Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.
Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
James C
JC
Yao
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Marianne
M
Pavel
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Catherine
C
Lombard-Bohas
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Eric
E
Van Cutsem
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Maurizio
M
Voi
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Ulrike
U
Brandt
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Wei
W
He
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
David
D
Chen
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Jaume
J
Capdevila
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Elisabeth G E
EGE
de Vries
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Paola
P
Tomassetti
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Timothy
T
Hobday
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Rodney
R
Pommier
James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX; Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ; Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN; Rodney Pommier, Oregon Health & Science University, Portland, OR; Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland; Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands; Paola Tomassetti, University of Bologna, Bologna, Italy; and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden.
Kjell
K
Öberg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000097:blood / Q000098:blood supply / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000098:blood supply / Q000188:drug therapy*; D011446:Prospective Studies; D015996:Survival Rate; D055815:Young Adult
D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068338:Everolimus