Background: First-line (1L) treatments for unresectable HCC (uHCC) include atezolizumab plus bevacizumab (ATEZO+BEV), and the tyrosine kinase inhibitors (TKIs) sorafenib (SOR) and lenvatinib (LEN). In clinical trials, these therapies were associated with clinically significant events (CSEs): bleeding, clotting, encephalopathy, and portal hypertension. The objective of this study was to evaluate the real-world incidence of these CSEs and their impact on healthcare resource utilization (HCRU) and costs in patients with uHCC receiving ATEZO+BEV or a TKI. Methods: We conducted a retrospective, observational, cohort study using Clinformatics Data Mart to characterize 1379 US patients diagnosed with uHCC between January 2007 and June 2021 who received treatment with ATEZO+BEV (n=271) or a TKI (SOR, n=891; LEN, n=217). Incidence of the selected CSEs was evaluated as incident cases per 100-person-years (PY) of treatment. Descriptive statistics assessed patient characteristics, HCRU, and medical costs. Results: Mean age at diagnosis was 67.7 years; most patients were male (76.1%), white (52.4%), and had Medicare (74.2%); these characteristics were consistent across treatment groups. While on ATEZO+BEV, SOR or LEN, 147 (54.2%), 481 (54.0%), and 121 (55.8%) patients experienced ≥1 CSEs, respectively. For the ATEZO+BEV group, the most common CSEs were clotting (61.2 cases/100-PY [95% confidence interval {CI}: 45.1, 81.1]) and bleeding (55.4 [40.3, 74.4]). For the SOR group the most common CSEs were encephalopathy (54.5 [46.9, 63.1]) and clotting events (51.3 [44.1, 59.4]), for the LEN group the most common CSEs were clotting events (63.5 [47.4, 83.3]) and encephalopathy (56.7 [42.2, 74.5]). Overall, mean HCRU was high in the outpatient visits, while increases in the cohorts and among events (e.g., for surgery and inpatient visits) were seen in patients with ≥1 CSEs versus those without CSEs. Mean monthly medical costs were also substantially higher with ≥1 CSEs (Table). Conclusions: There were high levels of CSEs in patients receiving ATEZO+BEV or TKIs for 1L uHCC, and the occurrence of these events is associated with an economic burden to the healthcare system. Safety should continue to be monitored for patients treated for uHCC and new therapy options with reduced risks for developing CSEs are needed.

CSE: Clinically Significant Event. Medical cost includes all non-pharmacy claims for inpatient, outpatient, and other medical services. ^*The % change was statistically significant.