Everolimus Improves Progression-Free Survival in Advanced Neuroendocrine Tumors of the Lung or Gastrointestinal Tract


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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.

Study Details

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%.

Adverse Events

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%.

Everolimus in Neuroendocrine Tumors

  • Everolimus significantly prolonged progression-free survival in patients with advanced nonfunctional neuroendocrine tumors of the lung or gastrointestinal tract.
  • Benefit with everolimus was observed among patients with and without prior somatostatin analog treatment and among those with better prognosis and worse prognosis sites of origin.

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.

Reference

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.



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