Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.
James C. Yao, MD, and colleagues
In a phase III trial (RADIANT-4) reported in The Lancet, James C. Yao, MD, of the University of Texas MD Anderson Cancer Center, and colleagues found that everolimus (Afinitor) and supportive care significantly prolonged progression-free survival vs placebo and supportive care in patients with advanced nonfunctional neuroendocrine tumors of the lung or gastrointestinal tract.1 The first interim analysis of overall survival showed a benefit of everolimus that did not reach the significance boundary.
In this double-blind trial, 302 adults with progressive, well-differentiated tumors from 97 sites in 25 countries worldwide were randomized 2:1 between April 2012 and August 2013 to receive everolimus at 10 mg/d (n = 205) or placebo (n = 97) with supportive care. Patients were stratified by tumor origin, performance status, and previous somatostatin analog treatment. The primary endpoint was progression-free survival assessed by central radiology review in the intent-to-treat population.
For the everolimus and placebo groups, median age was 65 and 60 years, and a greater proportion of the everolimus group was female (57% and 45%). Otherwise, the groups were generally balanced for World Health Organization performance status (0 for 73% and 75%), primary tumor site (eg, lung in 31% and 28%, ileum in 23% and 25%, rectum in 12% and 16%), tumor grade (1 in 63% and 67%), time from initial diagnosis (eg, ≤ 6 months for 13% and 12%, > 36 months for 42% and 39%), disease sites (liver in 80% and 78%, lymph node/lymphatic system in 42% and 46%, lung in 22% and 21%, bone in 21% and 16%, and peritoneum in 12% and 8%), and liver tumor burden (eg, none in 17% and 14% and ≤ 10% in 58% and 63%). A higher proportion of placebo patients had surgery (59% vs 72%), with similar proportions in the two groups having received chemotherapy (26% and 24%), radiotherapy (22% and 20%), and locoregional and ablative therapies (11% and 10%); 53% and 56% had received somatostatin analogs.
Improved Progression-Free Survival
Median progression-free survival was 11.0 months (95% confidence interval [CI] = 9.2–13.3 months) in the everolimus group vs 3.9 months (95% CI = 3.6–7.4 months) in the placebo group (hazard ratio [HR] = 0.48, P < .00001). Estimated 12-month progression-free survival rate was 44% vs 28%. On investigator assessment, median progression-free survival rate was 14.0 vs 5.5 months (HR = 0.39, P < .00001).
In subgroup analyses, hazard ratios favored everolimus across stratification factors, including hazard ratios of 0.52 (95% CI = 0.34–0.81) among 157 patients with and 0.60 (95% CI = 0.30–0.94) among 145 patients without prior somatostatin analog treatment and 0.63 (95% CI = 0.40–1.02) among 153 with better prognosis sites of origin and 0.43 (95% CI = 0.28–0.66) among 149 with worse prognosis sites of origin.
Hazard ratios were also similar among 159 patients aged < 65 years (0.55, 95% CI = 0.36–0.83) and 143 aged ≥ 65 years (0.59, 95% CI = 0.37–0.94) and among 194 with grade 1 tumors (0.57, 95% CI = 0.39–0.84) and 107 with grade 2 tumors (0.49, 95% CI = 0.29–0.83). Hazard ratios differed somewhat between 142 male patients (0.78, 95% CI = 0.51–1.22) and 160 female patients (0.39, 95% CI = 0.25–0.60) and among 230 white patients (0.83, 95% CI = 0.56–1.21), 50 Asian patients (0.19, 95% CI = 0.09–0.40), and 22 patients of other race/ethnicity (0.26, 95% CI = 0.08–0.85).
Overall Survival, Responses
The first preplanned interim overall survival analysis suggested a benefit with everolimus treatment (HR = 0.64, P = .037; boundary for significance = .0002). Data were not mature enough to permit estimate of median overall survival; Kaplan-Meier estimates for overall survival at the 25th percentile (25% of patients having survival events) were 23.7 months vs 16.5 months.
Objective response occurred in 2% vs 1% of patients, and disease stabilization occurred in 81% vs 64%. Among assessable patients, tumor shrinkage was observed in 64% vs 26%.
The most common treatment-related adverse events of any grade in the everolimus group were stomatitis (63% vs 19%), diarrhea (31% vs 16%), and fatigue (31% vs 24%). The most common grade 3 or 4 adverse events were stomatitis (9% vs 0%), diarrhea (7% vs 2%), infections (7% vs 0%), and anemia (4% vs 1%). Noninfectious pneumonitis occurred in 16% of the everolimus group (grade 3 in 1%). Treatment discontinuation due to drug-related grade 3 or 4 adverse events occurred in 12% vs 3%.
Death occurred during or within 30 days of discontinuing study treatment in seven everolimus patients (3.5%) and three placebo patients (3.1%). Three deaths in the everolimus group (1.5%; due to respiratory failure, septic shock, and cardiac failure) and two deaths in the placebo group (2.0%; due to lung infection and dyspnea) were not attributed to disease progression.
The investigators concluded: “Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.” ■
Disclosure: The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit www.thelancet.com.
1. Yao JC, Fazio N, Singh S, et al: Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, placebo-controlled, phase 3 study. Lancet 387:968-972, 2016.