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Abstract
Background IMvigor010 (NCT02450331) showed that atezolizumab reduced risk of death by approximately 40% in post-cystectomy ctDNA-positive patients.1 Whether ctDNA may predict toxicity of immune checkpoint inhibition is unknown. Theoretically the lack of tumor-derived immune suppression associated with the presence of cancer may result in more irAEs.
Methods Patients with high-risk muscle invasive bladder cancer treated with atezolizumab (n=300) vs observation (n=281) after surgical resection and with available baseline ctDNA assessment were included. The association between baseline ctDNA (either as status [positive vs negative] or as continuous MTM/mL measurement [mean tumor molecules per mL of plasma on log-scale]) and the time to onset of the first irAE of a specific type per patient was assessed in the atezolizumab arm using a Cox regression model adjusted for PD-L1 status, prior chemotherapy, race, sex and age. Plots of the cumulative incidence function (CIF) derived from the Aalen-Johansen estimator were used for visualization of the irAE risk over time stratified by ctDNA status, treatment arm and severity grade. Death was considered as a competing event for the safety endpoints in the CIF plots and Cox model (i.e., cause-specific approach treating death as censoring).
Results The risk of low grade (Grade 1/2) irAEs was higher in ctDNA-negative patients compared with ctDNA-positive patients at baseline (ctDNA-negative vs -positive: HR 1.97 [1.29, 2.99]) and in patients with lower baseline ctDNA levels (ctDNA log-MTM/mL: HR 0.92 [0.87, 0.97]) (figures 1 and 2). Low-grade irAEs were predominantly hepatitis, hypo-/hyperthyroidism and rash. For high-grade irAEs there was no clear association with baseline ctDNA; however, the number of events was very small. No conclusions could be drawn from on-treatment ctDNA-irAE analysis given the limited safety data available.
Conclusions Our exploratory analysis showed evidence of a higher risk of low-grade irAEs in ctDNA-negative vs ctDNA-positive patients treated with atezolizumab in the adjuvant setting. This supports the hypothesis of increased treatment-related toxicity in patients without cancer. It supports other ctDNA trials such as IMvigor011 (NCT04660344).
Acknowledgements Funded by F Hoffmann-La Roche Ltd/Genentech
Trial Registration ClinicalTrials.gov ID: NCT02450331
References
Jackson-Spence F, et al. IMvigor011: a study of adjuvant atezolizumab in patients with high-risk MIBC who are ctDNA+ post-surgery. Future Oncol. 2023;19(7):509–515.
Ethics Approval The trial was performed per Good Clinical Practice and the Declaration of Helsinki. Protocol approval was obtained from ethics committees or independent review boards for each study site. All patients provided written informed consent. Further details, including the study protocol, are published in the primary manuscript: Bellmunt J et al, Lancet Oncol. 22, 525–537 (2021).
Cumulative incidence function of the irAE risk stratified by baseline ctDNA status, separate plots by severity grade and treatment arm.
Forest plot of the baseline ctDNA effect, as (A) ctDNA status (positive vs negative), and (B) ctDNA log-MTM/mL, adjusted for PD-L1 immune cell status, race, age, sex and prior chemotherapy in the atezolizumab arm. Results of the prognostic ctDNA effect are reported in terms of hazard ratios (HRs), corresponding 95% Cls and nominal Wald test P values. The sample size (N) corresponds to patients with available data for baseline ctDNA and the adjusted confounders in the model. G, grade; AESI, adverse event of special interest.
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