OncoTargets and Therapy (Oct 2017)

Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4

  • Buzzoni R,
  • Carnaghi C,
  • Strosberg J,
  • Fazio N,
  • Singh S,
  • Herbst F,
  • Ridolfi A,
  • Pavel ME,
  • Wolin EM,
  • Valle JW,
  • Oh DY,
  • Yao JC,
  • Pommier R

Journal volume & issue
Vol. Volume 10
pp. 5013 – 5030

Abstract

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Roberto Buzzoni,1 Carlo Carnaghi,2 Jonathan Strosberg,3 Nicola Fazio,4 Simron Singh,5 Fabian Herbst,6 Antonia Ridolfi,7 Marianne E Pavel,8 Edward M Wolin,9 Juan W Valle,10 Do-Youn Oh,11 James C Yao,12 Rodney Pommier13 1IRCCS Foundation, National Institute of Tumors, Milan, Italy; 2Humanitas Clinical and Research Center, Rozzano, Italy; 3Moffitt Cancer Center, Tampa, FL, USA; 4European Institute of Oncology, Milan, Italy; 5Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 6Novartis AG, Basel, Switzerland; 7Novartis Pharma S.A.S., Rueil-Malmaison, France; 8Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 9Montefiore Einstein Center for Cancer Care, Bronx, NY, USA; 10Institute of Cancer Sciences, University of Manchester, The Christie Hospital, Manchester, UK; 11Seoul National University Hospital, Seoul, Republic of Korea; 12University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 13Oregon Health & Science University, Portland, OR, USA Background: Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P<0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. Trial registration: ClinicalTrials.gov identifier: NCT01524783. Patients and methods: Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. Results: A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37–0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36–0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19–0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42–0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24–0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42–0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%–65%), fatigue (27%–35%), and diarrhea (24%–34%) among the subgroups. Conclusion: These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET. Keywords: neuroendocrine tumors, progression-free survival, somatostatin analogs, chemotherapy, PRRT

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