Everolimus treatment significantly prolongs progression-free survival (PFS) compared with placebo in patients with progressive, non-functional neuroendocrine tumours (NETs) of the gastrointestinal tract or lung origin, suggest phase III trial results.
The findings were presented at the European Society for Medical Oncology Asia Congress in Singapore and simultaneously published in The Lancet.
The RADIANT-4 trial included 302 patients with well-differentiated gastrointestinal or lung NETs who were randomly assigned to receive either everolimus 10 mg/day or placebo, with both groups receiving best supportive care.
The primary endpoint of PFS as assessed by central review was longer for the 205 everolimus-treated patients than for the 97 participants given placebo, at a median of 11.0 versus 3.9 months, equating to a significant hazard ratio for progression or death of 0.48. Do-Youn Oh, from Seoul National University Hospital in the Republic of Korea, reported that the PFS benefit conferred by everolimus was consistent across most predefined subgroups.
The objective response rate was comparable, at 2% for the everolimus arm and 1% for the placebo arm. But the disease control rate was higher for patients who received the mammalian target of rapamycin inhibitor (82 vs 65%), as was the proportion of patients achieving tumour shrinkage (64 vs 26%). And fewer patients in the everolimus than in the placebo group had progressive disease as the best outcome, at 9% versus 27%.
An interim prespecified overall survival analysis showed that everolimus reduced the risk of mortality by 36%, but the result did not reach statistical significance.
Stomatitis was the most common adverse event of grade 3 or 4 among everolimus-treated patients (9%), followed by diarrhoea (7%) and infections (7%).
But the majority of side effects were of grade 1 or 2 and consistent with the known safety profile, said Do-Youn Oh. Moreover, the on-treatment mortality rate was also comparable between the everolimus and placebo arms (3.5 vs 3.1%).
“Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of NET including those arising from the pancreas, lung, and [gastrointestinal] tract”, the speaker concluded.
In a discussion following the presentation of the main results, Sun Young Rha, from Yonsei University College of Medicine in Seoul, Republic of Korea, hailed the findings as “practice changing”.
She highlighted that in approximately half the study participants, the primary tumour site was the lung, rectum, stomach or colon, which are sites generally associated with a poor prognosis. But everolimus treatment led to an improved PFS regardless of the primary tumour site, and patients with better and worse prognosis, based on the location of the primary malignancy, derived a benefit.
Sun Young Rha commented that recently several agents have been added to the treatment armamentarium for patients with non-functional NETs, with everolimus now joining as a therapeutic option for advanced NETs of gastrointestinal or lung origin.
Yao JC, Singh S, Wolin E,et al. RADIANT-4: Efficacy and safety of everolimus in advanced, nonfunctional neuroendocrine tumors (NET) of the lung or gastrointestinal (GI) tract. Presented at: ESMO Asia 2015 Congress. Singapore; 18–21 December 2015; 368O
Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2015; Advance online publication 15 December