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.
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.



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.



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.



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.
Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Finland. Electronic address: Petri.Bono@hus.fi.
Petri
P
Bono
Department of Oncology, Georges Pompidou Hospital, Paris, France.
Stephane
S
Oudard
National Institute of Oncology, Budapest, Hungary.
Istvan
I
Bodrogi
Medical Oncology, US Oncology/Baylor-Sammons Cancer Center, Dallas, TX.
Thomas E
TE
Hutson
Immunotherapy Unit, Gustave Roussy Institute, Villejuif, France.
Bernard
B
Escudier
Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain, Brussels, Belgium.
Jean-Pascal
JP
Machiels
Medical Oncology, Seattle Cancer Care Alliance, Seattle, WA.
John A
JA
Thompson
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Robert A
RA
Figlin
Medical Oncology Hôpital, Saint André CHU, Bordeaux, France.
Alain
A
Ravaud
Institute of Oncology, Istanbul University, Istanbul, Turkey.
Mert
M
Basaran
Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy.
Camillo
C
Porta
Medical Oncology, San Donato Hospital, Istituto Toscano Tumori (ITT), Arezzo, Italy.
Sergio
S
Bracarda
Novartis Pharma S.A.S., Rueil-Malmaison, France.
Thomas
T
Brechenmacher
Novartis Pharmaceuticals, East Hanover, NJ.
Chinjune
C
Lin
Novartis Pharmaceuticals, East Hanover, NJ.
Maurizio
M
Voi
Clinic for Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany.
Viktor
V
Grunwald
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
Robert J
RJ
Motzer
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000453:epidemiology*; D006943:Hyperglycemia / Q000139:chemically induced / Q000453:epidemiology*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D000068338:Everolimus
Association of AEs and clinical efficacy; Class effects of mTOR inhibition; Targeted therapy; mTOR inhibitor