Regulatory Decision Summary for AFINITOR

The efficacy and safety data supporting the use of Afinitor in patients with advanced non-functional NET of gastrointestinal or lung origin with progressive disease have been generated in the randomized, placebo-controlled Phase III study T2302 (RADIANT-4). In this study, a total of 302 patients were randomized in a 2:1 ratio to receive either Afinitor 10 mg daily (Number of patients [n] = 205) or placebo (n = 97). Patients with history of or active symptoms of carcinoid syndrome were excluded and patients who had received prior somatostatin analogue therapy were required to have discontinued this treatment at least 4 weeks prior to study entry.

The study met its primary endpoint. Progression-free survival (PFS) results as per central radiology review showed a statistically significant 52% risk reduction in favor of Afinitor (Hazard Ratio [HR] 0.48; 95% Confidence Interval [CI]: 0.35, 0.67). The 7.1-month prolongation in median PFS (from 3.9 months for placebo to 11.0 months for Afinitor) is considered to represent a clinical benefit. However, overall survival (OS) results at an interim analysis were not statistically significant.

Multiple preplanned sensitivity and subgroup analyses showed a positive treatment effect on PFS across predefined stratification factors (site of tumor origin based on prognosis, prior somatostatin analogue exposure, and World Health Organization Performance Status score) and across major demographic, prognostic, and tumor site of origin subgroups with the notable exception of the ileum as the site of primary tumor origin. However, while a positive treatment effect was shown across subgroups (with the exception of the noted exception), the magnitude of the treatment effect was variable across subgroups and suggested that the effectiveness of Afinitor in NETs with a better prognosis may be more limited compared to that for NETS with a poorer prognosis.

The safety and tolerability profile of Afinitor in advanced non-functional NET is consistent with prior experience in the oncology setting. The most common adverse events were stomatitis, infections, diarrhea, edema peripheral, fatigue and rash. The most common Grade 3-4 adverse events were diarrhea, stomatitis, anemia, hyperglycemia and fatigue.

It is concluded that Afinitor has a positive benefit-risk profile when used for the treatment of unresectable, locally advanced or metastatic, well differentiated non-functional NETs of gastrointestinal or lung origin in adults with progressive disease. Afinitor is not indicated for use in combination with a somatostatin analogue in patients with NETs from gastrointestinal or lung origin or for use in patients with functional carcinoid tumors.