The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial

Phosphatidylinositol 3-kinase delta (PI3Kδ) promotes tumour cell growth directly or indirectly by activating immune-suppressive cells. In contrast to previous PI3Kδ inhibitors, roginolisib is a selective, non-ATP competitive inhibitor, which locks PI3Kδ into an inactive state and causes an allosteric modulation. In a First-in-Human dose study, continuous daily dosing of roginolisib was investigated in patients with solid and haematologic malignancies. In Part A, 24 patients received escalating doses of roginolisib. In Part B, 20 mostly pre-treated metastatic uveal melanoma (mUM) patients received a dose associated with continuous PI3Kδ inhibition of >90%. The primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) profile, clinical anti-tumour responses assessments. Exploratory endpoints included immunophenotyping, proteomics, genomics. No Dose Limiting Toxicity or drug related toxicities requiring dose modifications were observed ( ≥ Grade 3 toxicities: 3/44; 6.8%). In mUM, median Overall Survival (mOS) was 20.8 months (data-cut off December 2023) and 18.4 months (data-cut-off February 2026). mOS in mUM patients with Stable Disease at Week 16 ( = Cycle 5) was 28.5 months, while patients who progressed at Week 16 had a median OS of 12.3 months. Roginolisib was safe, had a predictable PK profile, T regulatory cell abundance was decreased while activated CD8+ T cells increased together with soluble plasma IL-15. ClinicalTrials.gov registration: NCT04328844. First generation inhibitors of phosphatidylinositol 3-kinase delta (PI3Kδ) had limited selectivity due to the conserved ATP binding pocket, resulting in toxicity when used as anti-cancer agent. Here, the authors report the results of a first-in-human clinical trial of Roginolisib, a next generation conformation-selective PI3Kδ inhibitor, in patients with advanced or metastatic cancer with dose expansion in patients with metastatic uveal melanoma.

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Journal
Nature Communications
Published
2026-10-09
DOI
https://doi.org/10.1038/s41467-026-77358-7
Primary Topic
PI3K/AKT/mTOR signaling in cancer
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article
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article

The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial

G. Amato, Nikhil Sindhwani, Umberto Postiglione, Vincenzo D’Alonzo et al.
Nature Communications
PI3K/AKT/mTOR signaling in cancer
article

The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial

G. Amato, Nikhil Sindhwani, Umberto Postiglione, Vincenzo D’Alonzo, Thomas R. Jeffry Evans, Michele Maio, Matteo Simonelli, Vincent Vuaroqueaux, Anna Maria Di Giacomo, Mariaelena Occhipinti, Tracey Hammett, Michael Lahn, Pavlina Spiliopoulou, Gillian Hopton, Tadepally Lakshmikanth, Carmelo Carlo‐Stella, Giusy Di Conza, Hugo Barcenilla, Marco Durini, Alessio Bevilacqua, Ziyang Tan, Anette Johnsson, Anikó Meijer, Ming Jye Poi, Petter Brodin, Andrea Corsi, David B. Spetzler, Agnese Losurdo, Lars Anders van der Veen, Armando Santoro, Laura González, Ayad Abdul-Ahad, Rebeca Zorrilla, Monica Valente, Gregory Price, Paramjit Kaur, Emily Wood, Jill Graham, Robert Snijder, Anne-Lise Peille
article en

Abstract

Phosphatidylinositol 3-kinase delta (PI3Kδ) promotes tumour cell growth directly or indirectly by activating immune-suppressive cells. In contrast to previous PI3Kδ inhibitors, roginolisib is a selective, non-ATP competitive inhibitor, which locks PI3Kδ into an inactive state and causes an allosteric modulation. In a First-in-Human dose study, continuous daily dosing of roginolisib was investigated in patients with solid and haematologic malignancies. In Part A, 24 patients received escalating doses of roginolisib. In Part B, 20 mostly pre-treated metastatic uveal melanoma (mUM) patients received a dose associated with continuous PI3Kδ inhibition of >90%. The primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) profile, clinical anti-tumour responses assessments. Exploratory endpoints included immunophenotyping, proteomics, genomics. No Dose Limiting Toxicity or drug related toxicities requiring dose modifications were observed ( ≥ Grade 3 toxicities: 3/44; 6.8%). In mUM, median Overall Survival (mOS) was 20.8 months (data-cut off December 2023) and 18.4 months (data-cut-off February 2026). mOS in mUM patients with Stable Disease at Week 16 ( = Cycle 5) was 28.5 months, while patients who progressed at Week 16 had a median OS of 12.3 months. Roginolisib was safe, had a predictable PK profile, T regulatory cell abundance was decreased while activated CD8+ T cells increased together with soluble plasma IL-15. ClinicalTrials.gov registration: NCT04328844. First generation inhibitors of phosphatidylinositol 3-kinase delta (PI3Kδ) had limited selectivity due to the conserved ATP binding pocket, resulting in toxicity when used as anti-cancer agent. Here, the authors report the results of a first-in-human clinical trial of Roginolisib, a next generation conformation-selective PI3Kδ inhibitor, in patients with advanced or metastatic cancer with dose expansion in patients with metastatic uveal melanoma.

Nature CommunicationsVol. 17(1)
University of Siena (IT), Indiana University Health (US), University of Liège (BE), Beatson West of Scotland Cancer Centre (GB), Karolinska Institutet (SE), Caris Life Sciences (United States) (US), Italian Network for Tumor Biotherapy Foundation (IT), Fondazione Toscana Gabriele Monasterio (IT), MRC London Institute of Medical Sciences (GB), IRCCS Humanitas Research Hospital (IT), Postnova Analytics (Germany) (DE), Richmond upon Thames College (GB), Indiana University Melvin and Bren Simon Comprehensive Cancer Center, iOnctura SA (Switzerland) (CH), Imperial College London (GB), University of Glasgow (GB)
Openalex Percentile: Top 23%
PI3K/AKT/mTOR signaling in cancer
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