Novartis drug Afinitor® effective in patients with non-cancerous kidney tumors associated with TSC in Phase III trial

A Phase III study of Afinitor® (everolimus) tablets* in patients with non-cancerous kidney tumors, or angiomyolipomas, associated with tuberous sclerosis complex (TSC) met its primary endpoint of best overall angiomyolipoma response rate, which includes reduction in kidney tumor size and absence of new tumors. Findings from the trial, known as EXIST-2, were presented today at the International TSC Research Conference in Belfast, Northern Ireland[1].

Tuberous sclerosis complex is a genetic disorder that may cause non-cancerous tumors to form in vital organs, including the brain (SEGAs) and kidney (angiomyolipomas)[3]. These kidney tumors occur in up to 80% of patients, usually occurring between the ages of 15 and 30 and increasing in prevalence with age[2],[3]. Angiomyolipomas are the greatest cause of morbidity and mortality in adult TSC patients, as larger tumors may cause severe bleeding, require surgical intervention or result in kidney failure[2],[3]. Tumor symptoms may include nausea, vomiting, pain and bleeding[3],[6],[7].

Results of the 118-patient, randomized, placebo-controlled Phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial showed 42% of patients (33 of 79) experienced a response in the everolimus arm versus 0% of patients (0 of 39) on placebo (p<0.0001) based on best overall response rate[1]. These results add to the recent positive Phase III data from a separate trial in patients with TSC, which demonstrated reduction in the size of non-cancerous brain tumors (SEGAs) with everolimus[5].

“For the first time, a large placebo-controlled study has focused specifically on angiomyolipomas in TSC patients, an area with clear unmet need,” said Dr. John Bissler, lead study author and Clark D. West Endowed Chair of Nephrology at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. “In addition to the tumor reduction seen with everolimus in this trial, significant improvement in skin lesions including facial angiofibromas was observed, which can be a key concern for people living with TSC.”

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism[8]. Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes[9]. 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[2],[9]. By inhibiting mTOR activity in this signaling pathway, everolimus may reduce cell proliferation and blood vessel growth related to angiomyolipoma associated with TSC[2],[8],[9].

“The positive findings seen in this trial coupled with the known efficacy of everolimus in patients with SEGA point to the important role of mTOR inhibition with everolimus in treating these manifestations of TSC,” said Hervé Hoppenot, President, Novartis Oncology. “The outcomes support our further research efforts evaluating everolimus as a treatment option across the various conditions associated with TSC.”

Affecting approximately one to two million people worldwide, TSC is associated with a variety of resulting disorders including skin lesions, seizures, swelling in the brain (hydrocephalus) and developmental delays[3],[9].

About EXIST-2

EXIST-2 is a prospective, double-blind, randomized, parallel group, placebo-controlled, international, multicenter Phase III study of everolimus versus placebo for the treatment of patients with angiomyolipoma associated with TSC[1],[10]. 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 starting dose of 10 mg. By the cut-off of June 30, 2011, the median treatment duration in the double-blind period was 38.1 weeks (range 2-105 weeks) in the everolimus arm and 34.0 weeks (range 9-112 weeks) in the placebo arm[1].

In the study, the definition of angiomyolipoma response included a reduction of at least 50% relative to baseline in the sum of the volumes of all target lesions, and the absence of new lesions greater than or equal to one centimeter in diameter, with a confirmed response by radiographic scan approximately 12 weeks later[1].

Everolimus demonstrated superiority to placebo for both secondary endpoints assessed: skin lesion response rate and time to angiomyolipoma progression per central review. Skin lesion response rate, defined as the proportion of patients with a best overall skin lesion response of either complete clinical response or partial response, was 26% in patients (20 of 77) on everolimus and 0% (0 of 37) on placebo (p=0.0002). Median time to angiomyolipoma progression (time from date of randomization to date of first documented angiomyolipoma progression) was 11.37 months in the placebo arm and was not reached in the everolimus arm. Progressions were observed in 4% of patients (3 of 79) on everolimus and 21% (8 of 39) on placebo. The estimated progression-free rates at six months were 98% on everolimus and 83% on placebo (p<0.0001)[1].

The most common adverse events (AEs) in the everolimus arm (with an incidence of at least 20%) included stomatitis, nasopharyngitis, acne, headache, cough and hypercholesterolaemia. Renal events were less frequent in the everolimus arm compared to the placebo arm. The most common Grade 3 AEs in the everolimus arm (with an incidence of at least 2%) were amenorrhea, aphthous stomatitis, decreased blood phosphorus and mouth ulceration. Single Grade 4 cases of convulsion, increased blood uric acid, hypertensive crisis and neutropenia were reported in the everolimus arm[1].

Adverse events observed in this study were consistent with the known safety profile of everolimus in the TSC setting. Adverse events leading to trial discontinuation were reported more commonly in the placebo arm. During the study, one death in the everolimus arm occurred due to convulsion, though it was not considered related to the study drug by the investigator[1].

EXIST-2 enrolled 118 patients in the US, Germany, the Netherlands, Japan, the UK, Russia, Italy, Canada, Poland, Spain and France. This study is part of a Phase III trial program investigating everolimus in the various manifestations of TSC[1],[10].

About everolimus

Everolimus is approved in the European Union (EU) as Votubia® (everolimus) tablets and in the United States (US) as Afinitor® (everolimus) tablets to treat patients with subependymal giant cell astrocytoma (SEGA) associated with TS who require therapeutic intervention but are not candidates or amenable for surgery. The effectiveness of everolimus is based on an analysis of change in SEGA volume in patients 3 years of age and older. Further clinical benefit has not been demonstrated.

Afinitor® (everolimus) tablets is also approved in more than 70 countries and regions including the US and the EU in the oncology settings of advanced renal cell carcinoma (RCC) following vascular endothelial growth factor (VEGF)-targeted therapy and advanced progressive neuroendocrine tumors of pancreatic origin (NET).

Everolimus is available from Novartis for use in 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. Access to everolimus outside of the approved indications has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. As an investigational compound, 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/Votubia

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections, and renal failure which could be fatal. 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. 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 and diabetes. Cases of hepatitis B reactivation and blood clot in the lung have been reported.

* Known as Votubia® (everolimus) tablets for certain patients with SEGA associated with TSC in the EU and Switzerland.

References

1. Kingswood et al. A randomized, double-blind, placebo-controlled, phase 3 study of everolimus in the treatment of angiomyolipoma in patients with either tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. International TSC Research Conference. September 2011, Belfast, Northern Ireland.
2. Ewalt, et al. Long-term outcome of transcatheter embolization of renal angiomyolipomas due to Tuberous Sclerosis Complex. J Urol 2005:174:1764-1766.
3. 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 2011.
4. Roach, et al. Diagnosis of Tuberous Sclerosis Complex. J Child Neuro 2004;19:643-649.
5. Franz, et al. Long-term safety and efficacy results of oral everolimus in patients with subependymal giant cell astrocytomas (SEGA) in tuberous sclerosis complex (TSC). International TSC Research Conference. July 2011, Washington, D.C.
6. Harabayashi, et al. Management of renal angiomyolipomas associated with Tuberous Sclerosis Complex. J Urol 2004;171(1):102-105.
7. Singer. Angiomyolipoma. Available at http://www.medscape.com/viewarticle/415099. Accessed September 2011.
8. Motzer, et al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer 2010 Sep;116(18):4256-4265.
9. Krueger, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. New Eng J Med 2010;363:1801-11.
10. US National Institutes of Health. Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2). Available at: http://clinicaltrials.gov/ct2/show/NCT00790400?term=exist-2&rank=1. Accessed September 2011.