FDA Approves AFINITOR® for Advanced NeuroEndocrine Tumors of GI or Lung Origin

SUMMARY: The FDA on February 26, 2016 approved AFINITOR® (Everolimus) for the treatment of adult patients with progressive, well-differentiated non-functional, NeuroEndocrine Tumors (NET) of GastroIntestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2.

Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis. Somatostatin analogues, such as long acting SANDOSTATIN® LAR Depot (Octreotide), has been shown in the PROMID study to control tumor growth, as well as improve symptoms, in patients with newly diagnosed, well-differentiated metastatic midgut NETs. Following progression on SANDOSTATIN®, these patients have limited treatment options. Everolimus (AFINITOR®), is a mTOR (mammalian Target Of Rapamycin) inhibitor, which has shown activity in advanced NETs, in phase II trials.

The FDA approved AFINITOR® in 2011, for the treatment for patients with progressive, metastatic pancreatic NETs. This approval was based on the phase III RADIANT-3 study, in which the primary end point of Progression Free Survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 4.6 months in the placebo group (HR=0.35; P<0.001).

RADIANT-4 is a randomized, double blind phase III trial, in which 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), NeuroEndocrine Tumors (NETs) of gastrointestinal or lung origin, were randomly assigned in a 2:1 ratio, to receive AFINITOR® (Everolimus) 10 mg orally once daily plus best supportive care (N=205) or placebo plus BSC (N=97). Tumor locations were, GI tract (N=175), Lung (N=90) and Unknown origin (N=36). The median age was 63 years. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), response, and safety.

The median PFS were 11 months and 3.9 months in the AFINITOR® and placebo groups, respectively (HR=0.48; P<0.001), with a 52% reduction in the risk of progression in the AFINITOR® group. In a subgroup analysis which specifically looked at GI NETs, the median PFS was 13.1 months with AFINITOR® versus 5.4 months with placebo (HR=0.56), with a 44% risk reduction in favor of AFINITOR®. In patients with NETs of unknown primary, the median PFS was 13.6 months with AFINITOR® versus 7.5 months with placebo. (HR=0.60), with a 40% risk reduction in favor of AFINITOR®. The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash.

The authors following this subgroup analysis concluded that, there was a 40-44% risk-reduction in favor of AFINITOR®, compared to placebo, for patients with metastatic GI NeuroEndocrine Tumors, as well as NeuroEndocrine Tumors from an unknown primary, thus providing a new treatment option for this patient group. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial. Singh S, Carnaghi C, Buzzoni R, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 315)