Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial

Catherine Lombard-Bohas, James C Yao, Timothy Hobday, Eric Van Cutsem, Edward M Wolin, Ashok Panneerselvam, Sotirios Stergiopoulos, Manisha H Shah, Jaume Capdevila, Rodney Pommier, Catherine Lombard-Bohas, James C Yao, Timothy Hobday, Eric Van Cutsem, Edward M Wolin, Ashok Panneerselvam, Sotirios Stergiopoulos, Manisha H Shah, Jaume Capdevila, Rodney Pommier

Abstract

Objective: The aim of this study was to evaluate efficacy and safety of everolimus in patients with pancreatic neuroendocrine tumors (pNET) by prior chemotherapy use in the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3).

Methods: Patients with advanced, progressive, low- or intermediate-grade pNET were prospectively stratified by prior chemotherapy use and World Health Organization performance status and were randomly assigned (1:1) to everolimus 10 mg/d (n = 207) or placebo (n = 203).

Results: Of the 410 patients, 204 (50%) were naive to chemotherapy (chemonaive). Baseline characteristics were similar for patients with or without prior chemotherapy. Everolimus significantly prolonged median progression-free survival regardless of prior chemotherapy use (prior chemotherapy: 11.0 vs 3.2 months; hazard ratio, 0.34; 95% confidence interval, 0.25-0.48; P < 0.0001) (chemonaive: 11.4 vs 5.4 months; hazard ratio, 0.42; 95% confidence interval, 0.29-0.60; P < 0.0001). Stable disease was the best overall response in 73% of everolimus-treated patients (151/207). The most common drug-related adverse events included stomatitis (60%-69%), rash (47%-50%), and diarrhea (34%).

Conclusions: As more treatment options become available, it is important to consider the goals of treatment and to identify patients who would potentially benefit from a specific therapy. Findings from this planned subgroup analysis suggest the potential for first-line use of everolimus in patients with advanced pNET.

Trial registration: ClinicalTrials.gov NCT00510068.

Figures

FIGURE 1
FIGURE 1
Progression-free survival assessed by local investigators for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B).
FIGURE 2
FIGURE 2
Progression-free survival review by the central adjudication committee for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B).
FIGURE 3
FIGURE 3
Percentage change from baseline in size of target lesion (waterfall plot) for both treatment arms (everolimus and placebo) in the patients who received prior chemotherapy (A) and did not receive prior chemotherapy (B). A, Data for 11 patients with lesions that could be evaluated in the everolimus arm and 24 in the placebo arm were not included in the analysis for the following reasons: 6 in the everolimus arm (6.1%) and 16 in the placebo arm (17.0%) showed a change in the available target lesion that contradicted the overall response of PD. One patient in the everolimus arm (1.0%) showed a change in the available target lesion, but the overall response was UNK. The change in the target lesion could not be assessed in 4 patients in the everolimus arm (4.0%) and 8 in the placebo arm (8.5%). B, For the chemonaive patients, data for 19 patients with lesions that could be evaluated in the everolimus arm and 18 in the placebo arm were not included in the analysis for the following reasons: 8 in the everolimus arm (8.7%) and 12 in the placebo arm (12.6%) showed a change in the available target lesion that contradicted the overall response of PD. The change in the target lesion could not be assessed in 11 patients in the everolimus arm (12.0%) and 6 in the placebo arm (6.3%). PD, progressive disease; UNK, unknown.

References

    1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26: 3063– 3072.
    1. Phan AT, Yao JC. Neuroendocrine tumors: novel approaches in the age of targeted therapy. Oncology. 2008; 22: 1617– 1623; discussion 1623–1624, 1629.
    1. Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008; 19: 1727– 1733.
    1. Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007; 14: 3492– 3500.
    1. Yao J, Phan AT. Optimising therapeutic options for patients with advanced pancreatic neuroendocrine tumours. Eur Oncol Haematol. 2012; 8: 217– 223.
    1. US Food and Drug Administration: drugs @ FDA. Available at: Accessed July 22, 2013.
    1. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992; 326: 519– 523.
    1. Pavel M, Baudin E, Couvelard A, et al. Barcelona Consensus Conference participants: ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012; 95: 157– 176.
    1. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008; 26: 4311– 4318.
    1. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010; 28: 69– 76.
    1. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 514– 523.
    1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000; 92: 205– 216.
    1. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at: Accessed July 22, 2013.
    1. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980; 303: 1189– 1194.
    1. Eriksson B, Skogseid B, Lundqvist G, et al. Medical treatment and long-term survival in a prospective study of 84 patients with endocrine pancreatic tumors. Cancer. 1990; 65: 1883– 1890.
    1. Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999; 86: 944– 948.
    1. McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol. 2004; 27: 485– 488.
    1. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004; 22: 4762– 4771.
    1. Delaunoit T, Ducreux M, Boige V, et al. The doxorubicin-streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma: a judicious option? Eur J Cancer. 2004; 40: 515– 520.
    1. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011; 117: 268– 275.
    1. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006; 24: 401– 406.
    1. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-Methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009; 15: 338– 345.
    1. Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012; 30: 2963– 2968.
    1. Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol. 2011; 29: 934– 943.
    1. Hadoux J, Ducreux M. Bevacizumab and subtype-adapted chemotherapy backbone in neuroendocrine tumors. J Clin Oncol. 2013; 31: 976– 977.
    1. Kulke MH. Systemic therapy for advanced pancreatic neuroendocrine tumors. Semin Oncol. 2013; 40: 75– 83.
    1. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 501– 513.
    1. Wolin EM. Long-term, open-label everolimus in patients with pancreatic neuroendocrine tumors: two case presentations from RADIANT-3 [abstract]. International Society of Gastrointestinal Oncology 2012 Gastrointestinal Oncology Conference. Available at: Accessed July 22, 2013.
    1. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011; 378: 2005– 2012.

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