164P - Roginolisib (IOA-244), the first highly selective oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3K_), has immuno-modulatory effects associated with clinical benefits in patients with metastatic uveal melanoma

Background

Roginolisib continuously administered inhibits its target at IC₉₀ in patients (pts). In pts with pretreated uveal melanoma (UM), a median overall survival (OS) of 15.9 months (m) (CI95%:10.7-26.4 m) and median PFS of 5.3 m (CI95% 3.7-5.9) was observed. Biomarker data from the completed Phase I DIONE-01 study may explain the mechanism of action of roginolisib.

Methods

Roginolisib was initially investigated in a dose escalation of 10-80 mg in pts with solid tumours and Follicular Lymphoma. Subsequently, continuous 80 mg QD was investigated in 20 additional uveal melanoma pts (Part A: 9 pts; Part B: 20 pts). Primary objective: Safety. Secondary objectives: radiographic responses (RECIST 1.1.); PFS and OS. Exploratory studies: circulating immune cells, proteins; genomic and transcriptomic of tumour tissue; response assessment by radiomics.

Results

Among the 29 pts with metastatic uveal melanoma there were two groups based on radiographic responses at Week 16: Group 1, i.e. pts with stable disease (SD) (13/29; 45%) and a median OS of 28.5 m; Group 2, i.e., pts with progressive disease (PD) (16/29; 55%) and a median OS of 10.9 m. Differences between these two groups were observed: (a) by proteomics: PI3K/mTOR-associated protein (e.g., AKT1S1, FKBP4) were down-regulated in pts of Group 1, and same proteins were up-regulated in pts of Group 2. (b) by transcriptomics in tumor tissue (14/29 pts): 7/14 pts from Group 1 had 325 genes down-regulated, mostly GPCR-related genes; (c) by immune cells: decreased circulating T_reg cells (22/29 pts), while CD39⁺CD8⁺ T cells increased. Independent of Group 1 and 2, 23/29 pts had immune cell changes associated with increased plasma levels of IL15, IL17D, sIFNGR2 and decreased levels in CXCL13, CD5, and CD5L. GNAQ/GNA11 mutations were observed in 11/12 pts and 3/18 pts were HLA-A02:01 positive. ctDNA was reduced in 10/17 pts of which 6 had a clearance at Week 8.

Conclusions

Long-term continuous dosing of roginolisib rebalances the immune response at Week 16 by modulating PI3K-δ-targets, of which some have the potential to predict OS.

Clinical trial identification

NCT04328844.

Legal entity responsible for the study

iOnctura SA.

Funding

iOnctura.

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, Glaxo; Financial Interests, Personal, Invited Speaker: Glaxo, Bristol Myers Squibb; Financial Interests, Personal, Other, Data Monitoring Committee: Sanofi; Financial Interests, Personal, Other, Steering Committee: BMS/Celgene; Financial Interests, Personal, Other, Travel grant: Roche; Financial Interests, Personal, Other, Travel Grant: Pfizer. M. Lahn: Financial Interests, Personal, Full or part-time Employment: Michael Lahn. G. Di Conza, T. Hammett, P. Kaur: Financial Interests, Personal, Full or part-time Employment: iOnctura. M. Occhipinti: Financial Interests, Personal, Full or part-time Employment: Radiomics. T.R.J. Evans: Financial Interests, Institutional, Advisory Board, 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 Board, Advisory Boards - GI cancers, melanoma: Roche / Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche / Genentech; Financial Interests, Institutional, Advisory Board, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board, advisory board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board, 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, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board, 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, Personal, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Personal, 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, Personal, 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, Personal, Other, Editor-in-Chief: British Journal of Cancer; Other, Personal, Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Personal, 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, Personal, Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, Personal, 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.