The United States Food and Drug Administration (FDA) approved Novartis' Afinitor (everolimus) tablets for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Afinitor received a priority review designation providing a shortened review period for drugs that treat serious conditions and offer a significant improvement in safety or effectiveness.

"Afinitor is the first treatment approved for progressive, nonfunctional NET of lung origin, and one of very few options available for progressive, nonfunctional GI NET, representing a shift in the treatment paradigm for these cancers," said Bruno Strigini, president, Novartis Oncology. "We are proud of our Afinitor development programme, which has translated to meaningful benefits for patients with several different cancers and rare diseases."

Neuroendocrine tumors are a rare type of cancer that originate in neuroendocrine cells throughout the body, and are most often found in the GI tract, lungs or pancreas. NET can be defined as functional or nonfunctional. Functional NET are characterized by symptoms caused by the oversecretion of hormones and other substances. Nonfunctional NET may be 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. More than 70 per cent of patients with NET have nonfunctional tumours. At the time of diagnosis, 5 per cent-44 per cent (depending on site of tumor origin) of patients with NET in the GI tract and 28 per cent of patients with lung NET have advanced disease, meaning the cancer has spread to other areas of the body, making it difficult to treat. Progression, or the continued growth or spread of the tumour, is typically associated with poor outcomes.

The approval of Afinitor was based on efficacy and safety data from a pivotal study (RADIANT-4) showing Afinitor reduced the risk of progression in patients with progressive, well-differentiated, nonfunctional NET of GI or lung origin by 52 per cent (hazard ratio [HR] = 0.48; 95 per cent confidence interval [CI], 0.35-0.67; p<0.001) vs placebo. Additionally, the data showed Afinitor increased median progression-free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95 per cent CI, 9.2-13.3) in the Afinitor arm and 3.9 months (95 per cent 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 per cent) for Afinitor and placebo, respectively, were infections (11.0 per cent vs 2.0 per cent), diarrhea (9.0 per cent vs 2.0 per cent), stomatitis (9.0per cent vs 0.0 per cent), fatigue (5.0 per cent vs 1.0 per cent) and hyperglycemia (5.0 per cent vs 0.0 per cent).

Additional worldwide regulatory filings for this indication are underway, with a decision in the EU anticipated in 2016.

RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors), part of the largest clinical trial programme in advanced NET, is a phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. It examined the efficacy and safety of Afinitor 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 major efficacy outcome measure of RADIANT-4 was PFS based on independent radiological assessment evaluated by Response Evaluation Criteria in Solid Tumors. Additional efficacy outcome measures were overall survival and best overall response rate (defined as complete response plus partial response).

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

The safety profile of Afinitor was consistent with what has been observed in previous studies of this drug. The most common treatment-related, all-grade AEs (incidence >=30 per cent) were stomatitis (63 per cent), infections (58per cent), diarrhea (41 per cent), peripheral edema (39 per cent), fatigue (37 per cent) and rash (30 per cent). Afinitor was discontinued for adverse reactions in 29 per cent of patients and dose reduction or delay was required in 70 per cent of Afinitor-treated patients.

Afinitor (everolimus) tablets is now approved by the United States (US) Food and Drug Administration (FDA) for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Additionally, Afinitor is approved in 99 countries, including the US and throughout the European Union, for locally advanced, metastatic or unresectable progressive NET of pancreatic origin. It is also approved in >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).

Afinitor is also approved in 102 countries including the US 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.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, middle ear infection and pneumonia), absence of menstrual periods, high levels of cholesterol, nausea, decreased appetite, low level of red blood cells, acne, abnormal taste, irregular menstrual periods, inflammation of lung tissue, swelling of extremities or other parts of the body, high level of blood sugar, itching, weight loss, nose bleeds, cough and headache. The most common grade 3-4 adverse drug reactions (incidence >=2 per cent) are mouth ulcers, infections (including pneumonia), low level of red blood cells, absence of menstrual periods, high level of blood sugar, feeling tired or weak, diarrhea, low white blood cells, inflammation of lung tissue and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.