Everolimus effective for lung and gastrointestinal neuroendocrine tumors

Last Updated: 2015-12-28

By Will Boggs MD

NEW YORK (Reuters Health) - Everolimus significantly improves progression-free survival in patients with advanced, nonfunctional neuroendocrine tumors (NETs) of the lung or gastrointestinal tract, according to results from the RADIANT-4 study.

"There are very few treatment options for this patient population," Dr. James C. Yao from the University of Texas M.D. Anderson Cancer Center, Houston, told Reuters Health by email. "For example, there is no proven therapy in lung or colorectal NETs. We believe everolimus should become standard of care for progressive NETs."

Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been shown to have antitumor activity in advanced nonpancreatic NETs, and phase 2 studies have shown nonsignificant improvements in progression-free survival (PFS) in patients with these tumors.

Dr. Yao and colleagues investigated whether oral everolimus at a daily dose of 10 mg (versus placebo) prolongs PFS in patients with advanced, nonfunctional, progressive NETs of lung or gastrointestinal origin.

Their randomized, double-blind, phase 3 study included 302 patients from 97 centers in 25 countries, according to the December 15 online report in The Lancet.

Median radiology-assessed PFS, the primary endpoint, was significantly longer in the everolimus group (11.0 months) than in the placebo group (3.9 months), and everolimus was associated with a 52% reduction in the estimated risk of disease progression or death (p<0.00001).

Estimated PFS at 12 months was 44% with everolimus versus 28% with placebo.

Results were consistent across subgroups and irrespective of the extent of liver metastasis.

A preliminary analysis showed a trend in favor of better overall survival with everolimus, but statistical significance was not reached.

"Up to two additional overall survival analyses will be done according to the statistical plan as the survival follow-up data mature," the researchers note.

Four everolimus patients and one placebo patient had objective responses, and disease stabilization was the best overall response in 81% of everolimus patients and 64% of placebo patients. About two-thirds of everolimus patients (64%) and a quarter of placebo patients (26%) showed some degree of tumor shrinkage.

After a median 21 months of follow-up, median duration of treatment was about twice as long with everolimus (40.4 weeks) as with placebo (19.6 weeks), though treatment discontinuation due to grade 3 or 4 adverse events related to study drug were more common with everolimus (24 patients, 12%) than with placebo (3 patients, 3%).

"We saw consistent benefit across a broad group of tumors including those not known to harbor somatic mTOR pathway mutations," Dr. Yao said. "This suggests that the mTOR pathway may be dysregulated in a wider variety of tumors through other mechanisms such as epigenetic regulation."

"While most treatment in NETs has only proven efficacy in some subgroups such as pancreas or midgut, everolimus is broadly active in well differentiated, G1/G2 NETs," Dr. Yao concluded. "It has demonstrated efficacy in NETs of lung, pancreas, gastrointestinal tract, and unknown primary."

"Everolimus has significantly contributed to the understanding of treatment options for neuroendocrine neoplasms, but the drug's precise place in the treatment algorithm needs to be further analyzed in studies comparing other treatment alternatives," writes Dr. Kjell Oberg, from Uppsala University Hospital, Sweden, in a related editorial.

Dr. Nicola Fazio, director of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy, told Reuters Health by email, "Everolimus is a further therapeutic option to consider for patients with well or moderately differentiated (also named low/intermediate grade) NETs from lung (typical and atypical carcinoids), gastrointestinal (GI), and unknown primary site. In lung and non-midgut GI NETs it could be considered in pre-treated but also in untreated patients, whereas in midgut NETs more commonly at progression on somatostatin analog."

"RADIANT-4 trial design improved some aspects of the previous RADIANT trials, including prospective stratification for some known prognostic factors that minimized confounding," Dr. Fazio added. "Furthermore, due to its design, this could be the first phase 3 trial in NETs showing a significant overall survival improvement, as suggested by the promising trend arising from the first overall survival interim analysis."

Novartis Pharmaceuticals Corporation funded the trial, employed four of the 22 authors, and had various relationships with all but three of the other authors, including Dr. Yao.

SOURCE: http://bit.ly/1ITmhZM and http://bit.ly/1knD4sp

Lancet 2015.