William P Tew1, Michael W Sill2, Joan L Walker3, Angeles Alvarez Secord4, Albert J Bonebrake5, Jeanne M Schilder6, Ashley Stuckey7, Laurel Rice8, Krishnansu S Tewari9, Carol A Aghajanian10. 1. Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America. Electronic address: teww@mskcc.org. 2. NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park, Buffalo, NY 14263, United States of America. Electronic address: msill@gogstats.org. 3. Department of Gynecologic Oncology, The Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States of America. Electronic address: joan-walker@ouhsc.edu. 4. Dept. of Obstetrics/Gynecology, Division of Gynecology Oncology, Duke University Medical Center, Durham, NC 27710, United States of America. Electronic address: secor002@mc.duke.edu. 5. Cancer Research for the Ozarks-Cox Health, Ferrell_Duncan Clinic GYN-ONC, Springfield, MO 65807, United States of America. Electronic address: albert.bonebrake@coxhealth.com. 6. Indiana University Medical Center, Cancer Pavilion - Section of GYN Oncology, Indianapolis, IN 46202, United States of America. Electronic address: jschilde@iupui.edu. 7. Women and Infants Hospital, Program in Women's Oncology, Providence, RI 02905, United States of America. Electronic address: astuckey@wihri.org. 8. University of Wisconsin, Obstetrics & Gynecology, Division of Gyn/Oncology, Madison, WI 53792, United States of America. Electronic address: lwrice@wisc.edu. 9. The Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, CA 92868, United States of America. Electronic address: ktewari@uci.edu. 10. Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America. Electronic address: aghajanc@mskcc.org.
Abstract
PURPOSE:Bevacizumab (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 METHODS: Eligible 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. RESULTS:150 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. CONCLUSION: The 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.
RCT Entities:
PURPOSE:Bevacizumab (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 METHODS: Eligible OCpatients 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. RESULTS: 150 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. CONCLUSION: The 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.
Authors: Shogo Shigeta; Goldie Y L Lui; Reid Shaw; Russell Moser; Kay E Gurley; Grace Durenberger; Rachele Rosati; Robert L Diaz; Tan A Ince; Elizabeth M Swisher; Carla Grandori; Christopher J Kemp Journal: Mol Cancer Ther Date: 2021-01-28 Impact factor: 6.009
Authors: Luigi Carlo Turco; Gabriella Ferrandina; Virginia Vargiu; Serena Cappuccio; Anna Fagotti; Giuseppina Sallustio; Giovanni Scambia; Francesco Cosentino Journal: Ann Transl Med Date: 2020-12
Authors: Eleftherios P Samartzis; S Intidhar Labidi-Galy; Michele Moschetta; Mario Uccello; Dimitrios R Kalaitzopoulos; J Alejandro Perez-Fidalgo; Stergios Boussios Journal: Ann Transl Med Date: 2020-12