A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.
BACKGROUND
Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I-II study assessed the safety and efficacy of co-administering everolimus with imatinib in imatinib-resistant GIST.


METHODS
In phase I, patients received imatinib (600/800 mg/day) combined with weekly (20 mg) or daily (2.5/5.0 mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5 mg plus imatinib 600 mg/day. Primary end point was 4-month progression-free survival (PFS).


RESULTS
Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.


CONCLUSIONS
Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST.
Schöffski
P
P
Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be.
Reichardt
P
P
Department of Hematology and Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Blay
J-Y
JY
Department of Oncology, Centre Leon Berard, Lyon, France.
Dumez
H
H
Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
Morgan
J A
JA
Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ray-Coquard
I
I
Department of Oncology, Centre Leon Berard, Lyon, France.
Hollaender
N
N
Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
Jappe
A
A
Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
Demetri
G D
GD
Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016879:Salvage Therapy; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000068338:Everolimus; D020123:Sirolimus