Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

• Published in: The lancet oncology 2017-10, Vol.18 (10), p.1411-1422
• Main Authors: Pavel, Marianne E, Singh, Simron, Strosberg, Jonathan R, Bubuteishvili-Pacaud, Lida, Degtyarev, Evgeny, Neary, Maureen P, Carnaghi, Carlo, Tomasek, Jiri, Wolin, Edward, Raderer, Markus, Lahner, Harald, Valle, Juan W, Pommier, Rodney, Van Cutsem, Eric, Tesselaar, Margot E T, Fave, Gianfranco Delle, Buzzoni, Roberto, Hunger, Matthias, Eriksson, Jennifer, Cella, David, Ricci, Jean-François, Fazio, Nicola, Kulke, Matthew H, Yao, James C
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cancer; Cancer therapies; Clinical trials; Disease; Disease-Free Survival; Double-Blind Method; Double-blind studies; Everolimus - adverse effects; Everolimus - therapeutic use; Female; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - mortality; Gastrointestinal Neoplasms - pathology; Gastrointestinal Neoplasms - psychology; Humans; Inhibitor drugs; Internationality; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lung Neoplasms - psychology; Lungs; Male; Metastases; Metastasis; Middle Aged; Motivation; Neoplasm Invasiveness - pathology; Neoplasm Staging; Neuroendocrine tumors; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - mortality; Neuroendocrine Tumors - pathology; Neuroendocrine Tumors - psychology; Patients; Placebos - therapeutic use; Prognosis; Proportional Hazards Models; Quality of Life; Risk Assessment; Somatostatin; Studies; Survival; Survival Analysis; Targeted cancer therapy; Treatment Outcome; Tumors
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(17)30471-0

In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy—General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27–19·35) with everolimus and 9·23 months (5