Higher rates of immune-related adverse events in circulating tumor DNA (ctDNA)-negative patients following adjuvant checkpoint inhibitor therapy

BACKGROUND: IMvigor010 demonstrated potential for circulating tumor DNA (ctDNA) to guide treatment in muscle-invasive urothelial carcinoma (MIUC), in which adjuvant atezolizumab (AA) reduced the risk of death by approximately 40% in ctDNA-positive patients. However, ctDNA-negative patients received no survival benefit from AA and had higher rates of immune-related adverse events (irAEs). Here, we further explore the relationship between ctDNA and irAEs. PATIENTS AND METHODS: Association between baseline (BL) and on-treatment (OT) ctDNA and time to first irAE was assessed in MIUC patients treated with AA (n = 384) versus observation (n = 397). Cox proportional hazard model was used with adjustment for BL covariates, sensitivity analyses were carried out at 6 months to address survival bias, and landmark analysis was carried out at day (D) 43 for patients with OT ctDNA. RESULTS: All grade irAE rates were higher in AA patients with negative BL ctDNA versus positive (54.7% versus 32.5%, respectively) and mainly driven by low-grade irAEs [hazard ratio (HR) 1.91 (1.25; 2.90)]. irAE rates decreased with increasing ctDNA levels as a continuous variable [ctDNA log-MTM/ml: HR 0.92 (0.87; 0.97)]. There was no association with BL ctDNA and high-grade irAEs [HR 0.87 (0.38; 1.98)], but discontinuation for AEs was higher in BL ctDNA-negative patients versus positive (3.3% versus 0%). Patients who cleared OT ctDNA after D43 had no association between ctDNA and irAEs versus non-clearance [HR 1.13 (0.35; 3.59)]. Patients who progressed to positive ctDNA after D43 did not experience any irAEs versus non-progressors. CONCLUSIONS: Low-grade irAEs and discontinuation due to AEs were higher in ctDNA-negative patients receiving AA despite the lack of a survival benefit. Continued evaluation of the potential role of ctDNA is warranted, as it may help identify patients who may be curable with only local therapy and where additional systemic treatment may only increase toxicity without improving survival.