A phase 2 study of the sphingosine‐1‐phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma. Issue 4 (11th October 2016)

• Record Type: Journal Article
• Authors: Pal, Sumanta K.; Drabkin, Harry A.; Reeves, James A.; Hainsworth, John D.; Hazel, Susan E.; Paggiarino, Dario A.; Wojciak, Jon; Woodnutt, Gary; Bhatt, Rupal S.
• Is Part Of: Cancer. Volume 123:Issue 4(2017)
• Page Start: 576
• Page End: 582
• Publication Date: 2016-10-11
• Subjects: renal cell carcinoma -- resistance -- sonepcizumab -- sphingosine‐1‐phosphate (S1P); Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.30393
• Languages: English
• ISSNs: 0008-543X

Abstract

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 . Abstract : In the current study, the authors assess the activity of sonepcizumab, a first‐in‐class sphingosine‐1‐phosphate inhibitor, within the context of previously treated patients with renal cell carcinoma. The encouraging overall survival and safety profile associated with this agent make it valid for further study.