Everolimus, 177Lu-dotatate extend neuroendocrine tumour PFS

Oct 7 2015

By Lynda Williams, Senior medwireNews Reporter

Positive progression-free survival (PFS) results from the RADIANT-4 and NETTER-1 trials extend the armamentarium for physicians treating patients with neuroendocrine tumours (NETs).

The studies, indicating efficacy for the mTOR inhibitor everolimus and the peptide receptor radionuclide therapy lutetium (Lu)¹⁷⁷-dotatate, respectively, were presented at the European Cancer Congress held in Vienna, Austria.

The primary endpoint of PFS in the RADIANT-4 trial, as determined by central radiological review, was 11.0 months in the 205 patients with non-functional NETs of the gastrointestinal tract or lung who were randomly assigned to receive everolimus 10 mg/day compared with 3.9 months in the 97 patients given placebo, with a significant hazard ratio (HR) of 0.48.

The “robust benefit” was confirmed by investigator assessment, with PFS of 14.0 months versus 5.5 months in the everolimus and placebo groups, and a significant HR of 0.39.

The first planned interim overall survival analysis showed a 36% reduction in the risk of death in favour of everolimus and, although this was not statistically significant, the researchers believe that analysis of mature data in 2016 may show a significant result.

“Although we knew from previous studies that everolimus could delay the growth of pancreatic NETs, this is the first time we have been able to conclusively show that it is effective in other NET sites”, said James Yao, from the University of Texas MD Anderson Cancer Center in Houston, USA, and RADIANT-4 co-investigators in a press release.

“We hope that our results will provide a new treatment option for lung and gastrointestinal NETs, and we look forward to reporting further results from the trial, including those on final overall survival and quality of life, in the future.”

And a new treatment option may also be available for patients with grade 1 or 2 metastatic midgut NETs who progressed on first-line somatostatin analogue (SSA) therapy, said Philippe Ruszniewski, from Beaujon Hospital in Clichy, France, who presented preliminary findings for the NETTER-1 phase III trial of ¹⁷⁷Lu-dotatate.

In all, 229 patients in Europe or the USA were randomly assigned to receive four doses of ¹⁷⁷Lu-dotatate (7.4 GBq) at 8-week intervals plus the SSA octreotide 30 mg every 4 weeks, or the SSA octreotide 60 mg every 4 weeks.

Median PFS was unreached in the ¹⁷⁷Lu-dotatate group and 8.4 months for the octreotide only group, giving a significant HR of 0.21.

Evaluation of 201 patients gave a RECIST criteria objective response rate of 19% versus 3%, with one complete response and 18 partial responses in the ¹⁷⁷Lu-dotatate-treated patients compared with just three partial responses in the octreotide only group. Progressive disease occurred in 4% and 24%, respectively, with stable disease in 66% and 62%.

Speaking at a press conference, Ruszniewski said the interim intention-to-treat overall analysis “was not yet significant”, but with 13 deaths in the ¹⁷⁷Lu-dotatate group and 22 in the octreotide only group so far, there is a trend towards this benefit.

Noting that current safety results confirm earlier research indicating a “favorable safety profile”, Ruszniewski concluded: “We have now… reasonable evidence that this is a major advance in the population of patients with progressive midgut NETs.”

Press conference chair, Christoph Zielinski, from the Medical University of Vienna in Austria, described the two sets of results as “practice changing” and said a head-to-head trial would be needed to directly compare the therapies.

Ruszniewski emphasised that most NETs patients will be given all available treatments and “it was a question of order”, but that tumour expression of somatostatin receptors and patient tolerance of long-term everolimus would also influence choice.

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