Roginolisib Demonstrates Preliminary Activity in Metastatic Uveal Melanoma

The conformation-selective PI3Kδ inhibitor roginolisib demonstrated preliminary antitumor activity and a safety profile supporting further evaluation in patients with advanced or metastatic cancers, including metastatic uveal melanoma, according to data from a first-in-human phase 1 study (NCT04328844) published in Nature Communications.^1,2

Findings showed that at the February 2026 data cutoff, patients with metastatic uveal melanoma (n = 27) who received the agent achieved an updated median overall survival (OS) of 18.4 months (95% CI, 9.66-29.47).¹ In the study’s overall efficacy-evaluable population (n = 40), which included patients with uveal melanoma (n = 27), cutaneous melanoma (n = 4), mesothelioma (n = 1), and non-Hodgkin lymphoma/follicular lymphoma (n = 8), the median OS was 28.5 months (95% CI, 11.3-31.8) at a median follow-up of 17.9 months.

“In this patient population [with uveal melanoma], a safe agent like roginolisib is not common, and the length of treatment was remarkable from the very beginning,” Anna Maria Di Giacomo, MD, a professor of medical oncology at the University of Siena and head of the phase 1 clinical trials program at University Hospital of Siena in Italy, stated in a news release.²

What is the mechanism of action of roginolisib?

Roginolisib was developed to inhibit PI3Kδ selectively over the course of continuous dosing.^1,2 According to iOnctura, the company developing the agent, the clinical data support moving forward with randomized trials in uveal melanoma and non–small cell lung cancer.²

Roginolisib binds and stabilizes kα12, the catalytic C-terminal helix of the enzyme, holding PI3Kδ in an inactive conformation, blocking ATP-driven activation, and limiting production of the signaling molecule PIP3.¹

How was the phase 1 study designed?

To enroll in the open-label, nonrandomized study, adult patients needed to have histologically or cytologically confirmed advanced or metastatic cancer, measurable disease, and an ECOG performance status of 0 or 1; patients with non-Hodgkin lymphoma could have an ECOG performance status of 2.^1,3 Investigators focused on patients with metastatic malignant mesothelioma, cutaneous melanoma, and uveal melanoma due to associated overexpression of PI3Kδ.¹

Additional criteria were specific to each disease, such as confirmed metastatic uveal melanoma or previously treated follicular lymphoma. In the lymphoma cohorts, prior treatment with a PI3K inhibitor or a Bruton tyrosine kinase inhibitor was allowed following a 4-week washout period. When feasible, patients were also asked to provide tumor biopsies before and during treatment.

Patients received oral roginolisib once daily. A total of 44 patients were included in the trial, including 24 who enrolled in the dose-escalation portion and 20 with uveal melanoma who enrolled in the expansion portion. Patients with solid tumors received doses ranging from 10 mg to 80 mg, and the 80-mg daily dose was chosen for expansion.^1,2

Safety was the primary end point, with adverse effects (AEs) graded per Common Terminology Criteria for Adverse Events version 5.0. Secondary end points included pharmacokinetics, pharmacodynamics, objective response rate, duration of response, progression-free survival (PFS), and OS.²

Across the overall population, the median age was 59.0 years (range, 27-82), 50% of patients were women, and 72.7% had an ECOG performance status of 0.¹ In the overall population, of the 29 patients with uveal melanoma, 26 had received prior systemic therapy, with a median of 2.0 prior lines (range, 1-7). Additionally, 89.7% had liver metastases, and 55.2% had lung metastases.

What additional efficacy and safety findings were reported?

In patients with uveal melanoma evaluable for efficacy, the median PFS was 5.3 months (95% CI, 3.7-5.9); 1 patient (3.7%) experienced a partial response (PR). Among evaluable patients across the trial, 6.3% had a PR. The median PFS for the overall population was 3.8 months (95% CI, 3.6-5.8).¹

Regarding safety, grade 3 or higher treatment-emergent AEs occurred in 31.8% of patients, and grade 3 or higher treatment-related AEs occurred in 6.8%. No dose-limiting toxicities were observed. One patient required a dose reduction because of grade 2 diarrhea, and 1 patient discontinued treatment due to grade 2 uveitis.

References

1. 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
2. A promising new chapter for PI3Kδ inhibition: Nature Communications publications reveal novel mechanism behind iOnctura's roginolisib. News release. iOnctura. October 9, 2026. Accessed October 21, 2026. https://markets.businessinsider.com/news/stocks/a-promising-new-chapter-for-pi3k-inhibition-nature-communications-publications-reveal-novel-mechanism-behind-ionctura-s-roginolisib-1036611822
3. A study to assess a PI3Kδ inhibitor (IOA-244) in patients with metastatic cancers. ClinicalTrials.gov. Updated July 8, 2026. Accessed October 21, 2026. https://clinicaltrials.gov/study/NCT04328844