A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.
Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%).



This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS).



Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.



The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
José
J
Baselga
H. de Lleida Arnau de Vilanova, Lérida, Spain.
Serafin M
SM
Morales
Institut Jules Bordet, Brussels, Belgium.
Ahmad
A
Awada
Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA.
Joanne L
JL
Blum
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.|Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.
Antoinette R
AR
Tan
Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Marianne
M
Ewertz
Ramon y Cajal University Hospital, Madrid and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Javier
J
Cortes
Massachusetts General Hospital, Boston, MA, USA.
Beverly
B
Moy
Mayo Clinic, Rochester, MN, USA.
Kathryn J
KJ
Ruddy
University of Minnesota Masonic Clinical Cancer Center, Minneapolis, MN, USA.
Tufia
T
Haddad
Hospital 12 de Octubre, Madrid, Spain.
Eva M
EM
Ciruelos
Clinique Sainte Elisabeth, Namur, Belgium.
Peter
P
Vuylsteke
Merck & Co., Inc., Kenilworth, NJ, USA.
Scot
S
Ebbinghaus
Merck & Co., Inc., Kenilworth, NJ, USA.
Ellie
E
Im
Merck & Co., Inc., Kenilworth, NJ, USA.
Lamar
L
Eaton
Merck & Co., Inc., Kenilworth, NJ, USA.
Kumudu
K
Pathiraja
Merck & Co., Inc., Kenilworth, NJ, USA.
Christine
C
Gause
Merck & Co., Inc., Kenilworth, NJ, USA.|Checkmate Pharmaceuticals, Cambridge, MA, USA.
David
D
Mauro
Merck & Co., Inc., Kenilworth, NJ, USA.
Mary Beth
MB
Jones
UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., San Francisco, CA, USA. Hope.Rugo@ucsf.edu.
Hope S
HS
Rugo
D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011960:Receptors, Estrogen / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013280:Stomatitis / Q000139:chemically induced / Q000473:pathology*
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047072:Aromatase Inhibitors; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; C515074:ridaforolimus; C569480:dalotuzumab; C056516:exemestane; D020123:Sirolimus
Breast cancer; Dalotuzumab; IGF1R; Ridaforolimus; mTOR