67O - Polygenic risk score associations with immune checkpoint inhibitors related endocrine toxicity

Background

Endocrine immune related adverse events (EirAEs) caused by treatment with immune checkpoint inhibitors (ICIs), including thyroid dysfunction (ICI-T), type 1 diabetes mellitus (ICI-DM) and hypophysitis (ICI-HP), are largely irreversible and may pose significant clinical management challenges. As germline genetic variations can predispose to autoimmune conditions, understanding genetic factors contributing to the development of EirAEs is a crucial unmet need for identifying patients at higher risk.

Methods

We included 6300 ICI treated patients with multiple cancer types from centres across US, Canada, EU and Australia. The EirAEs in these patients were: ICI-T (n=806), ICI-HP (n=163) and ICI-DM (n=75). Cases of adrenal insufficiency were considered as ICI-HP unless accompanied by elevated adrenocorticotropic hormone. Patients without these irAEs were considered controls. Associations between polygenic risk score (PRS) (calculated from publicly available summary statistics of large GWAS for hypothyroidism (Khan 2022), type 1 diabetes (T1D) (Oram 2015)) and ICI-T, ICI-DM, ICI-HP were tested in patients of European ancestry after adjustment for type of ICI (PD-1/PD-L1 monotherapy, anti-CTLA-4 monotherapy, and the combination of the two), sex, age and five principal components. The results were then meta-analysed across all groups using inverse-variance weighting with random effects.

Results

The PRS for hypothyroidism and T1D were significantly associated with the development of ICI-T (odds ratio per standard deviation [OR per SD] =1.41, p=1.23e-17) and ICI-DM (OR per SD=1.97, p=9.91e-6), respectively. However, a high PRS for T1D showed a non-significant trend for decreased risk for ICI-HP (OR per SD=0.79, p=0.13).

Conclusions

We demonstrate that the genetic variations associated with risk of thyroid autoimmunity and T1D contribute to susceptibility of developing EirAEs. The PRS results for ICI-T and ICI-DM demonstrated robustness across multiple cohorts. These findings could be considered as part of safety stratification approaches to optimise the benefit/risk balance of ICI therapy.

Clinical trial identification

Editorial acknowledgement

Significant contributions by E. Bergmann, C. Fahey, E. Mukherjee, K. Herold, A. Menzies and M. McCarthy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

Z. Quandt: Financial Interests, Personal, Advisory Role: Sanofi, Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: Sanofi, Novartis. A. Saha: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Other, patents/other intellectual property: Genentech; Financial Interests, Personal, Research Funding: Genentech; Financial Interests, Personal, Royalties: Genentech. Y. Xu: Financial Interests, Institutional, Research Funding: Incyte. A. Stravodimou: Financial Interests, Institutional, Advisory Role: AstraZeneca, Daiichi Sankyo, Exact Sciences, Eli Lilly, Pierre Fabre, Novartis, Roche, Seagen; Financial Interests, Institutional, Speaker, Consultant, Advisor: Novartis, Eli Lilly, Pfizer, Pierre Fabre, Roche, Seagen, MSD. E. Shearer-Kang: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks or ownership: Roche. M. Aldrich: Financial Interests, Personal, Advisory Role: Guardant Health; Financial Interests, Personal, Speaker, Consultant, Advisor: Guardant Health; Financial Interests, Institutional, Research Funding: Genentech; Financial Interests, Institutional, Research Grant: NIH/NCI. E.J. Philips: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Verve, Regeneron, Novavax, Biocryst, AstraZeneca, Ramboll Esperion, UpToDate. G. Liu: Financial Interests, Personal, Advisory Board: Anheart, Amgen, AstraZeneca, Bayer, EMD Serono, Jazz, Johnson and Johnson, Merck, Novartis, Pfizer, Roche, Sterimax, Takeda; Financial Interests, Personal, Coordinating PI: Takeda, AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Pfizer, Takeda. A. Schoenfeld: Financial Interests, Personal, Other, Consulting: Johnson and Johnson, KSQ Therapeutics, Perceptive Advisors, Legend Biotech, Iovance Biotherapeutics, Oppenheimer and Co; Financial Interests, Personal, Advisory Board: BMS, Enara Bio, Umoja Biopharma, Prelude Therapeutics, Immunocore, Amgen, Lyell Immunopharma, Heat Biologics; Financial Interests, Personal and Institutional, Steering Committee Member: Merck; Financial Interests, Institutional, Steering Committee Member: Iovance Biotherapeutics; Financial Interests, Institutional, Local PI: GSK, Achilles Therapeutics, BMS; Financial Interests, Local PI: Synthekine; Financial Interests, Institutional, Coordinating PI: Obsidian; Non-Financial Interests, Principal Investigator: GSK, Achilles Therapeutics, Iovance Therapeutics, BMS, Merck, PACT pharma. D. Johnson: Financial Interests, Personal, Advisory Board: BMS, Merck, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Role: Teiko, Targovax, Mosaic; Financial Interests, Personal, Research Grant: BMS, Incyte. J. Fellay: Non-Financial Interests, Institutional, Advisory Board: Imagine Institute; Financial Interests, Institutional, Full or part-time Employment: Lausanne University Hospital and University of Lausanne, Swiss Federal Institute of Technology; Non-Financial Interests, Institutional, Member of Board of Directors: Swiss Tropical and Public Health Institute; Financial Interests, Institutional, Research Funding: Roche; Financial Interests, Institutional, Research Grant: Swiss National Science Foundation. R. Mohindra: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. J.M. Balko: Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Mallinckrodt; Financial Interests, Institutional, Research Funding: Roche, Incyte; Financial Interests, Personal, Speaker, Consultant, Advisor: Ellipses; Financial Interests, Personal, Stocks/Shares: CRISPR Therapetics, BEAM therapeutics. G.S. Chandler: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.