Health-related quality of life in patients with advanced, nonfunctional, well-differentiated gastrointestinal or lung neuroendocrine tumors with everolimus vs. placebo in the phase 3, randomized, RADIANT-4 trial

BACKGROUND
In the phase 3 RADIANT-4 trial, everolimus improved progression-free survival (PFS) vs. placebo in 302 patients with advanced, progressive, nonfunctional, well-differentiated gastrointestinal (GI) or lung neuroendocrine tumors (NET). We now report pre-specified and post-hoc analyses to assess the treatment effect on health-related quality of life (HRQoL) and to evaluate the extent to which disease progression is associated with a decline in HRQoL and utility scores.

METHODS
RADIANT-4 was a randomized, double-blind, placebo-controlled phase 3 trial conducted in 97 centers in 25 countries worldwide. Adult patients (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) NET of lung or GI origin. Patients were randomized in a 2:1 ratio by an interactive voice response system to receive oral everolimus at a dose of 10 mg per day or placebo, both with best supportive care (BSC). Patients were stratified by tumor origin, performance status, and previous somatostatin analogue treatment. The primary endpoint was PFS assessed by central radiology review. HRQoL was assessed with 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 randomization and every 12 weeks thereafter until study drug discontinuation. The analyses were performed on the full analysis set, consisting of all randomized patients. Pre-specified analysis of the secondary endpoint, time to definitive deterioration (TDD) of ≥7 points in FACT-G total score was analyzed with the Kaplan-Meier method and a Cox regression model. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization. Only data collected while on their randomized treatment were included in this analysis. Other endpoints were post-hoc. Enrollment for RADIANT-4 was completed 23 August, 2013, but the trial is ongoing pending final analysis of key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783.

FINDINGS
A total of 302 patients were enrolled between April 3, 2012, and Aug 23, 2013; 205 patients were randomized to the everolimus arm and 97 patients to the placebo arm. Compliance rate for FACT-G completion at baseline was 94·1% (193 of 205) in the everolimus arm, and 97·9% (95 of 97) in the placebo arm, respectively, and at week 48 83·3% (70 of 84) in the everolimus arm and 84·6% (22 of 26) in the placebo arm. No statistically significant differences were observed between the two treatments (p-value of log-rank test: 0·3102) with an estimated median TDD of 11·27 (95% CI: 9·27; 19·35) months for everolimus and 9·23 (95% CI: 5·52; NE) months for placebo, respectively. The adjusted HR from the stratified Cox model was 0·81 (95% CI: 0·55, 1·21).

INTERPRETATION
HRQoL was maintained, with no statistically or clinically relevant differences between everolimus vs placebo-treated advanced nonfunctional GI or lung NET patients. Together with the analysis of the RADIANT-4 primary endpoint, this study provides potentially practice-changing evidence that everolimus delays disease progression while preserving overall HRQoL even with the usual toxicities related to active targeted drug treatment for cancer.