% CI 0.02-0.37; p<0.0001). Skin lesion response rate was significantly higher in the everolimus arm. A partial clinical response in skin lesions (corresponding to a 50% or greater improvement) was observed by Physician Global Assessment in 26% of patients on everolimus, compared with 0% of patients on placebo (p=0.0011). No complete responses were observed[4].

The most common adverse reactions reported in the everolimus arm during the double-blind period (with an incidence at least 15%) included stomatitis, hypercholesterolemia, aphthous stomatitis, mouth ulceration, and acne. The most common Grade 3 adverse reactions in the everolimus arm (with an incidence of at least 2%) were amenorrhea, aphthous stomatitis, and mouth ulceration. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hypertriglyceridemia and anemia. The most common Grade 3-4 laboratory abnormality (incidence >= 3%) was hypophosphatemia[4].

About everolimus
Everolimus is approved as Afinitor® (everolimus) tablets in the United States (US) for the treatment of adult patients with renal angiomyolipomas and tuberous sclerosis complex (TSC), not requiring immediate surgery. The effectiveness of Afinitor in treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. Should everolimus be approved in the European Union (EU) for this patient population, the trade name will be Votubia.

Everolimus is also approved in the US as Afinitor and Afinitor Disperz(TM) in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. The effectiveness is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC have not been demonstrated. In the EU, everolimus is approved as Votubia® (everolimus) tablets for the treatment of patients aged 3 years and older with SEGA associated with TSC who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

Everolimus is approved as Afinitor in 90 countries including the US and throughout the EU in the adult oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy in the EU and after failure of treatment with sunitinib or sorafenib in the US. Afinitor is approved for the treatment of locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin in adults in the US and EU. Afinitor is also approved in the EU for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor, and in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Everolimus is also available from Novartis for use in other non-oncology patient populations under the brand names Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country.

Important Safety Information about Votubia/Afinitor
Votubia/Afinitor can cause serious side effects including lung or breathing problems, infections, and renal failure which can lead to death. Mouth ulcers and mouth sores are common side effects. Votubia/Afinitor can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Votubia/Afinitor may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor and for up to 8 weeks after ending treatment. Women taking Votubia/Afinitor should not breast feed.

The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common Grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, diabetes and amenorrhea. Cases of hepatitis B reactivation and blood clot in the lung and leg have been reported.

*Known as Afinitor® (everolimus) tablets for this patient population in the US. If approved in the EU for this patient population, the trade name will be Votubia.

References

[1] Ewalt D, et al. Long-term outcome of transcatheter embolization of renal angiomyolipomas due to tuberous sclerosis complex. J Urol. 2005;174:1764-1766.
[2] National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Fact Sheet. Available at http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. Accessed September 2012.
[3] European Medicines Agency. Orphan drugs and rare diseases at a glance. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069805.pdf. Accessed September 2012.
[4] Novartis Data on File.
[5] Motzer, et al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer. 2010 Sep;116(18):4256-4265.
[6] Krueger D, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. N Engl J Med. 2010 Nov;363(19):1801-11.
[7] Dixon B, et al. Tuberous Sclerosis Complex Renal Disease. Nephron Exp Nephrol. 2011:118:e15-e20.
[8] O’Callaghan F, et al. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU International. 2004:94:853-857.
[9] Cox J, et al. The natural history of renal angiomyolipomata (AMLs) in Tuberous Sclerosis Complex (TSC). European Renal Association – European Dialysis and Transplant Association Congress. 2012, Paris, France.

Source: Novartis Newsletter.