The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial.
Anna Maria Di Giacomo, Matteo Simonelli, Agnese Losurdo et al.
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In 30 seconds
This first-in-human, phase I dose-escalation and expansion trial evaluated continuous daily roginolisib in patients with solid and haematologic malignancies. Twenty-four patients received escalating doses; a further 20, mostly pre-treated patients with metastatic uveal melanoma, received a dose associated with greater than 90% continuous PI3Kδ inhibition. No dose-limiting toxicities or drug-related toxicities requiring dose modification were reported. In the metastatic uveal melanoma group, median overall survival was 18.4 months at the February 2026 data cut-off. Roginolisib was associated with changes in immune-cell measures, including reduced regulatory T cells and increased activated CD8+ T cells.
Key findings
- No dose-limiting toxicities or drug-related toxicities requiring dose modification were observed; grade 3 or higher toxicities occurred in 3/44 patients (6.8%).
- Median overall survival in metastatic uveal melanoma was 20.8 months at the December 2023 data cut-off and 18.4 months at the February 2026 cut-off.
- Among metastatic uveal melanoma patients with stable disease at Week 16, median overall survival was 28.5 months, compared with 12.3 months for those who had progressed.
- Treatment was associated with decreased regulatory T-cell abundance, increased activated CD8+ T cells, and increased soluble plasma IL-15.
Why it matters
The trial provides early clinical safety, pharmacokinetic and immune-profile data for a PI3Kδ inhibitor with a distinct allosteric mechanism. The reported survival outcomes in a mostly pre-treated metastatic uveal melanoma group are clinically relevant signals, while the association between Week 16 disease status and survival underscores the importance of interpreting these results in the context of an early-phase study.
What to keep in mind
This was a small, non-randomised first-in-human phase I study, with 20 patients in the metastatic uveal melanoma group; survival findings cannot establish comparative treatment benefit.