TY - JOUR
T1 - Relationship between metabolic toxicity and efficacy of everolimus in patients with neuroendocrine tumors
T2 - A pooled analysis from the randomized, phase 3 RADIANT-3 and RADIANT-4 trials
AU - Fazio, Nicola
AU - Carnaghi, Carlo
AU - Buzzoni, Roberto
AU - Valle, Juan W.
AU - Herbst, Fabian
AU - Ridolfi, Antonia
AU - Strosberg, Jonathan
AU - Kulke, Matthew H.
AU - Pavel, Marianne E.
AU - Yao, James C.
N1 - Funding Information:
The study was sponsored by Novartis Pharmaceuticals Corporation.
Funding Information:
Nicola Fazio is on the steering committees for Novartis, Ipsen, Merck Serono, MSD, Pharmacyclics, Incyte, Halozyme, Roche, Astellas, Pfizer, FivePrime, and BeiGene; is an advisory board member and a public speaker for Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications, MSD, Sanofi‐Aventis, and Wren Laboratories Europe. Juan W. Valle reports personal fees from Agios, AstraZeneca, Debiopharm, Delcath Systems, Genoscience Pharma, Imaging Equipment Limited, Incyte, Ipsen, Keocyt, Merck, Mundipharma EDO, Novartis, NuCana, PCI Biotech, Pieris Pharmaceuticals, Pfizer, QED, Servier, and Wren Laboratories; grants from NuCana and Servier; and nonfinancial support from NuCana and Pfizer outside the submitted work. Antonio Ridolfi is an employee of Novartis SAS. Jonathan Strosberg reports personal fees from Novartis, Ipsen, and Lexicon outside the submitted work. Marianne E. Pavel reports personal and other fees from Novartis. James C. Yao reports personal fees from Advanced Accelerator Applications, Chiasma, Crinetics, Hutchison MediPharma, Ipsen, Novartis, and Tarveda outside the submitted work. The other authors made no disclosures.
Publisher Copyright:
© 2021 American Cancer Society
PY - 2021/8/1
Y1 - 2021/8/1
N2 - BACKGROUND: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors such as everolimus. This post hoc pooled analysis assessed the potential impact of these events on the efficacy of everolimus. METHODS: Patients with advanced, low- or intermediate-grade pancreatic, gastrointestinal, or lung neuroendocrine tumors received either oral everolimus at 10 mg/d or a placebo in the RAD001 in Advanced Neuroendocrine Tumors 3 (RADIANT-3) and RAD001 in Advanced Neuroendocrine Tumors 4 (RADIANT-4) trials. A landmark progression-free survival (PFS) analysis by central review was performed for patients treated for at least 16 weeks (n = 308) and according to the occurrence of any-grade adverse events (AEs) within this treatment period. RESULTS: The overall PFS with everolimus from the pooled analysis was 11.4 months (95% confidence interval, 11.01-13.93 months), which was consistent with the findings of RADIANT-3 and RADIANT-4. Overall, 19.1% and 9.8% of patients in RADIANT-3 and 11.9% and 6.4% of patients in RADIANT-4 developed any-grade hyperglycemia and hypercholesterolemia, respectively (regardless of the study drug). The duration of everolimus exposure was longer in patients who developed these AEs versus patients without these AEs. Overall, 308 patients were exposed to treatment for at least 16 weeks (hyperglycemia, 39 of 269 patients; hypercholesterolemia, 20 of 288 patients). No association was observed between the development of these AEs and PFS (18.8 and 14.1 months with and without hyperglycemia, respectively, and 14.1 and 14.8 months with and without hypercholesterolemia, respectively). CONCLUSIONS: Although limitations apply because of the small number of AEs observed, there was no significant impact of these AEs on PFS; this suggests similar efficacy in the presence or absence of these events.
AB - BACKGROUND: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors such as everolimus. This post hoc pooled analysis assessed the potential impact of these events on the efficacy of everolimus. METHODS: Patients with advanced, low- or intermediate-grade pancreatic, gastrointestinal, or lung neuroendocrine tumors received either oral everolimus at 10 mg/d or a placebo in the RAD001 in Advanced Neuroendocrine Tumors 3 (RADIANT-3) and RAD001 in Advanced Neuroendocrine Tumors 4 (RADIANT-4) trials. A landmark progression-free survival (PFS) analysis by central review was performed for patients treated for at least 16 weeks (n = 308) and according to the occurrence of any-grade adverse events (AEs) within this treatment period. RESULTS: The overall PFS with everolimus from the pooled analysis was 11.4 months (95% confidence interval, 11.01-13.93 months), which was consistent with the findings of RADIANT-3 and RADIANT-4. Overall, 19.1% and 9.8% of patients in RADIANT-3 and 11.9% and 6.4% of patients in RADIANT-4 developed any-grade hyperglycemia and hypercholesterolemia, respectively (regardless of the study drug). The duration of everolimus exposure was longer in patients who developed these AEs versus patients without these AEs. Overall, 308 patients were exposed to treatment for at least 16 weeks (hyperglycemia, 39 of 269 patients; hypercholesterolemia, 20 of 288 patients). No association was observed between the development of these AEs and PFS (18.8 and 14.1 months with and without hyperglycemia, respectively, and 14.1 and 14.8 months with and without hypercholesterolemia, respectively). CONCLUSIONS: Although limitations apply because of the small number of AEs observed, there was no significant impact of these AEs on PFS; this suggests similar efficacy in the presence or absence of these events.
KW - adverse events
KW - everolimus
KW - landmark analysis
KW - mammalian target of rapamycin (mTOR) inhibitors
KW - RAD001 in Advanced Neuroendocrine Tumors 3 (RADIANT-3)
KW - RAD001 in Advanced Neuroendocrine Tumors 4 (RADIANT-4)
KW - targeted therapy
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U2 - 10.1002/cncr.33540
DO - 10.1002/cncr.33540
M3 - Article
C2 - 33857327
AN - SCOPUS:85104354288
SN - 0008-543X
VL - 127
SP - 2674
EP - 2682
JO - Cancer
JF - Cancer
IS - 15
ER -