Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer

Gynecol Oncol. 2019 Jun;153(3):555-561. doi: 10.1016/j.ygyno.2019.03.246. Epub 2019 Mar 28.

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.

Keywords: Nintedanib; Ovarian cancer; Peritoneal cancer.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / blood
  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Bevacizumab / therapeutic use
  • Biomarkers, Tumor / blood
  • Carcinoma, Ovarian Epithelial / blood
  • Carcinoma, Ovarian Epithelial / drug therapy*
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Fallopian Tube Neoplasms / blood
  • Fallopian Tube Neoplasms / drug therapy*
  • Female
  • GPI-Linked Proteins / blood
  • Humans
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Interleukin-6 / blood
  • Kaplan-Meier Estimate
  • Middle Aged
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / drug therapy*
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / drug therapy*
  • Peritoneal Neoplasms / blood
  • Peritoneal Neoplasms / drug therapy*
  • Progression-Free Survival
  • Response Evaluation Criteria in Solid Tumors
  • Vascular Endothelial Growth Factor D / blood

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • GPI-Linked Proteins
  • IL6 protein, human
  • Indoles
  • Interleukin-6
  • VEGFD protein, human
  • Vascular Endothelial Growth Factor D
  • Bevacizumab
  • 5'-Nucleotidase
  • NT5E protein, human
  • nintedanib