title: A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.
abstract: BACKGROUND
  Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy.
  
  
  METHODS
  Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc.
  
  
  RESULTS
  A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations.
  
  
  CONCLUSIONS
  The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society.
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Drabkin
authors.affiliation: Florida Cancer Specialists, Fort Myers, Florida.
authors.forename: James A
authors.initials: JA
authors.lastname: Reeves
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.affiliation: Lpath Inc, San Diego, California.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hazel
authors.affiliation: Lpath Inc, San Diego, California.
authors.forename: Dario A
authors.initials: DA
authors.lastname: Paggiarino
authors.affiliation: Lpath Inc, San Diego, California.
authors.forename: Jon
authors.initials: J
authors.lastname: Wojciak
authors.affiliation: Lpath Inc, San Diego, California.
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.affiliation: Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D008246:Lysophospholipids; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C060506:sphingosine 1-phosphate; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D013110:Sphingosine; C000619670:sonepcizumab
keywords: renal cell carcinoma; resistance; sonepcizumab; sphingosine-1-phosphate (S1P)