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 coadministering everolimus with imatinib in imatinib-resistant GIST. Patients and methods: In phase I, patients received imatinib (600/800mg/day) combined with weekly (20mg) or daily (2.5/5.0mg) 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 2.5mg plus imatinib 600mg/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. Conclusion: 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.