Everolimus Becomes the New Standard of Care for Patients With GI NETs

Patients with either gastrointestinal (GI) neuroendocrine tumors (NETs) or NETs of unknown primary origin experienced a 40% or more decrease in their risk of disease progression when treated with everolimus (Afinitor), according to a subanalysis of the phase III RADIANT-4 trial.

Simron Singh, MD

Patients with either gastrointestinal (GI) neuroendocrine tumors (NETs) or NETs of unknown primary origin experienced a 40% or more decrease in their risk of disease progression when treated with everolimus (Afinitor), according to a subanalysis of the phase III RADIANT-4 trial.

Everolimus, an mTOR inhibitor, improved progression-free survival (PFS) by 7.7 months in patients with GI NETS when compared to a placebo, and 6.1 months when compared with a placebo in patients with NETS of unknown origin. Subgroup data also showed that the PFS benefit with everolimus was maintained regardless of whether patients had midgut or non-midgut NETS, or whether or not they had received prior somatostatin analog (SSA) therapy.

“Everolimus is an effective and new exciting treatment option in a disease where we’ve had very few treatment options to date,” lead study author Simron Singh, MD, medical oncologist, Sunnybrook’s Odette Cancer Centre in Toronto, Canada, said while presenting data on a presscast held ahead of the 2016 Gastrointestinal Cancers Symposium.

The phase III RADIANT-4 trial included 302 patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NETS in the GI tract (n = 175), lung (n = 90), or unknown origin (n = 36). GI NETs were located in the stomach, colon, rectum, appendix, caecum, ileum, duodenum, jejunum, or small intestine. The most common locations were the ileum (41%), rectum (23%), and jejunum (13%).

Patients were randomized 2:1 to receive best supportive care plus either everolimus at 10 mg per day (n = 205) or placebo (n = 97). Treatment was administered until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was PFS, with secondary endpoints including overall survival, overall response rate, and safety. Crossover to the everolimus arm at progression was not allowed.

Singh said in the GI NETs subgroup, 118 patients received everolimus and 57 were randomized to placebo. The median patient age was 63 years, 55% of patients were female, and 73% of patients were white. Three-fourths of patients enrolled had G1 tumors, and the remaining 25% had G2 cancers. Seventy-eight percent of patients had a WHO PS of 0, while the remaining 22% had a WHO PS of 1.

Previous treatment in the GI NETs everolimus cohort included SSAs (59%), surgery (70%), and chemotherapy (19%). Among the GI NETs placebo group, 63%, 84%, and 12% of patients had received prior SSAs, surgery, and chemotherapy, respectively.

In the unknown primary subgroup, 23 patients received everolimus and 13 patients were randomized to placebo. Baseline characteristics among these patients were similar to those in the GI NETs cohort, according to Singh. Among patients in the unknown primary group who received everolimus, 52%, 26%, and 30%, of patients had prior SSA, surgery, and chemotherapy, respectively. The rates were 54%, 31%, and 23%, respectively, among the unknown primary patients who received placebo.

In the previously reported primary analysis data, median PFS was 11.0 months with everolimus compared with 3.9 months for placebo (HR, 0.48; 95% CI, 0.35-0.67;P<.00001).

In the presscast-reported GI subgroup data, the median PFS was 13.1 months with everolimus versus 5.4 months with placebo (HR, 0.56; 95% CI, 0.37-0.84). Median PFS was 13.6 versus 7.5 months (HR, 0.60; 95% CI, 0.24-1.51), respectively, in the unknown origin cohort.

For the midgut versus non-midgut PFS analysis, midgut NETS were defined as primary tumors originating in the ileum, jejunum, caecum, duodenum, appendix, and small intestine (ileum and jejunum), and non-midgut NETs included primary tumors originating from the stomach, colon, and rectum.

In the midgut subgroup, the median PFS was 17.28 months with everolimus versus 10.87 months with placebo (HR, 0.71; 95% CI, 0.40-1.26). Among patients with non-midgut NETS, the median PFS was 8.11 months versus 1.94 months, respectively (HR, 0.27; 95% CI, 0.15-0.51).

Among patients with prior SSA therapy, median PFS was 11.20 versus 4.47 months (HR, 0.54; 95% CI, 0.32-0.89). The median PFS was 16.59 versus 7.52 months (HR, 0.52; 95% CI, 0.29-0.94), respectively, in patients who had not received SSAs.

“Regardless of prior treatment, the patients appeared to benefit from everolimus across the board,” said Singh.

He also reported safety data for the GI NETs and unknown primary NETs subgroups. “These [data] showed the typical type of side effects that we see with everolimus and that we’re comfortable with managing.”

The most common all-grade adverse events (AEs) in the GI NETs everolimus arm included stomatitis (71.9%), infections (59.0%), diarrhea (44.4%), peripheral edema (40.2%), and fatigue (36.8%). The most frequently reported grade 3/4 AEs with everolimus versus placebo were infections (12.8% vs 3.4%), diarrhea (11.1% vs 3.4%), stomatitis (7.7% vs 0), anemia (6.8% vs 1.7%) and fatigue (5.1% vs 1.7%).

In patients with NETs of unknown primary origins, the most frequently occurring all-grade AEs in the everolimus arm were stomatitis (63.6%), infections (45.5%), fatigue (40.9%), and diarrhea (36.4%). The most common grade 3/4 AEs with everolimus versus placebo were stomatitis (13.6% vs 0), abdominal pain (13.6% vs 0), fatigue (4.5% vs 0), diarrhea (4.5% vs 0), and peripheral edema (4.5% vs 0).

Everolimus was approved by the FDA in 2011 for treatment of patients with advanced pancreatic NETs.

“While everolimus is already approved to treat pancreatic neuroendocrine tumors, these results demonstrate that it may also be effective for a broader group of patients with neuroendocrine cancer,” Smitha Krishnamurthi, MD, ASCO Spokesperson and moderator of the presscast, said in a statement. “The findings may add a new treatment option for patients whose tumors have worsened despite other treatments.”


  1. Singh S, Carnaghi C, Buzzoni R, et al. 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.J Clin Oncol34, 2016 (suppl 4S; abstr 315).