Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study

Abstract

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2.

Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated.

Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm.

Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates.

Clinical trial number: NCT00412061, www.clinicaltrials.gov.

Keywords: carcinoid syndrome; everolimus; neuroendocrine tumors; overall survival.

Figure 1

Patient disposition. *All patients were unblinded at the time of progression or at the end of the double-blind phase, after primary analysis, and were allowed to cross over to open-label everolimus. Additional reasons for patient discontinuation in either arm of the double-blind phase included AEs, death, patient consent withdrawal, protocol violation, and loss to follow-up. **At the time of study termination, patients receiving everolimus were rolled over to study RAD001C2X01B (ClinicalTrials.gov identifier, NCT01789281) or to commercial everolimus. AE, adverse event; LAR, long-acting repeatable; OS, overall survival.

Supplementary Data

Figure 2

Kaplan–Meier plot of overall survival (full analysis set).

Figure 3

Kaplan–Meier plot of overall survival by baseline CgA level, irrespective of treatment arm (full analysis set). HR was obtained from unadjusted Cox's model stratified by treatment group. P value was obtained from the 2-sided log-rank test stratified by treatment group.