Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163.
OBJECTIVE
To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response.


METHODS
Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response.


RESULTS
The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer.


CONCLUSIONS
Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.
Ellard
Susan L
SL
BC Cancer Agency-Southern Interior, 399 Royal Ave, Kelowna, British Columbia, Canada V1Y 5L3. sellard@bccancer.bc.ca
Clemons
Mark
M
Gelmon
Karen A
KA
Norris
Brian
B
Kennecke
Hagen
H
Chia
Stephen
S
Pritchard
Kathleen
K
Eisen
Andrea
A
Vandenberg
Ted
T
Taylor
Marianne
M
Sauerbrei
Eric
E
Mishaeli
Moshe
M
Huntsman
David
D
Walsh
Wendy
W
Olivo
Martin
M
McIntosh
Lynn
L
Seymour
Lesley
L
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus