Novartis announces FDA approval of Afinitor for progressive, nonfunctional neuroendocrine tumors of GI

Novartis today announced that the United States Food and Drug Administration (FDA) approved Afinitor^® (everolimus) tablets 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. 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 program, 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% of patients with NET have nonfunctional tumors. At the time of diagnosis, 5%-44% (depending on site of tumor origin) of patients with NET in the GI tract and 28% 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 tumor, 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% (hazard ratio [HR] = 0.48; 95% 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% CI, 9.2-13.3) in the Afinitor 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 Afinitor and placebo, respectively, were infections (11.0% vs 2.0%), diarrhea (9.0% vs 2.0%), stomatitis (9.0% vs 0.0%), fatigue (5.0% vs 1.0%) and hyperglycemia (5.0% vs 0.0%).

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

RADIANT-4 Study: Part of the largest clinical trial program in advanced NET
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 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%) were stomatitis (63%), infections (58%), diarrhea (41%), peripheral edema (39%), fatigue (37%) and rash (30%). Afinitor was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of Afinitor-treated patients.