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.
Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be.
P
P
Schöffski
Department of Hematology and Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
P
P
Reichardt
Department of Oncology, Centre Leon Berard, Lyon, France.
J-Y
JY
Blay
Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
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H
Dumez
Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
J A
JA
Morgan
Department of Oncology, Centre Leon Berard, Lyon, France.
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I
Ray-Coquard
Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
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N
Hollaender
Department of Oncology, Novartis Pharma AG, Basel, Switzerland.
A
A
Jappe
Department of General Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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GD
Demetri
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