626P - Roginolisib (IOA-244), a first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with metastatic uveal melanoma

Background

Roginolisib, a highly selective modulator of PI3Kδ, reinvigorates antitumor immunity in patients with metastatic uveal melanoma (mUM).

Methods

Roginolisib was investigated in a First-in-human (FIH) dose escalation (Part A) and in a dose expansion (Part B) study at the biologically effective dose (BED) of 80 mg QD in mUM pts. Primary objective: Safety. Secondary objectives: PK; PD (e.g., CD63 expression on basophils, changes in immune cell subsets in peripheral blood); radiographic responses (RECIST v1.1); PFS and OS. Exploratory: changes in circulating immune cells by mass cytometry; response assessments by radiomics and blood-based proteins.

Results

At the BED of 80 mg QD, no treatment-related dose modifications or dose-limiting toxicity (DLT) were seen. Twenty-nine patients had mUM (Part A: 9 pts; Part B: 20 pts). Mean time on treatment: 10.9 mo (range: 1.5-42.6 mo). ORR (RECIST v1.1): PR: 1/29 (3%); SD: 20/29 (69%). Median OS for Part A: 20.8 mo; Part B: ongoing; Part A+B: ongoing. Roginolisib decreased circulating regulatory T cells and concomitantly increased CD8T and NK cells. This pattern of immune cell balances was accompanied by a decrease in soluble CTLA4 and an increase of IL15. Volumetric reduction in spleen was observed in most of the mUM patients. Based on RECIST v1.1, two distinct groups were recognized at Week 16 (3.8 mo): pts with SD (median OS: 20 mo; 13/29; 45%) and pts with PD (median OS: 10 mo). Pts with SD had slow volumetric increases by radiomic evaluation of all tumour lesions. Both patient groups had similar tumour genetic backgrounds. The main differences between SD and PD pts at Week 16 were increased activated CD8T cells and IFNγ signaling for SD pts. Furthermore, PI3K-associated signaling molecules and immune-exhaustion markers were significantly higher at baseline in the SD compared to PD pts and decreased only in the SD pts.

Conclusions

Uninterrupted administration of roginolisib in mUM pts with advanced malignancies is well tolerated, exhibits immuno-modulatory effects, and in a subset of pts with mUM, shows immune cell activation with associated survival benefit.

Clinical trial identification

NCT04328844.

Editorial acknowledgement

The authors thank the patients and their families. Also, we thank all study personal at the clinical investigation centers, the Fortrea Drug Development team and the statistical support from Veramed.

Legal entity responsible for the study

iOnctura SA.

Funding

iOnctura SA.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Novartis, Immunocore; Financial Interests, Personal, Invited Speaker: Sanofi. M. Simonelli: Financial Interests, Personal, Advisory Board: Incyte, Cytovia; Financial Interests, Personal, Invited Speaker: GSK, Bristol Myers Squibb; Financial Interests, Personal, Other, Data Monitoring Committee: Sanofi. M. Lahn: Financial Interests, Personal, Officer: iOnctura SA. G. Di Conza, T. Hammett, R. Zorrilla: Financial Interests, Personal, Membership or affiliation: iOnctura. P. Kaur: Financial Interests, Institutional, Full or part-time Employment, I was employed at AstraZeneca until March 31st 2023: AstraZeneca; Financial Interests, Institutional, Full or part-time Employment, I have been employed at iOnctura since April 2023: iOnctura SA; Financial Interests, Personal, Stocks/Shares, Received shares as part of my employment up until 31 March 2023 - I have retained these shares: AstraZeneca; Non-Financial Interests, Member, Registered member as April 2023: European Hematology Association. T. Lakshmikanth: Financial Interests, Personal, Stocks/Shares, Cofounder and share holder in Cytodelics AB, Sweden with no remuneration: Cytodelics AB. M. Occhipinti: Financial Interests, Personal, Officer: Radiomics. P. Spiliopoulou: Financial Interests, Personal, Invited Speaker: Pfizer. T.R.J. Evans: Financial Interests, Institutional, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Boards - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board, advisory board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche/Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland. M. Maio: Financial Interests, Personal, Advisory Board: BMS, Roche, GSK, Sanofi, Alfasigma, Amgen, Sciclone, Eli Lilly, MSD, Incyte, Pierre Fabre, AstraZeneca, Pfizer, Merck Serono; Financial Interests, Personal, Stocks/Shares: Epigen, Theravance. All other authors have declared no conflicts of interest.