oe VOL. 15, NO. 2, may 2016 23

Report from the ASCO Gastrointestinal Cancers Symposium

GI-tract neuroendocrine tumoursEVErOLimus iN adVaNcEd Or prOgrEssiVE disEasE

Elena Tsvetkova, MD, FRCPC, medical Oncologist, Juravinski cancer centre, Hamilton

TRial suMMaRy: RaDiaNT-4 subgroup analysissimon singh, carlo camaghi, roberto Buzzoni, et al. Efficacy and safety of everolimus in advanced, progressive, non-functional neuro-endocrine tumours (NET) of the gastrointestinal (gi) tract and unknown primary: a subgroup analysis of the phase iii radiaNT-4 trial. J Clin Oncol 2016;34(suppl 4s; abstract 315).

The randomized phase 3 RADIANT-4 trial reported signif-icantly prolonged median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (G1/G2), nonfunctional neuroendocrine tumours (NET) of gastrointestinal (GI) or bronchopulmo-nary origin who received everolimus compared to placebo; HR=0.48; 95% CI: 0.35, 0.67); p<0.00001.1 Patients were randomized 2:1 to everolimus or placebo. Of 302 patients, 175 had GI NET and 36 had NET of unknown primary (UP); 118 in GI group and 23 in UP group were treated with everolimus. In the GI NET group, median age was 63 and 55% were women and 73% were Caucasian; 75% were G1 and 25% were G2; 73%. Similar characteristics were observed in patients with UP NET. The most common tumour sites in GI subgroups were ileum (41%), rectum (23%) and jejunum (13%). In the GI NET group, 59% of patients treated with everolimus had received prior treat-ment with somatostatin analogues (SSA) (vs 63% in the pla-cebo group), 70% had undergone prior surgery (vs 84% in placebo group), and 19% had received chemotherapy (vs 12% in placebo group). In UP NET group, 52% of patients treated with everolimus had received prior treatment with SSA (vs 54% in placebo group), 26% had undergone sur-gery (vs 31% in placebo group), and 30% had received che-motherapy (vs 23% in placebo group).

Results: In patients with GI NET, median PFS by central review was 13.1 (95% CI: 9.2, 17.3) months in the everoli-mus group, vs 5.4 (3.6, 9.3) months in the placebo group, with an estimated 44% risk reduction in favour of everolim-us (HR=0.56; 95% CI: 0.37–0.84). In UP NET, median PFS was 13.6 (95% CI: 4.1, not evaluable) months of

everolimus vs 7.5 (95% CI: 1.9, 18.5) months (HR=0.60; 95% CI: 0.24, 1.51) for placebo. The most frequent grade 3/4 side effects reported in more than 5% of patients in the GI NET group were diarrhea, hypertension, stomatitis, abdominal pain, fatigue and acute renal failure. This sub-group analysis of RADIANT-4 trial demonstrates improved PFS in patients with GI NET and suggests efficacy in patients with UP NET treated with everolimus, with an estimated 40% to 44% risk reduction in favour of everolim-us. The safety profile is consistent with previous reports.

CoMMENTaRy: Everolimus has been approved for meta-static pancreatic NET since results of open-label phase 2 study demonstrated significant objective response rate and PFS in patients who progressed on or after chemotherapy.1 However, treatment options for nonpancreatic GI NET were very limited. In 2015, at the European Society for

IN BRIEFalready known• Everolimus prolongs progression-free survival (pFs)

over placebo in patients with advanced, progressive, well-differentiated (g1/g2), nonfunctional neuroen-docrine tumours (NET) of gastrointestinal (gi) or bronchopulmonary origin.

What this study showed• The subgroup of patients with gi NET demonstrated

improved pFs. a risk reduction of over 40% was also seen in patients with NET of unknown primary.

Next steps• consider everolimus in metastatic NET of gi origin.

laNdmaRks

24 oe VOL. 15, NO. 2, may 2016

laNdmaRks

Medical Oncology (ESMO) meeting in Spain, reports from the phase 3 randomized RADIANT-4 trial showed signifi-cant improvement in PFS by 7.1 months in patients with advanced progressive nonfunctional GI or pulmonary tumours vs placebo; (HR=0.48; 95% CI: 0.35, 0.67; p<0. 00001). GI tumour sites included stomach, colon, rectum, appendix, cecum, duodenum, ileum jejunum and small intestine; the most common sites were ileum (41%), rectum (23%), and jejunum (13%). Of 302 patients, 175 had GI NET, and 59% of this group underwent previous treatment with SSA and 19% with chemotherapy. Patients were ran-domly assigned 2:1 to everolimus (10 mg p.o. daily) or pla-cebo. In the analysis presented by Dr. Simon Singh, evero-

limus demonstrated a 40% risk reduction in disease progres-sion, with a median PFS of 13.1 months vs 5.4 months in the placebo group. Reported adverse events were consistent with the known side effect profile of everolimus. The most common G3/4 events were diarrhea, stomatitis, fatigue, hypertension, abdominal pain and acute renal failure. This report supports the use of everolimus in metastatic NET of GI origin.

Reference

1. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cyto-toxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69-76.