KIRROS: A phase II trial in progress of first-line atezolizumab (atezo) with or without bevacizumab (bev) in patients with unresectable hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis.

TPS647 Background: HCC treatment is more complex for the sizable proportion of patients with CPB cirrhosis. These patients have poor survival due to both the cancer and underlying liver dysfunction. As such, they are typically excluded from pivotal clinical trials for first-line systemic therapy for unresectable HCC. The IMbrave150 trial established atezo + bev as a global standard of care for unresectable HCC, demonstrating a statistically significant improvement in overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR) of atezo + bev vs sorafenib (Finn N Engl J Med 2020; Cheng J Hepatol 2022). Real-world studies have consistently suggested benefit of atezo + bev in patients with HCC and CPB cirrhosis (e.g., Tanaka Hepatol Res 2022, D’Alessio Hepatol [Baltimore, Md] 2022). However, prospective clinical trial data are needed to comprehensively characterize safety and efficacy in this population. Single-agent immunotherapy is often used in patients with HCC and CPB cirrhosis given potential safety concerns of combination therapy. Safety data from real-world studies are limited by ascertainment and measurement biases. Therefore, a prospective study is warranted to address the unmet need for safety and efficacy data for first-line atezo ± bev in patients with CPB cirrhosis. Methods: KIRROS (NCT06096779) is a prospective, open-label, multicohort, multicenter phase II study in patients aged ≥18 years who have measurable and confirmed unresectable HCC, and CPB-7 or -8 cirrhosis who have not received prior systemic therapy. Eligible patients will be recruited into 2 cohorts for which endpoints will be non-comparatively assessed: Cohort A (n=60) patients will be treated with atezo 1200 mg intravenous (IV) + bev 15 mg/kg every 3 weeks (Q3W), and Cohort B (n=60) patients, those who do not meet Cohort A inclusion criteria (e.g., main portal vein tumor thrombus and proteinuria), will receive atezo 1200 mg IV Q3W only. Patients will receive treatment until unacceptable toxicity or loss of clinical benefit. The primary objective is to evaluate the safety of the treatment regimens as determined by incidence, nature and severity of adverse events and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Secondary objectives are to estimate efficacy with ORR, duration of response, and PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC modified RECIST, as well as OS. Quality-of-life secondary endpoints include patient-reported tolerability of the treatment regimens assessed by PRO-CTCAE and EORTC IL46, and health-related quality of life per EORTC QLQ-C30 and QLQ-HCC18 scores. As of September 2024, the KIRROS study is recruiting patients at 40 sites in the US and Puerto Rico. Clinical trial information: NCT06096779 .