Abstract 160P
Background
Checkpoint inhibitors (CPIs) have significantly enhanced cancer treatment, yet immune-related adverse events (irAEs) remain a clinical challenge. Identifying biomarkers predictive of irAEs is crucial for enhancing patient care. For non-standard cancer immunotherapies (CITs), aggregated clinical data are scarce, and the exploration of biomarkers is in its nascent stages.
Methods
To investigate associations of biomarkers with irAEs, we established a harmonized data mart from 23 early-phase CIT trials, encompassing 12 molecules with diverse mechanisms targeting various cancers. This comprehensive dataset includes a total of 3,568 patients, both CPI-naïve and CPI-experienced, and features clinical and longitudinal biomarker data as well as comprehensive genotyping information.
Results
Our results identify several soluble biomarkers that consistently associate with irAEs during treatment. Meta-analysis reveals that elevated liver enzymes increase hepatitis risk (hazard ratio [HR] 95% CI: 1.50 [1.34, 1.68]), while increased levels of myeloid cells (HR: 0.86 [0.79, 0.93]) and more T-cells (HR: 0.77 [0.61, 0.96]) are associated with lower risks of rash and colitis, respectively. Further analysis of tumor burden metrics indicates that patients with liver metastases have an increased risk of hepatitis (HR: 1.96 [1.41, 2.71]), while the same group exhibits a reduced risk of rash (HR: 0.75 [0.62, 0.91]), as do patients with smaller target lesion sizes (HR: 0.81 [0.76, 0.87]). Finally, serum and immune cell biomarkers show a significant association with their corresponding polygenic scores (PGS). However, the maximal observed variance explained is no greater than 4%, presumably due to the high level of environmental variation in these cancer patients. Consequently, the use of PGS does not improve the prediction of irAEs, suggesting limited clinical utility in this early-phase trial setting.
Conclusions
In conclusion, we find promising biomarkers linked to irAEs in non-standard CITs. Additional biomarker data and more research are needed to uncover the molecular basis of these toxicities and help refine patient selection and risk-benefit evaluations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
F. Hoffmann-La Roche AG.
Funding
F. Hoffmann-La Roche AG.
Disclosure
B.P. Fairfax: Financial Interests, Institutional, Advisory Board, I sit on a scientific advisory board for Roche regarding immunotherapy toxicity: Roche; Financial Interests, Institutional, Advisory Board, I have sat on a scientific advisory board for Pathios Therapeutics: Pathios Therapeutics; Financial Interests, Institutional, Invited Speaker, I have given a talk and provided consultancy for Immunocore and may provide further input for their work as a scientific advisor: Immunocore; Financial Interests, Personal, Advisory Board, I have given a talk and provided consultancy for UCB, last in 2022.: UCB; Financial Interests, Personal, Invited Speaker, I have provided an educational talk for Bristol Myers Squibb for local Oncology meeting in Birmingham UK and may provide further such talks.: BMS; Financial Interests, Personal, Invited Speaker, I have been asked to present my group's work at GSK in 2024: GSK; Financial Interests, Personal, Advisory Board, I have been asked to sit on a scientific advisory board for TCypher BIO: TCypher BIO. V.C. Schmid: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Achilles therapeutics. D.F. Lamparter: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche AG; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche AG, Verge Analytics, Lonza AG. T. Kam-Thong: Financial Interests, Personal, Full or part-time Employment: Hoffmann-La Roche; Financial Interests, Personal, Stocks/Shares: Hoffmann-La Roche. P. Scepanovic, 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. G. Duchateau-Nguyen: Financial Interests, Institutional, Full or part-time Employment: Hoffmann-La Roche; Financial Interests, Institutional, Stocks/Shares: Hoffmann-La Roche. A. Roller: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche. V. Karanikas: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. D. Heinzmann, S.L. Mycroft: Financial Interests, Institutional, Full or part-time Employment: Roche; Financial Interests, Institutional, Stocks/Shares: Roche. C. Adams: Financial Interests, Personal, Full or part-time Employment, I am a scientist at Genentech.: Genentech; Financial Interests, Personal, Stocks/Shares, I have received RSUs/SARs as part of my compensation from Genentech.: Genentech. N. Städler: Financial Interests, Personal, Full or part-time Employment, employee of Roche: F. Hoffmann-La Roche AG; Financial Interests, Personal, Stocks/Shares, Roche Holding AG Genussscheine: F. Hoffmann-La Roche AG; Non-Financial Interests, Project Lead, As employee I lead projects: F. Hoffmann-La Roche AG.
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