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: Sumanta K Pal, Harry A Drabkin, James A Reeves, John D Hainsworth, Susan E Hazel, Dario A Paggiarino, Jon Wojciak, Gary Woodnutt, Rupal S Bhatt
• Journal: Cancer (Cancer) Vol. 123 Issue 4 Pg. 576-582 (Feb 15 2017) ISSN: 1097-0142 [Electronic] United States
• PMID: 27727447 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © 2016 American Cancer Society.

Chemical References

• Antibodies, Monoclonal
• Biomarkers, Tumor
• DNA-Binding Proteins
• Lysophospholipids
• Nuclear Proteins
• PBRM1 protein, human
• Transcription Factors
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• sphingosine 1-phosphate
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human
• Sphingosine
• sonepcizumab

Topics

• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Biomarkers, Tumor (genetics)
• Carcinoma, Renal Cell (drug therapy, genetics, immunology, pathology)
• DNA-Binding Proteins
• Disease-Free Survival
• Drug-Related Side Effects and Adverse Reactions (pathology)
• Female
• Humans
• Kaplan-Meier Estimate
• Lysophospholipids (antagonists & inhibitors, immunology)
• Male
• Middle Aged
• Neoplasm Metastasis
• Nuclear Proteins (genetics)
• Sphingosine (analogs & derivatives, antagonists & inhibitors, immunology)
• Transcription Factors (genetics)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)