Roginolisib Shows No Dose-Limiting Toxicities in Metastatic Uveal Melanoma

No dose-limiting toxicities were observed with continuous once-daily roginolisib (IOA-244; iOnctura), an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, in a first-in-human trial (NCT04328844) that included an expansion cohort in metastatic uveal melanoma (mUM), according to results published in Nature Communications.

The authors described roginolisib as a selective inhibitor that does not compete with ATP and holds PI3Kδ in an inactive state, unlike earlier ATP-competitive PI3Kδ inhibitors. In Part A, 24 patients with solid tumors or follicular non-Hodgkin lymphoma received escalating doses from 10mg to 80mg; in Part B, 20 mostly pretreated patients with mUM received 80mg daily. Safety was the primary endpoint, and the investigators identified 80mg once daily as the biologically effective dose.

Among 44 patients, drug-related grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 3 (6.8%): decreased platelet count, increased lipase, and decreased neutrophil count. All were transient and resolved during treatment. All-cause grade 3 or higher TEAEs occurred in 31.8% of patients. Serious adverse events in 7 patients (15.9%) were all considered unrelated to roginolisib. One patient with mUM discontinued treatment because of grade 2 uveitis.

Among 27 patients with mUM evaluable for efficacy, 1 had a partial response (3.7%) and 20 had stable disease as best overall response; median progression-free survival was 5.3 months. Median overall survival (OS) in patients with mUM was 20.8 months at the December 2023 data cutoff, 15.9 months at a December 2024 cutoff, and 18.4 months (95% CI, 9.66-29.47) at a February 2026 cutoff. In an exploratory post hoc analysis that the authors noted carries potential bias, median OS was 28.5 months among patients with stable disease at week 16 vs 12.3 months among those with progressive disease.

The authors acknowledged the small number of patients. They noted that, as with most single-arm studies with a low response rate and long OS relative to historical data, it remains uncertain whether roginolisib has sufficient single-agent activity in mUM. A randomized phase 2 trial, OCULE-01 (NCT06717126), comparing roginolisib with investigator’s choice therapy in patients who progressed on prior immunotherapy, has closed recruitment.

Source: Di Giacomo AM, Simonelli M, Losurdo A, et al. The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial. Nat Commun. 2026;17(1):10219. doi:10.1038/s41467-026-77358-7