Regulatory Decision Summary for SOMATULINE AUTOGEL

This supplementary indication for the treatment of advanced enteropancreatic neuroendocrine tumors is supported by one well conducted, randomized, placebo-controlled, Phase III study demonstrating a significant delay in progression of disease for patients who received Somatuline Autogel compared to placebo. The efficacy findings are supported by an acceptable safety profile with limited risks, including most commonly, gastrointestinal and local reaction adverse events, and less commonly, an increase in the risk of gallstone formation and hypo/hyperglycemic events. Somatuline Autogel, administered as a deep subcutaneous injection every 4 weeks, is an effective and well tolerated treatment for patients with enteropancreatic neuroendocrine tumors.

• Treatment with Somatuline Autogel demonstrated a statistically significant increase in progression-free survival (PFS) compared with placebo(Hazard Ratio [HR]: 0.47 [95% Confidence Interval, 0.30, 0.73], p = 0.0002).
• The median PFS in patients treated with Somatuline Autogel was greater than 96 weeks compared to 72 weeks for patients who received placebo.
• Although it is clear that treatment with Somatuline Autogel significantly delays disease progression, whether this will translate to a survival advantage is unknown. There were an insufficient number of deaths at the end of the study period to assess survival. As well, deaths were balanced between arms, suggesting no positive trend towards a survival benefit for the treatment arm.
• A delay in progression was observed in all primary tumor location subgroups treated with Somatuline Autogel, with the exception of hindgut, which may have been due to the insufficient and unbalanced number of patients in that subgroup.
• Overall, no new adverse event or any increase in frequency of previously reported adverse events (for other indications) was observed.

Neuroendocrine tumors generally follow a slow, indolent growth pattern, and the optimal time for initiating treatment in patients with unresectable, locoregional or metastatic disease is unknown. It is unclear whether treating relatively stable/clinically non-significant progressive disease is beneficial over a “wait and watch” approach, delaying treatment until there is evidence of progression or substantial tumor burden.

Health Canada concluded that this submission demonstrated a favourable benefit-risk ratio for Somatuline Autogel in the treatment of enteropancreatic neuroendocrine tumors in patients with Grade 1 or a subset of Grade 2 (equivalent to Ki67 < 10%) unresectable, locally advanced or metastatic disease to delay progression. It is important to note that the effectiveness of Somatuline Autogel is based on a Phase III placebo-controlled study which demonstrated a benefit in PFS in patients classified with stable disease by Response Evaluation Criteria in Solid Tumours (RECIST) criteria (<20% growth) over 12 to 24 weeks. There was no evidence of an overall survival benefit. Data on hindgut tumors were limited.