Everolimus Boosts PFS For Progressive Lung, Gastrointestinal NET Patients

Everolimus extends progression-free survival in patients with non-functional, progressive neuroendocrine tumours

medwireNews: RADIANT-4 study findings support the use of everolimus for patients with progressive non-functional, well differentiated neuroendocrine tumours (NETs) of the lung or gastrointestinal tract.

The phase III trial’s primary endpoint of progression-free survival (PFS) assessed by central radiology review was significantly longer in the 205 patients randomly assigned to receive the mammalian target of rapamycin (mTOR) inhibitor than the 97 patients given placebo, at 11.0 versus 3.9 months.

This translated to a 52% reduction in the estimated risk of disease progression or death with everolimus treatment, the researchers report in The Lancet.

Everolimus was also associated with a trend towards improved overall survival at the first interim analysis, although the hazard ratio of 0.64 did not reach statistical significance.

While data were not mature for median overall survival analysis, the Kaplan-Meier estimates for overall survival after 25% of patients died was 23.7 months for everolimus versus 16.5 months for placebo.

A confirmed partial objective response was found in just 2% of everolimus-treated patients and 1% of those given placebo, with 81% and 64% achieving stable disease.

“Therefore, the prolongation in progression-free survival with everolimus was probably secondary to the stabilisation of disease or minor tumour shrinkage and to fewer cases of progressive disease”, write James Yao, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Dose reductions or interruptions occurred in 67% of the everolimus group versus 30% of the placebo group and the treatment adverse event profile for everolimus was consistent with previous reports, with largely grade 1 or 2 side effects. The most common grade 3 or 4 events were stomatitis, diarrhoea and infection.

But the researchers observe that differences in the safety profiles may also reflect the significantly longer median treatment duration in the everolimus group compared with the placebo group, at 40.4 versus 19.6 weeks.

“Taken together with results from the previous RADIANT-3 study in pancreatic neuroendocrine tumours […], the findings from RADIANT-4 study provide robust, practice-changing evidence to support the antitumour efficacy of everolimus across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, or gastrointestinal tract”, they conclude.

Kjell Öberg, from Uppsala University Hospital in Sweden, writes in an accompanying comment that everolimus “provides a valid alternative” to existing therapies, including somatostatin analogues for small intestinal NETs, and tyrosine kinase inhibitors and cytotoxic agents for pancreatic NETs.

Nevertheless, he cautions that everolimus’s “precise place in the treatment algorithm needs to be further analysed in studies comparing other treatment alternatives.”


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. DOI: http://dx.doi.org/10.1016/S0140-6736(15)00817-X

Öberg K. Universal everolimus for malignant neuroendocrine tumours? Lancet 2015; Advance online publication 15 December. DOI: http://dx.doi.org/10.1016/S0140-6736(15)01234-9

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