Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Previously Treated With Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens
Mené sur 71 patients atteints d'un cancer colorectal métastatique réfractaire aux traitements à base d'irinotecan, d'oxaliplatine, de fluoropyrimidine ou bevacizumab, cet essai de phase II évalue l'efficacité et la toxicité de l'everolimus, un inhibiteur de mTOR
Purpose: Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is seen in 40-60% of colorectal cancer (CRC) patients. Everolimus, an oral inhibitor of mTOR, demonstrated efficacy in metastatic CRC (mCRC) patients in phase I studies. Experimental Design: In sequential phase II studies assessing 2 dosing schedules, mCRC patients refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/week (N=99) or 10 mg/d (N=100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses. Results: 71 patients were included in the per protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 months and 4.9 months and 1.8 months and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = .008) and lower DCR (P = .035) compared with those with wild-type KRAS in exploratory biomarker analyses. Conclusions: Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.