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Afinitor And Sandostatin LAR Phase II Data Show Advanced Pancreatic NET Patients Remain Progression-Free For Nearly 17 Months

Main Category: Cancer / Oncology

Article Date: 29 Jun 2009

New data demonstrate that treatment with Afinitor® (everolimus) in combination with Sandostatin® LAR® (octreotide acetate suspension for injection) and Afinitor monotherapy may have the potential to stabilise tumour growth in patients with advanced pancreatic neuroendocrine tumours (NET). These results were presented at the 11th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

RADIANT-1 (RAD001 In Advanced Neuroendocrine Tumours) is an open label, Phase II study of 160 patients with pancreatic NET resistant to treatment with cytotoxic chemotherapy. Patients were stratified according to their previous use of octreotide either to have everolimus as monotherapy or in combination.

The final analysis shows that patients with progressive disease who received everolimus in combination with octreotide, an approved treatment for symptom control in certain types of NET, had a median progression-free survival period of 16.7 months; 4% of these patients had a partial response and 78% had stable disease. For patients who took everolimus as monotherapy, the median progression-free survival was 9.7 months, 8% of these patients had a partial response and 69% had stable disease*1.

Pancreatic NET is an uncommon form of NET, a cancer formed from cells that have roles both in the endocrine and nervous systems. At the time of diagnosis, nearly 60% of all patients have advanced disease, with a median survival of 17 months2.

"These are very exciting data," said Professor Ashley Grossman, Professor of Neuroendocrinology at St Bartholomew's Hospital London. "Neuroendocrine tumours are much less rare than we used to think, and are an important type of gastrointestinal cancer. We have had very few treatments for patients with progressive disease. These data suggest that progression can be halted, at least for a period of time, in these cancers, confirming earlier uncontrolled studies. I very much look forward to the long term results, especially in terms of patient survival."

"Novartis is hopeful that the biomarkers being studied for this trial will provide a valuable insight into which patients are most likely to benefit from everolimus and potentially lead to a much needed alternative treatment option for this form of cancer," said Panos Alexakos, Oncology Business Unit Head for Novartis in the UK.

RADIANT-3, a Phase III trial to further investigate Afinitor as a potential treatment option for patients with pancreatic NET, has completed enrollment and is underway. The study will evaluate the potential of Afinitor plus best supportive care to extend progression-free survival (PFS) and reach overall survival (OS), as well as to examine the biomarker CgA as a secondary objective.

RADIANT-1 study details

RADIANT-1 is a Phase II international, multicentre, open-label, stratified study of everolimus in patients with advanced pancreatic NET who became resistant to prior treatment with cytotoxic chemotherapy. Patients enrolled in the study were divided into one of two treatment groups based on prior therapy with Sandostatin LAR. In the monotherapy treatment group, 115 patients who had not taken Sandostatin LAR received daily everolimus. In the combination treatment group, 45 patients who had taken Sandostatin LAR for at least three consecutive months at study entry continued with the addition of daily everolimus. Prior to the start of the study, patients in the combination treatment group were required to have experienced disease progression while taking Sandostatin LAR. The study was not designed to compare the two treatment groups1.

The primary endpoint of RADIANT-1 is objective response rate (ORR) in the monotherapy group. The secondary endpoints include ORR in the combination treatment group, as well as PFS, duration of response, OS, safety and pharmacokinetics in both groups. Exploratory objectives of this trial include evaluation of biomarkers1.

Monotherapy treatment group results

For those in the monotherapy treatment group, clinical benefit rate (ORR plus stable disease) was seen in 77% of patients1. The ORR, based on central radiology review, was 9.6% (11/115; 95% confidence interval [CI], 4.9-16.5)1. Stable disease (SD) was noted in an additional 78 patients (67.8%) and 16 patients (13.9%) had disease progression as best overall response1. Further, the median PFS in the monotherapy arm was 9.7 months (95% CI, 8.3-13.3) and median OS was reached at 24.9 months (95% CI, 20.2-27.1)1.

The most common adverse events in patients who received everolimus monotherapy were stomatitis (45%), rash (40%), diarrhoea (39%), fatigue (31%), nausea (30%), headache (22%), aphthous stomatitis (17%), vomiting (17%), asthenia (15%), peripheral oedema (15%), weight decrease (15%), anaemia (13%), anorexia (13%), hyperglycaemia (13%) and pruritis (12%)1.

Combination treatment group results

In the study, clinical benefit was seen in 84.4% of patients1. The ORR, based on central radiology review, was 4.4% (2/45; 95% CI, 0.5-15.1)1 but SD was noted in an additional 36 patients (80%). Further, the median PFS in the combination treatment group was 16.7 months (95% CI, 11.1-NA)1. At time of analysis, median OS had not been reached. However, the 24-month survival rate was 54.7% (95% CI, 21.7-87.8)1.

The most common adverse events in patients taking everolimus in combination with Sandostatin LAR were stomatitis (49%), rash (44%), diarrhoea (31%), fatigue (36%), nausea (33%), aphthous stomatitis (13%), vomiting (13%), asthenia (11%), oedema peripheral (13%), weight decrease (16%), anaemia (16%), anorexia (16%), hyperglycaemia (13%), dysgeusia (13%), dry skin (13%), thrombocytopaenia (13%), neutropaenia (13%) and dyspnoea (11%)1.

About neuroendocrine tumours

There are many different types of NET, which can occur throughout the body3. However, most are found in the digestive system4 and are collectively called gastroenteropancreatic neuroendocrine tumours (GEP-NET)4,5. Pancreatic NET, also known as pancreatic endocrine tumours or islet cell carcinomas, is a type of GEP-NET that accounts for nearly 8% of all GEP-NET2,3.

About Afinitor (everolimus)

Everolimus has been approved by the US Food and Drug Administration (FDA) as the first oral, daily therapy (5 mg and 10 mg tablets) to treat advanced kidney cancer after failure of treatment with sunitinib or sorafenib. Recently, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion supporting EU approval of Afinitor to treat patients with advanced renal cell carcinoma whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy6.

In cancer cells, everolimus is thought to continuously target mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism. Everolimus is being studied in multiple cancer types, including NET, renal cell carcinoma (RCC), breast, gastric and hepatocellular carcinoma (HCC), as well as tuberous sclerosis complex (TSC) and non-Hodgkin's lymphoma (NHL).

About Sandostatin LAR

Sandostatin LAR is a long-acting, injectable depot formulation of octreotide acetate that is indicated for the treatment of acromegaly; for patients in whom surgery or radiotherapy is inappropriate or ineffective; for patients until radiotherapy becomes fully effective; and, for the relief of symptoms associated with functional GEP-NET. Octreotide has been used to treat the clinical syndromes associated with NET and substantially reduces, and in many cases can control, growth hormone and/or normalize IGF-1 levels in patients with acromegaly, a disease caused by a GH-secreting pituitary adenoma.

Sandostatin LAR was first approved in France in June 1995 and is currently approved in 85 countries. For more than a decade, Sandostatin LAR has achieved a long-standing track record of sustained efficacy with a well-established safety profile.

Not all indications are approved in every country.

Sandostatin LAR important safety information

The most common (≥ 1/10) adverse drug reactions in clinical studies with Sandostatin LAR were diarrhoea, abdominal pain, nausea, constipation, flatulence, headache, cholelithiasis, hyperglycemia and injection-site localized pain. Common (≥ 1/100, < 1/10) adverse drug reactions were dyspepsia, vomiting, abdominal bloating, steatorrhea, loose stools, discoloration of feces, dizziness, hypothyroidism, thyroid dysfunction (e.g., decreased thyroid stimulating hormone, decreased Total T4 and decreased Free T4), cholecystitis, biliary sludge, hyperbilirubinaemia, hypoglycaemia, impairment of glucose tolerance, anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnoea and bradycardia.

The uncommon (≥ 1/1000, <1/100) adverse drug reactions were dehydration and tachycardia. The following adverse reactions have been reported postmarketing: anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphatase levels and increased gamma glutamyl transferase levels.

References

1 Yao, et al. A Phase II Trial of Daily Oral RAD001 (Everolimus) in Patients With Metastatic Pancreatic Neuroendocrine Tumours (NET) After Failure of Cytotoxic Chemotherapy. 33rd European Society for Medical Oncology Congress, Stockholm, Sweden.

2 Halfdanarson, et al. Pancreatic neuroendocrine tumours (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008.

3 Yao, J. One Hundred Years After "Carcinoid:" Epidemiology of and Prognostic Factors for Neuroendocrine Tumours in 35,825 Cases in the United States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.

4 American Cancer Society. What are the Key Statistics about Gastrointestinal Carcinoid Tumours? Available here. Accessed May 2009.

5 Gunter K, Perren A, Heitz PU The Gastroenteropancreatic Neuroendocrine Cell System and Its Tumours: The WHO Classification. Ann. of the New York Acad of Sci. 2006 Jan 16 2005;1014:13-27.

6 CHMP website - Last accessed 26 June 2009

Source
Novartis

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Afinitor And Sandostatin LAR Phase II Data Show Advanced Pancreatic NET Patients Remain Progression-Free For Nearly 17 Months

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