• William P Tew, Michael W Sill, Joan L Walker, SecordAngeles AlvarezAADept. of Obstetrics/Gynecology, Division of Gynecology Oncology, Duke University Medical Center, Durham, NC 27710, United States of America. Electronic address: secor002@mc.duke.edu., Albert J Bonebrake, Jeanne M Schilder, Ashley Stuckey, Laurel Rice, Krishnansu S Tewari, and Carol A Aghajanian.
• Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America. Electronic address: teww@mskcc.org.
• Gynecol. Oncol. 2018 Nov 1; 151 (2): 257-263.

PurposeBevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC).Patients And MethodsEligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response.Results150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash.ConclusionThe combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.Copyright © 2018 Elsevier Inc. All rights reserved.

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