Sonepcizumab Failed PFS Endpoint, but Had Promising OS, in Metastatic RCC

A phase II study of sonepcizumab has failed to meet its primary progression-free survival endpoint in patients with metastatic renal cell carcinoma.

A phase II study of the sphingosine-1-phosphate (S1P) antibody sonepcizumab has failed to meet its primary progression-free survival (PFS) endpoint in patients with metastatic renal cell carcinoma (mRCC); however, researchers were encouraged by the overall survival (OS) and safety profile seen in the trial, and called for “further investigation of the agent in combination with vascular endothelial growth factor (VEGF)-directed agents or checkpoint inhibitors.”

According to the study published in Cancer, upregulation of S1P may mediate resistance to VEGF-directed therapies and inhibit antitumor immunity. This study was designed to see if the S1P inhibitor sonepcizumab had activity in patients with mRCC with a history of prior VEGF-directed therapy.

“Although the primary endpoint of the current phase II study was not achieved, sonepcizumab demonstrated an encouraging OS of > 20 months in a heavily pretreated population of patients with mRCC,” wrote Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues. “Acknowledging the caveats of cross-trial comparisons and the limitations of the current study (ie, small sample size), these data are comparable to survival observed in phase III experiences with cabozantinib (18.7 months) and nivolumab (25.0 months), which both recently were approved for patients with mRCC previously treated with VEGF-directed therapies.”

The researchers enrolled 40 patients with mRCC who had been on a median of 3 prior therapies; 78% of patients had intermediate-risk disease. Patients were initially enrolled at a dose of 15-mg/kg sonepcizumab weekly. The treatment dose was later modified from 15 mg/kg to 24 mg/kg.

Twelve of the 22 patients enrolled at the higher dose did not demonstrate the study endpoint of PFS at 2 months. Therefore, the researchers terminated the study. At that time, the median PFS for the intent-to-treat population was 2.2 months and the median OS was 21.7 months. Ten percent of patients achieved a partial response at some point during the study.

The researchers listed several possible reasons for the limited PFS benefit seen in the study. Among them, they wrote that “the phase III studies of nivolumab and cabozantinib in patients with mRCC allowed for up to 2 prior therapies and unlimited prior therapies, respectively. However, in both studies, approximately 75% of patients had received only 1 prior treatment. In the current study, a median of 2 prior therapies was rendered, and therefore we might anticipate a shorter PFS.”

There were no grade 3/4 treatment-related adverse events observed in > 5% of patients. The most frequent grade 1/2 adverse events were fatigue, weight gain, constipation, and nausea.

The researchers acknowledged that given the number of agents approved for RCC recently, it is hard to see sonepcizumab as a monotherapy for this patient population.

“However, the favorable safety profile of sonepcizumab suggests that the agent could be explored in combination with currently approved agents for mRCC,” they noted.