Two papers published in Nature Communications identified a distinct conformation-selective mechanism of action for roginolisib, an investigational phosphoinositide 3-kinase delta (PI3Kδ) inhibitor developed by Netherlands-based iOnctura, and reported Phase I clinical findings including median overall survival (OS) of 18.4 months in 29 patients with metastatic uveal melanoma (mUM) at the February 2026 data cutoff.
The structural study, conducted by researchers at the University of Geneva and Max Planck Institute of Biophysics, found that roginolisib binds within the PI3Kδ ATP-binding pocket while stabilizing its C-terminal helix kα12 in an inactive conformation. Using X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the researchers identified a binding mechanism distinct from that of the approved PI3Kδ inhibitor idelalisib. In ex vivo chronic lymphocytic leukemia (CLL) samples, roginolisib produced more sustained suppression of the downstream signaling molecule PIP3 than idelalisib, including activity in samples from patients refractory to both ibrutinib and venetoclax.
The separate first-in-human study (NCT04328844) enrolled 44 patients with advanced solid or hematological malignancies, including 29 with mUM. No dose-limiting toxicities or treatment-related dose modifications were reported, while Grade 3 or higher treatment-related toxicities occurred in three patients (6.8%). Median OS in the mUM population was initially estimated at 20.8 months in December 2023 and was 18.4 months (95% CI, 9.66–29.47) at the February 2026 cutoff. The investigators compared survival with approximately seven months reported in historical cohorts receiving second- or third-line treatment, although the study had no randomized control arm. Pharmacodynamic analyses also found reduced regulatory T-cell abundance, increased activated CD8+ T cells, and elevated circulating interleukin-15 (IL-15).