Everolimus

Retrospective evaluation of the efficacy and safety of belatacept with thymoglobulin induction and maintenance everolimus: A single‐center clinical experience

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Abstract

Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that belatacept with low‐dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post‐transplant ± corticosteroids would improve efficacy and maintain safety. Retrospective single‐center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1‐year eGFR was 61.4 (SD 18.4) mL/min/1.73 m2. There were five acute cellular rejections (11.4%) that occurred in patients who had changed from everolimus to mycophenolate mofetil due to side effects. Thirty‐two percent developed BK viremia and 12% developed CMV viremia. There were no cases of PTLD. A novel belatacept regimen with rATG induction and maintenance everolimus demonstrated a low acute rejection rate and maintained an excellent 1‐year eGFR.

Everolimus May Have Activity in Seizure Disorder

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The immunomodulatory drug everolimus (Afinitor) diminished seizure frequency in patients with tuberous sclerosis who’d been refractory to other therapy, researchers reported here.

In a phase III randomized controlled trial, seizure frequency was significantly reduced in those on either a high or low dose of the drug compared with those on placebo (about 40% and 29% versus 15%), Jacqueline French, MD, of NYU Langone Medical Center, reported at the American Academy of Neurology meeting here.

French explained that targeting the mTOR pathway may get at an underlying cause of the disease and could be a disease-modifying therapy.

“It is working on a different aspect from what we’ve considered to be the pathology of the disease,” said Natalia Rost, MD, of Harvard, who moderated the session during which the findings were presented. “It is not working on the excitability of the cells, but can we affect the milieu in which cells reside so that they are not sensitizing as much? Being able to modify the disease itself would be very interesting.”

Tuberous sclerosis complex, a rare genetic disorder, affects about one million people globally. It is thought to be caused by hyperactive signaling of the mTOR pathway, which can lead to cortical malformations, neuronal hyperexcitability, and impaired synaptic plasticity — and could ultimately contribute to seizures, French said.

Current treatment options include anti-epileptic drugs, vagal nerve stimulation, surgery, and a ketogenic diet, but these are limited.

To assess whether everolimus could be an additional therapeutic candidate, French and colleagues conducted the EXIST-3 study, a phase III, three-arm, double-blind, placebo-controlled study of the safety and efficacy of high and low doses of everolimus as adjunctive therapy in patients with tuberous sclerosis who have treatment-resistant seizures and are already taking one to three other anti-epileptic drugs.

They enrolled 366 patients who were randomized to either a low or high dose of everolimus (3 to 7 ng/mL or 9 to 15 ng/mL) or to placebo.

The percentage reduction from baseline in seizure frequency was significantly greater among patients randomized to either the low (29.3% P=0.003) or high dose of everolimus (39.6%, P<0.001) compared with placebo (14.9%).

A larger proportion of patients also had at least a 50% reduction in seizures with the low (28.2%, P=0.008) and high dose of the drug (40%, P<0.001) compared with placebo (15.1%).

French said the safety profile was consistent with the established tolerability profile of everolimus in other tuberous sclerosis trials and didn’t overlap with the safety profile of conventional anti-epileptic drugs.

The most common adverse events occurring in at least 20% of patients taking everolimus were stomatitis (28.2% and 30.8% versus 3.4%), mouth ulceration (23.9% and 21.5% versus 4.2%), and diarrhea (17.1% and 21.5% versus 5%).

 There were also more serious adverse events for those on the drug (13.7% and 13.8% versus 2.5%).

French concluded that the results from EXIST-3, along with existing evidence from treating SEGA and renal angiomyolipoma in patients with tuberous sclerosis, suggest that everolimus may be a disease-modifying therapy for this condition.

An extension phase of the EXIST-3 study is currently ongoing, she added.

Raghav Govindarajan, MD, of the University of Missouri, who was not involved in the study, said the work was “very promising.”

“It is very difficult to take care of these kids,” he told MedPage Today. “They have multiple seizures, they develop complications from seizures, and it affects the whole family. Most of the medications we now give are only a symptomatic treatment to try to control the seizures, and we keep adding on. When the third add-on doesn’t work, we try the ketogenic diet or vagal nerve stimulation. But it is a downward spiral.”

“But now,” he continued, “if this acts on the pathology itself, and not just as a bandaid, we could be in a whole new world in epilepsy treatment.”

Rost, who is a co-chair of the meeting’s scientific program committee, said the work opens the door to the question of whether everolimus could be useful in other seizure disorders.

“Just like we think of inflammatory disorders in general, could a subset of epilepsy disorders be modifiable from that perspective,” she told MedPage Today.

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.

Sequencing “Outlier” Genome Suggests Some Patients May Benefit from Cancer Drug.

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Clinical trials that fail to identify drugs that benefit most patients may still yield valuable information by identifying subsets of patients who would benefit from the drugs. That is the conclusion of a study in which researchers used whole-genome sequencing to salvage a potentially beneficial drug that might have been discarded.

In a report published August 23 in Science, researchers at Memorial Sloan-Kettering Cancer Center describe how they sequenced the tumor genome of a 73-year-old woman with advanced bladder cancer who had a complete response to the drug everolimus (Afinitor) that has lasted for more than 2.5 years. The patient was part of a 45-patient, early-phase clinical trial in which treatment with everolimus failed to improve progression-free survival, the trial’s primary endpoint, among the patient population enrolled in the trial as a whole.

“The patient was a dramatic outlier in terms of her clinical response,” said the study’s senior author, Dr. David Solit.

After targeted sequencing of a few specific genes in the woman’s tumor “didn’t turn up anything revealing,” Dr. Solit continued, the researchers decided to sequence the woman’s entire tumor genome to see if they could discover a molecular basis for her strong response.

Among the many genomic alterations the researchers identified, inactivating mutations in two genes, TSC1 and NF2, stood out. Evidence from laboratory studies had suggested that loss-of-function mutations in TSC1 and NF2 might increase sensitivity to everolimus.

The researchers then analyzed the tumor DNA from 13 other patients enrolled in the trial and found TSC1-inactivating mutations in the tumors of three more patients, two of whom had measurable tumor shrinkage and lived longer without their cancer progressing than patients whose tumors lacked a TSC1 mutation. None of the 13 patients’ tumors had an NF2 mutation.

Sequencing the TSC1 and NF2 genes in tumor samples from 96 other patients with advanced bladder cancer revealed five more patients with TSC1 mutations, but no NF2 mutations.

Dr. Solit and his colleagues hope to launch a small clinical trial testing everolimus in patients with bladder cancer tumors that have mutations in TSC1 or a related gene, TSC2.

“We often see cases where just a few patients in an otherwise negative trial have significant benefit,” Dr. Solit said. “With the in-depth analysis provided by novel technologies like whole-genome sequencing, we can possibly salvage potentially beneficial drugs that were otherwise going to fail.”

Source: NCI

 

Novartis drug Afinitor® approved by European Commission to treat patients with the most common form of advanced breast cancer.

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The European Commission has approved Afinitor® (everolimus) tablets* for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer (HR+ advanced breast cancer), in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor[1].
“The approval of Afinitor is an important milestone marking the first major advance for women in the European Union with hormone receptor-positive advanced breast cancer since the introduction of aromatase inhibitors more than 15 years ago,” said Hervé Hoppenot, President, Novartis Oncology. “Treatment with Afinitor gives women a new option in the battle against this advanced form of breast cancer, where there remains a significant unmet need.”

 

The approval was based on the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) trial[1]. The randomized, double-blind, placebo-controlled, multi-center study of 724 patients found that treatment with Afinitor plus exemestane more than doubled median progression-free survival (PFS) to 7.8 months, compared to 3.2 months with exemestane alone (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), by local investigator assessment[3]. An additional analysis based on an independent central radiology review showed Afinitor extended median PFS to 11.0 months compared to 4.1 months (hazard ratio=0.38 [95% CI: 0.31 to 0.48]; p<0.0001)[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[3].

 

“By boosting the effectiveness of endocrine therapy, Afinitor significantly extends the time women with hormone receptor-positive advanced breast cancer live without tumor progression,” said Jose Baselga, MD, PhD, Chief, Hematology/Oncology, Massachusetts General Hospital and co-lead investigator of the BOLERO-2 trial. “Afinitor, the first mTOR inhibitor to be approved for this disease, has the potential to redefine the way this common form of advanced breast cancer is treated.”

 

Each year, an estimated 220,000 women globally will be diagnosed with HR+ advanced breast cancer[1],[4]. For these women, endocrine therapy remains the cornerstone of treatment, but most will eventually develop resistance to therapy[5]. This therapeutic resistance has been associated with overactivation of the PI3K/AKT/mTOR pathway[5]. Afinitor works to target the mTOR pathway in cells. mTOR is a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism[5].

 

The European Commission decision follows the positive opinion adopted by the Committee for Medicinal Products for Human Use on June 21, 2012 for Afinitor for the treatment of HR+ advanced breast cancer and applies to all 27 EU member states, plus Iceland and Norway[6]. On July 20, 2012, the US Food and Drug Administration approved Afinitor in combination with exemestane in the HR+/HER2- population after failure of letrozole or anastrazole[7]. Additional regulatory submissions for Afinitor in advanced breast cancer are under way worldwide. Afinitor is also being studied in HER2-positive breast cancer in two ongoing Phase III trials.

 

About Advanced Breast Cancer

Advanced breast cancer is comprised of metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[8]. 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 bones or liver[8]. 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[8].

 

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[9],[10].

 

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[8]. The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most important predictive and prognostic markers in human breast cancers, and is collectively referred to as hormone receptor-positive[8].

 

About Afinitor (everolimus)

Afinitor® (everolimus) is approved in the European Union 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. In the United States, Afinitor is approved 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.

 

Afinitor (everolimus) tablets is approved in more than 80 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 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.

 

Afinitor® Important Safety Information

Afinitor®/Votubia® 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. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol 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.

 

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 clots in the lung and leg have been reported.

 

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as “potential,” “will,” “under way,” “being studied,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for any additional indications or labeling in any market or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding everolimus could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures; competition in general; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group’s assets and liabilities as recorded in the Group’s consolidated balance sheet; and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

 

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 126,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

 

References

  1. Novartis Data on File.
  2. Redmond C. Breast Cancer Hormone Therapy Options. Available at: http://christine-redmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed April 27, 2012.
  3. Piccart M et al. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Abstract #559. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
  4. Buckley N, Isherwood A, Breast Cancer. Decision Resources. 2011.
  5. Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. February 9, 2012.
  6. European Medicines Agency. Summary of Opinion for Afinitor. June 21, 2012.
  7. FDA Approval Announcement of Afinitor in Advanced HR+ Breast Cancer. July 20, 2012.
  8. National Cancer Institute. What You Need to Know About Advanced Breast Cancer. Available at: http://www.cancer.gov/cancertopics/wyntk/breast/WYNTK_breast.pdf. Accessed on March 8, 2012.
  9. Giordano S. Update on Locally Advanced Breast Cancer. The Oncologist, 2003.Buckley N, Isherwood A. Breast Cancer. Decision Resources, March 2011.
  10. Eniua A, Palmierib F and Perez E. Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist, 2005.

 

Source: Novartis News letter.

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer.

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Aromatase inhibitors are standard first-line treatment for postmenopausal women with hormone-receptor (HR)–positive advanced breast cancer. However, not all patients respond initially, and those who respond may ultimately relapse. Thus, new therapeutic strategies to enhance the efficacy of endocrine therapy are needed.

Resistance to aromatase inhibitors has been linked to activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. The mTOR pathway has been shown to interact with estrogen-receptor (ER) signaling. In preclinical and phase II studies, the mTOR inhibitor everolimus added to endocrine therapy demonstrated antitumor activity.

The international, double-blind, phase III Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study, sponsored by Novartis, evaluated the combination of everolimus and exemestane in women with advanced breast cancer refractory to nonsteroidal aromatase inhibitors (letrozole or anastrozole). Eligible patients were postmenopausal women with ER-positive, HER2-negative advanced breast cancer that recurred or progressed while they were receiving previous therapy with letrozole or anastrozole.

From June 2009 through January 2011, a total of 724 patients were randomized to receive everolimus (10 mg daily) or placebo in combination with exemestane (25 mg daily) at a 2:1 ratio favoring the combination-therapy group. A prespecified interim analysis, performed with a cutoff date of February 11, 2011, showed significant improvement in progression-free survival (PFS), the primary endpoint, with use of everolimus, compared with exemestane alone.

As assessed by the local investigators, median PFS was 6.9 months for everolimus/exemestane vs 2.8 months for exemestane/placebo, with a hazard ratio (HR) for progression or death of 0.43 (P <.001). With central assessment, use of everolimus extended PFS by more than 6 months, with median PFS of 10.6 months vs 4.1 months (HR 0.36; P <.001). The PFS results were consistent across all subgroups.

Response rates were significantly higher with everolimus: 9.5% vs 0.4% by local assessment, with similar results for central assessment (7.0% vs 0.4%; P <.001). Results for overall survival were immature at the interim analysis.

In the combination arm, 23% of patients had serious adverse events, compared with 12% in the exemestane-only arm. Everolimus was more likely than placebo to be discontinued due to adverse events (19% vs 4%) or withdrawal of consent (5% vs 2%). There were seven treatment-related deaths in the combination arm and one treatment-related death in the exemestane-only arm.

The most common grade 3/4 adverse events were stomatitis (8% in the combination arm vs 1% in the exemestane-only arm), anemia (6% vs <1%), dyspnea (4% vs 1%), hyperglycemia (4% vs <1%), fatigue (4% vs 1%), and pneumonitis (3% vs 0%). The time to deterioration of performance status and quality of life did not differ statistically between the two groups.

The authors pointed out that treatment options are limited for patients with HR-positive advanced breast cancer refractory to endocrine therapy. In the current study, the PFS benefit from adding everolimus to endocrine therapy compared favorably with that seen with other treatment options for HR-positive patients, including standard or high-dose fulvestrant and capecitabine plus taxanes or anthracyclines.

The benefit of adding everolimus to endocrine therapy must be weighed against the adverse effects seen with everolimus. In the current study, everolimus was discontinued due to side effects in a high percentage of patients. The authors noted that the longer duration of treatment in the everolimus group could have contributed to the high discontinuation rate. They advised careful monitoring of patients receiving everolimus and heightened awareness by physicians of the agent’s safety profile.

Source:OncoStat.