The New England Journal of Medicine(NEJM) published a study today showing thateverolimus tablets (Afinitor?, Novartis) plus best supportive care (BSC) more than doubled progression-free survival (PFS), or time without tumor growth, versus placebo plus BSC in patients with advanced pancreatic neuroendocrine tumors (NET) [1, 2].

Neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. [3] These tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions [4]

There are many types of NET that can occur throughout the body; however, most are found in the GI tract, pancreas and lungs [5, 6]. Many patients with NET have no symptoms or nonspecific symptoms, such as flushing and diarrhea, which often lead to delays in diagnosis of five to seven years [7, 8]. As a result, many patients with NET often have advanced disease when diagnosed, meaning the cancer has spread to other parts of the body and has become more difficult to treat [9,10]. Approximately 64% of patients with pancreatic NET are diagnosed in advanced stages [5].

Data from the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) study were first presented last year at the 12th World Congress on Gastrointestinal Cancer in Barcelona [11]. Based on the results of the study regulatory submissions for everolimus to treat this patient population are underway worldwide.

Doubling median progression-free survival
Results from the trial showed that everolimus more than doubled median PFS from 4.6 to 11.0 months when compared with placebo and reduced the risk of cancer progression by 65% (hazard ratio [HR] =0.35 [95% confidence interval (CI), 0.27 to 0.45]; p<0.001) in patients with advanced pancreatic NET. After 18 months, 34% of patients treated with everolimus (95% CI, 26 to 43) were alive and progression-free versus 9% of those treated with placebo (95% CI, 4 to 16), showing a more prolonged benefit for patients treated with everolimus [1].

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Pancreatic NET originates from the islet cells of the pancreas and can grow aggressively [9]. It is a distinct and uncommon disease that is different from what is generally referred to as pancreatic cancer or pancreatic exocrine cancer [5]. At time of diagnosis the majority of patients have advanced disease, meaning the cancer has spread to other parts of the body and has become more difficult to treat [9,10]. The median survival duration for patients with advanced pancreatic NET is 24 months [8].

“A patient diagnosed with advanced NET may have limited treatment options,” said James Yao, MD, Associate Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. “Results from the RADIANT-3 trial are encouraging and demonstrate the potential benefit of treating advanced pancreatic NET with the mTOR inhibitor everolimus.”

Regulatory Status
A phase III placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily), documented that everolimus, an oral rapamycin derivative within the mammalian target of rapamycin (mTOR)class of agents, stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. [2,3]

Everolimus has been granted regulatory approval in the US for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib and in the European Union (EU) for the treatment of patients with advanced RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

Everolimus is also approved in the US to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of everolimus is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been shown. Novartishas submitted marketing applications for everolimus to the European Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products (Swissmedic), and additional regulatory submissions are underway worldwide. Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism [12]. Preclinical and clinical data have established the role of mTOR in the development and progression of several types of tumors, including pancreatic NET.

The US Food and Drug Administration (FDA) has granted everolimus priority review designation for the application of advanced NET of gastrointestinal (GI), lung or pancreatic origin based on results of RADIANT-3 and another Phase III trial, RADIANT-2. Priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists [13].

This status accelerates the standard review time for everolimus from 10 to six months [13]. Since the data included in the submission may require further discussion, the FDA is likely to call an Advisory Committee meeting, which could result in the FDA extending the review period. Worldwide regulatory filings for everolimus in this indication are also underway.

The RADIANT-3 trial
RADIANT-3 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus BSC versus placebo plus BSC in 410 patients with advanced, low- or intermediate-grade pancreatic NET, also known as islet cell tumors. Patients who met the study entry criteria were randomized 1:1 to receive either everolimus 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC [1].

The primary endpoint of RADIANT-3 is PFS. Secondary endpoints include safety, objective response rate (confirmed according to RECIST), duration of response and overall survival [1]. In the study, everolimus maintained a safety profile consistent with the prescribing information and previous studies of the drug.

The most frequent all grade, drug-related adverse events (greater than or equal to 20%) were stomatitis/oral mucositis/ulcers (64% everolimus vs. 17% placebo; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), infections (23% vs. 6%), nausea (20% vs. 18%), peripheral edema (20% vs. 3%) and decreased appetite (20% vs. 7%); most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) include stomatitis/oral mucositis/ulcers (7% vs. 0%; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). Median exposure to everolimus was 2.3-fold longer than exposure to placebo (38 vs. 16 weeks) [1].

Efficacy and safety: RADIANT-2
RADIANT-2 is a Phase III randomized, double-blind, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus octreotide LAR (Sandostatin? LAR Depot) versus placebo plus octreotide LAR in 429 patients with advanced carcinoid tumors. Patients who met the study’s entry criteria were randomized 1:1 to receive either oral everolimus (10 mg daily) plus octreotide LAR (30 mg intramuscularly every 28 days) or placebo daily plus oc
treotide LAR. Patients had radiological documentation of disease progression within 12 months prior to randomization [14].

The study did not meet its primary endpoint of PFS as assessed by independent radiological review (p=0.026 vs. p=0.0246 predefined) (hazard ratio=0.77 [95% CI, 0.59 to 1.00]). Secondary endpoints from the trial include safety, overall response rate and overall survival [14].

In the initial review of the data an imbalance in baseline characteristics was observed between the two treatment arms, including prior treatment with chemotherapy, primary tumors located in the lung and a poorer World Health Organization (WHO) performance status (an assessment of each patient’s functional/physical performance). Further, inconsistencies were found between analyses of radiology scans, which resulted in censoring of patients from the trial. These imbalances and the censoring of data seem to favor the control arm and may have impacted the outcome of the study. Additional analyses to adjust for imbalances in the treatment arms show everolimus plus octreotide LAR significantly reduced risk of disease progression (HR=0.60 [95% CI, 0.44 to 0.84]) [14].

In the study, the most frequent all grade drug-related adverse events with everolimus plus octreotide LAR were stomatitis, rash, fatigue, diarrhea, nausea and infections; most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) with everolimus plus octreotide LAR were stomatitis (7%; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), fatigue (7%), diarrhea (6%), infections/infestations (5%) and hyperglycemia (5%) [14]

References:
[1] Yao JC, Shah MH, Ito T, Lombard Bohas C, Wolin EM, Van Cutsem E, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors N Engl J Med 2011 Feb 10; 364:514-523
[2] Jensen RT, Delle Fave G Promising Advances in the Treatment of Malignant Pancreatic Endocrine Tumors N Engl J Med 2011; Feb 10, 364:564-565
[3]. Chan HY, Grossman AB, Bukowski RM Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Adv Ther. 2010 Aug;27(8):495-511. Epub 2010 Jul 8
[4] National Library of Medicine and the National Institutes of Health. Neuroendocrine Tumor Last accessed February 2011
[5] American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors Last accessed February 2011
[6] Modlin, et al. Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst 2008;100:1282-1289
[7] National Library of Medicine and the National Institutes of Health. Carcinoid syndrome. Last accessed February 2011.
[8] Yao, et al. One Hundred Years After “Carcinoid:” Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18
[9] National Library of Medicine and the National Institutes of Health. Pancreatic islet cell tumor.Last accessed February 2011.
[10] Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008
[11] Yao, et al. Everolimus versus placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress on Gastrointestinal Cancer, Barcelona. July 1, 2010. [12] Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer 2010 Sep; 116(18):4256-4265.
[13] US Food and Drug Administration.Fast Track, Accelerated Approval and Priority ReviewLast accessed February 2011
[14] Pavel et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). 35th European Society for Medical Oncology Congress. October 9, 2010.

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