Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Afinitor (everolimus) tablets for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin in adults with progressive disease. If approved by the European Commission (EC), Afinitor would address an unmet need as there are currently few or no treatment options in Europe for patients with these diseases.

"This important milestone reinforces our long-standing commitment to the NET community by providing solutions to help improve outcomes for patients with these rare and difficult-to-treat cancers," said Alessandro Riva, MD, global head, Novartis Oncology Development and Medical Affairs.

Neuroendocrine tumours are a type of cancer that originate in neuroendocrine cells throughout the body, and most commonly arise in the GI tract, lungs or pancreas. NET can be defined as functional or nonfunctional. The majority of patients with NET (72%) have nonfunctional NET, which are characterized by symptoms caused by tumor growth, such as intestinal obstruction, pain and bleeding for GI NET, and asthma, chronic obstructive pulmonary disease and pneumonia for lung NET. In contrast, functional NET are characterized by symptoms caused by the oversecretion of hormones and other substances. Five to 44% (depending on site of tumor origin) of those with GI NET and 28% of those with lung NET have advanced disease at time of diagnosis, meaning the cancer has spread to other areas of the body and patients face limited treatment options. Progression, or the continued growth or spread of the tumor, is typically associated with poor prognoses.

The positive CHMP opinion was based on efficacy and safety data from a pivotal phase III study (RADIANT-4) showing everolimus reduced the risk of progression in patients with progressive, well-differentiated, nonfunctional, locally advanced or metastatic  NET of GI or lung origin by 52% (hazard ratio [HR] = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.00001) vs placebo. Additionally, the data showed everolimus increased median progression-free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.2-13.3) in the everolimus arm and 3.9 months (95% CI, 3.6-7.4) in the placebo arm.

In the pivotal trial, the most common treatment-related grade 3/4 adverse events (AEs) (>=5%) for everolimus and placebo, respectively, were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%) and infections (7.0% vs 0.0%)[1]. The most common treatment-related, all-grade AEs (incidence >=10%) were stomatitis (63%), diarrhea (31%), fatigue (31%), infections (29%), rash (27%) and peripheral edema (26%)[3].

The EC typically adheres to the recommendation of the CHMP and delivers its final decision within three months. The decision will be applicable to all 28 European Union member states plus Iceland and Norway.

In February, the US Food and Drug Administration approved Afinitor for the treatment of adult patients with progressive, well-differentiated, nonfunctional NET of GI or lung origin that are unresectable, locally advanced or metastatic. Additional worldwide regulatory filings for this indication are underway.

RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. It examined the efficacy and safety of everolimus plus best supportive care (BSC) vs placebo plus BSC in 302 patients with unresectable, progressive, well-differentiated, nonfunctional, locally advanced or metastatic NET of GI (excluding pancreatic) or lung origin. The primary endpoint of RADIANT-4 was PFS based on independent radiological assessment evaluated by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival and best overall response rate (defined as complete response plus partial response).

Patients were randomized 2:1 to receive a daily dose of 10 mg everolimus tablets or matching placebo. During treatment, all patients received BSC, which excluded somatostatin analogues (SSAs). Patients had low or intermediate grade histology, no history or active symptoms of carcinoid syndrome, and documented disease progression within the previous 6 months, and were required to have stopped treatment with SSAs for 4 weeks before study entry.

The safety profile of everolimus was consistent with what has been observed in previous oncology studies of this drug.

Afinitor (everolimus) tablets is approved in 99 countries, including the US and in the European Union, for locally advanced, metastatic or unresectable progressive NET of pancreatic origin. Afinitor is not indicated for the treatment of patients with functional carcinoid tumors in the US. Afinitor is now approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.

It is also approved in more than 120 countries including the US and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the US, specifically following sunitinib and sorafenib).

Additionally, Afinitor is approved in more than 100 countries including the United States and European Union for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.

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.