Dr Nathan on the Mechanism of Action of Roginolisib in Metastatic Uveal Melanoma

"For patients [with uveal melanoma], we struggle to [maintain long-term disease control], and we know that [these] tumors have an immunosuppressed microenvironment. Early data [with roginolisib] show that it appears to change the immune microenvironment in cancers to be more activated and less suppressed."

Paul Nathan, MBBS, PhD, MRCP, a consultant medical oncologist at Mount Vernon Cancer Centre in England, detailed the mechanism of action of roginolisib and discusses the rationale for its ongoing development in metastatic uveal melanoma.

Roginolisib is a novel non-ATP competitive allosteric modulator of PI3Kδ, which is an isoform of the PI3K enzyme. Early data suggest that roginolisib changes the immune microenvironment in cancers, making it more activated and less suppressed. These observations include a reduction in T-regulatory (Treg) cell infiltrate and changes in myeloid-derived suppressor cells.

This mechanism is particularly relevant to research in uveal melanoma, as these tumors are known to have an immunosuppressed microenvironment. Early data involving roginolisib in uveal melanoma suggest an association with the reversal of Treg-to-CD8 ratios. Furthermore, early-phase clinical studies have shown signs of clinical benefit with roginolisib. In the two-part phase 1 DIONE-01 study (NCT04328844), the median overall survival (OS) was 16 months among and he median progression-free survival was 5 months in patients with uveal melanoma across both cohorts (n = 29). Furthermore, roginolisib was well tolerated at the recommended phase 2 dose of 80 mg; no immune-mediated or dose-limiting toxicities were reported and no dose modifications were required. Of note, the agent demonstrated long-term tolerability, with treatment durations extending up to 4.5 years.

Roginolisib is currently being evaluated in the ongoing randomized phase 2 OCULE-01 trial (NCT06717126), Nathan noted. This study is comparing roginolisib against the standard of care for patients who have experienced progression after receiving prior immunotherapy. The trial's primary end point is overall survival, which Nathan described as a robust end point. Sites for the OCULE-01 trial have recently been opened across Europe, he concluded.