An encouraging OS and favorable safety profile warrant further investigation of sonepcizumab in combination with vascular endothelial growth factor–directed agents or checkpoint inhibitors for the treatment of metastatic renal cell carcinoma, according to results of a phase 2 study published in Cancer.
However, the study did not achieve its primary endpoint of 2-month PFS.
Sumanta K. Pal
“Despite the modest PFS (mean of 2.2 months) associated with sonepcizumab, the encouraging OS associated with this agent in a heavily pretreated population makes it worthy of further study,” Sumanta K. Pal, MD, co-director of City of Hope’s Kidney Cancer Program and a HemOnc Today Editorial Board member, and colleagues wrote.
Despite multiple advances in the treatment of metastatic renal cell carcinoma (mRCC), a vast majority of patients remain incurable. Because upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)–directed therapy, researchers have sought to develop anti-S1P therapies.
Pal and colleagues assessed the activity of sonepcizumab (LT1009, Lpath Inc), a first-in-class inhibitor of S1P, in 40 patients (median age, 66 years; range, 48-80) with mRCC who had a history of VEGF–directed therapy. Patients had received a median of three (range, 1-5) prior therapies, and 78% of patients had intermediate-risk disease, according to second-line International Metastatic Renal Cell Carcinoma Database Consortium criteria.
PFS served as the study’s primary endpoint. Additional endpoints included response rate and safety. Researchers also conducted a post-hoc OS analysis.
Seventeen patients were initially enrolled to receive a 15-mg/kg IV dose of sonepcizumab weekly. However, all other patients were enrolled at a 24-mg/kg IV dose due to favorable pharmacodynamics observed in a concurrent phase 1 study.
Because 12 of the 22 patients enrolled at the 24-mg/kg level did not achieve 2-month PFS, no additional patients were enrolled, and the study was terminated.
“It was unfortunate, but I hope folks in the field look further into what we were able to show and give it a second chance,” Pal told HemOnc Today.
At this time, researchers evaluated data from patients treated at both dose levels.
The median PFS for the intent-to-treat population was 2.2 months and the median OS was 21.7 months.
Three of the patients were free of disease progression at the time of study termination.
Four of 40 patients (10%) achieved a partial response at any time during the study. Median response duration was 5.9 months (range, 3.8-14.3).The most frequent grade 1 or grade 2 toxicity observed on the study included fatigue (30%), weight gain (18%), constipation (15%) and nausea (15%). No grade 3 or grade 4 treatment-related adverse events occurred in more than 5% of patients.
Pal and colleagues noted that despite the small sample size of the study, the OS data are comparable to that observed in phase 3 experiences with cabozantinib (Cometriq, Exelixis; OS, 18.7 months) and nivolumab (Opdivo, Bristol-Myers Squibb; OS, 25 months), which were recently approved for patients with mRCC previously treated with VEGF–directed therapies.
“In a crowded therapeutic landscape it is hard to envision [sonepcizumab’s] clinical development as a monotherapy,” Pal and colleagues wrote. “However, the favorable safety profile suggests that the agent could be explored in combination with currently approved agents for mRCC.” – by Chuck Gormley
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K. Pal, MD
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Disclosure: Lpath Inc funded this study. Pal reports paid consulting roles with Aveo, Bristol-Myers Squibb, Exelixis, Genentech, GlaxoSmithKline and Pfizer., and honoraria from Astellas Pharma, Medivation and Novartis for work performed outside of the current study. Other researchers report employment with Lpath Inc.