Everolimus provided a significant 52% risk reduction in patients with advanced, progressive lung/gastrointestinal (GI) neuroendocrine tumours (NET) who also achieved progression-free survival (PFS) 7.1 months longer than that experienced by similar patients receiving placebo. Findings from the pivotal RADIANT-4 study were reported at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September 2015.
Treatment of patients with advanced lung and gastrointestinal neuroendocrine tumours was associated with a 2.8 fold improvement in median progression-free survival from 3.9 months to 11 months.
Credit line: James Yao
Everolimus is a mammalian target of rapamycin inhibitor that has been approved in advanced pancreatic NET. However, advanced, non-functional NET of lung/GI origin remains an area of significant unmet medical need.
Lead investigator James Yao, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston, USA, presented results on behalf of the RADIANT-4 Study Group during the Presidential Session on 27 September. This was a randomised, placebo-controlled, double-blind, multicentre, phase III trial of everolimus versus placebo that was conducted in patients with advanced, progressive, well-differentiated, non-functional lung/GI NET.
In RADIANT-4, 302 patients were stratified by tumour origin, WHO performance status (PS), and prior somatostatin analogue treatment, then randomised 2:1 to receive best supportive care (BSC) plus either everolimus at 10 mg per day (n=205) or placebo (n=97).
Patient median age was 63 years, 53% of patients were female, and 76% were Caucasian. Disease status was grade1/grade 2 in 64% and 35% of patients, respectively, and WHO PS was 0 in 74% or 1 in 26% of patients. The most commonly reported tumour sites were the lung in 30%, and the ileum in 24% of patients.
The two arms were well balanced regarding prior treatment; 53% versus 56% of patients in the everolimus and placebo groups respectively had received prior somatostatin analogue therapy, 26% versus 24% had received chemotherapy and 22% versus 20% had undergone previous loco-regional and radiotherapy.
Findings from the RADIANT-4 study are practice-changing in this setting where few treatment options currently exist
The primary endpoint of progression-free survival (PFS) assessed by central radiology review (modified RECIST 1.0) was median 11.0 (95% CI 9.2, 13.3) months with everolimus compared to 3.9 months (95% CI3.6, 7.4) months with placebo, hazard ratio (HR) 0.48; 95% CI 0.35, 0.67 (p < 0.001).
Investigator-assessed PFS was consistent with the central review; PFS with everolimus was 14.0 (95% CI 11.2, 17.7) months compared to 5.5 (95%CI 3.7, 7.4) months with placebo, HR 0.39; 95% CI 0.28, 0.54 (p < 0.001). Subgroup PFS analyses by stratification factors also were consistent with these assessments.
Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. ORR by central review, showed no complete response but four (2%) everolimus and one (1%) placebo patients showed partial response (PR). DCR was higher in 82% with everolimus versus 65% with placebo. Progressive disease was reported for 9% of everolimus patients compared to 27% of patients receiving placebo. Tumour response was unknown in the remaining patients.
A pre-planned interim OS analysis showed a trend toward improved OS favouring everolimus, HR 0.64, 95% CI 0.40,1.05 (p = 0.037); however, OS difference did not achieve statistical significance.
The most commonly reported adverse events (AEs) grades 1/2 included stomatitis, diarrhoea, peripheral oedema, fatigue, and rash.
Grades 3/4 AEs of diarrhoea and anaemia were reported by 9% versus 2% and 5% versus 2% of patients receiving everolimus and placebo, respectively. Grades 3/4 abdominal pain was reported for 5% of each treatment arm and stomatitis was reported by 7% of patients receiving everolimus.
Good things to take home and issues not solved by RADIANT-4 study
Dr Enrique Grande of the Hospital Universitario Ramón y Cajal, Madrid, Spain who discussed the results of the RADIANT-4 study said that good things to take home after the presentation are: RADIANT-4 is a positive, well design and randomised clinical trial in non-pancreatic and non-functioning NETs that shows superiority of everolimus vs. placebo in term of PFS. Everolimus is the first ever drug to show in a randomised trial to have significant activity in lung NETs. No new safety concerns were found. A trend in OS improvement was observed in favour to everolimus, although statistically not significant.
RADIANT-1, -2, -3, and now -4 study results are all supportive for the use of everolimus in grade 1 and 2 disseminated and progressive NET, regardless of primary tumour origin.
However, despite of the encouraging activity of everolimus, we do not have the full picture yet (not matching the somatostatin analogue outcomes in other trials like PROMID and SWOG S0518 trials). Dr Grande questioned if everolimus should be pushed after somatostatin analogues failure? If so, is single agent everolimus better than maintenance of somatostatin analogue plus adding on everolimus.
No biomarker and no molecular selection of patients are pitfalls of the study. There is low (if any) radiographic response. Dr Grande underlined about recurrent problem while assessing radiographic response in NETs. He also questioned the strategy in patients with functioning tumours or lower hepatic tumour burden or good prognosis by primary tumour origin (stratum A).
Conclusions
The authors noted that treatment of patients with advanced, non-functional neuroendocrine tumours of the lung or GI tract currently poses a challenge due to a lack of prospective data from large clinical trials.
RADIANT-4 is the first large, placebo-controlled, prospective phase III study to unequivocally demonstrate clinical benefit with everolimus versus placebo.
These findings are particularly important, according to the investigators, because they represent practice-changing data that support the efficacy and safety of everolimus across the broad spectrum of neuroendocrine tumours where a significant unmet medical need for exists for safe and effective treatment options.
Disclosure: The RADIANT-4 trial was funded by Novartis.
Reference
5LBA Everolimus in advanced nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) origin: Efficacy and safety results from the placebo-controlled, double-blind, multicenter, Phase 3 RADIANT-4 study