Angeles Alvarez Secord1, Michael McCollum2, Brittany A Davidson3, Gloria Broadwater4, Robert Squatrito2, Laura J Havrilesky3, Anne C Gabel5, Mark D Starr6, J Chris Brady6, Andrew B Nixon6, Linda R Duska5. 1. Division of Gynecologic Oncology, Duke Cancer Institute, United States of America. Electronic address: secor002@mc.duke.edu. 2. Division of Gynecologic Oncology, Virginia Oncology Associates, United States of America. 3. Division of Gynecologic Oncology, Duke Cancer Institute, United States of America. 4. Department of Biostatistics and Bioinformatics, Duke Cancer Institute, United States of America. 5. Division of Gynecologic Oncology, University of Virginia, United States of America. 6. Department of Medicine, Duke Cancer Institute, Durham, NC 27710, United States of America.
Abstract
BACKGROUND: Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer. METHODS: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured. RESULTS: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03). CONCLUSIONS: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.
BACKGROUND:Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer. METHODS: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured. RESULTS: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PDpatients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SDpatients. IL6 was associated with worse PFS (p = 0.03). CONCLUSIONS: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.
Authors: Jung-Min Lee; Christina M Annunziata; John L Hays; Liang Cao; Peter Choyke; Minshu Yu; Daniel An; Ismail Baris Turkbey; Lori M Minasian; Seth M Steinberg; Helen Chen; John Wright; Elise C Kohn Journal: Gynecol Oncol Date: 2020-08-01 Impact factor: 5.482
Authors: Angeles Alvarez Secord; Kirsten Bell Burdett; Kouros Owzar; David Tritchler; Alexander B Sibley; Yingmiao Liu; Mark D Starr; J Chris Brady; Heather A Lankes; Herbert I Hurwitz; Robert S Mannel; Krishnansu S Tewari; David M O'Malley; Heidi Gray; Jamie N Bakkum-Gamez; Keiichi Fujiwara; Matthew Boente; Wei Deng; Robert A Burger; Michael J Birrer; Andrew B Nixon Journal: Clin Cancer Res Date: 2020-01-09 Impact factor: 12.531
Authors: Hossein Taghizadeh; Robert M Mader; Leonhard Müllauer; Stefanie Aust; Stephan Polterauer; Heinz Kölbl; Veronika Seebacher; Christoph Grimm; Alexander Reinthaller; Gerald W Prager Journal: Oncologist Date: 2020-05-08