Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia

Combined Subgroup Analyses of the RECORD-1 and REACT Trials

Petri Bono, Stephane Oudard, I. Bodrogi, Thomas E. Hutson, Bernard Escudier, Jean Pascal Machiels, John A. Thompson, Robert A. Figlin, Alain Ravaud, Mert Basaran, Camillo Porta, Sergio Bracarda, Thomas Brechenmacher, Chinjune Lin, Maurizio Voi, Viktor Grunwald, Robert J. Motzer

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

Original languageEnglish
JournalClinical Genitourinary Cancer
DOIs
Publication statusAccepted/In press - Nov 29 2015

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Compassionate Use Trials
Hypercholesterolemia
Renal Cell Carcinoma
Hyperglycemia
Clinical Trials
Disease-Free Survival
Everolimus
Lymphopenia
Sirolimus
Patient Safety
Vascular Endothelial Growth Factor A
Anemia

Keywords

  • Association of AEs and clinical efficacy
  • Class effects of mTOR inhibition
  • MTOR inhibitor
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia : Combined Subgroup Analyses of the RECORD-1 and REACT Trials. / Bono, Petri; Oudard, Stephane; Bodrogi, I.; Hutson, Thomas E.; Escudier, Bernard; Machiels, Jean Pascal; Thompson, John A.; Figlin, Robert A.; Ravaud, Alain; Basaran, Mert; Porta, Camillo; Bracarda, Sergio; Brechenmacher, Thomas; Lin, Chinjune; Voi, Maurizio; Grunwald, Viktor; Motzer, Robert J.

In: Clinical Genitourinary Cancer, 29.11.2015.

Research output: Contribution to journalArticle

Bono, P, Oudard, S, Bodrogi, I, Hutson, TE, Escudier, B, Machiels, JP, Thompson, JA, Figlin, RA, Ravaud, A, Basaran, M, Porta, C, Bracarda, S, Brechenmacher, T, Lin, C, Voi, M, Grunwald, V & Motzer, RJ 2015, 'Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials', Clinical Genitourinary Cancer. https://doi.org/10.1016/j.clgc.2016.04.011
Bono, Petri ; Oudard, Stephane ; Bodrogi, I. ; Hutson, Thomas E. ; Escudier, Bernard ; Machiels, Jean Pascal ; Thompson, John A. ; Figlin, Robert A. ; Ravaud, Alain ; Basaran, Mert ; Porta, Camillo ; Bracarda, Sergio ; Brechenmacher, Thomas ; Lin, Chinjune ; Voi, Maurizio ; Grunwald, Viktor ; Motzer, Robert J. / Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia : Combined Subgroup Analyses of the RECORD-1 and REACT Trials. In: Clinical Genitourinary Cancer. 2015.
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abstract = "Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results: In RECORD-1, 12{\%} (33 of 277) and 20{\%} (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6{\%} (78 of 1367) and 1{\%} (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82{\%}/68{\%} of patients with hyperglycemia and 75{\%}/71{\%} of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.",
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T2 - Combined Subgroup Analyses of the RECORD-1 and REACT Trials

AU - Bono, Petri

AU - Oudard, Stephane

AU - Bodrogi, I.

AU - Hutson, Thomas E.

AU - Escudier, Bernard

AU - Machiels, Jean Pascal

AU - Thompson, John A.

AU - Figlin, Robert A.

AU - Ravaud, Alain

AU - Basaran, Mert

AU - Porta, Camillo

AU - Bracarda, Sergio

AU - Brechenmacher, Thomas

AU - Lin, Chinjune

AU - Voi, Maurizio

AU - Grunwald, Viktor

AU - Motzer, Robert J.

PY - 2015/11/29

Y1 - 2015/11/29

N2 - Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

AB - Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

KW - Association of AEs and clinical efficacy

KW - Class effects of mTOR inhibition

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KW - Targeted therapy

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