A multicenter, open-label study of RP2 oncolytic immunotherapy expressing anti–CTLA-4 in combination with second-line atezolizumab plus bevacizumab in advanced hepatocellular carcinoma (HCC) or in combination with first-line durvalumab in advanced biliary tract cancer (BTC).

Abstract

TPS614 Background: Despite recent breakthroughs in first-line treatment of advanced HCC using immune checkpoint inhibitors (ICIs) with or without vascular endothelial growth factor inhibition, second-line options after progression on ICIs remain limited. In BTC, first-line therapy also includes ICIs, but outcomes remain suboptimal. RP2 is an enhanced potency herpes simplex virus type 1 (HSV-1) oncolytic immunotherapy that expresses GM-CSF, a fusogenic glycoprotein (GALV-GP-R − ), and an anti–CTLA-4 antibody. RP2 showed clinical activity as a single agent and when combined with ICIs in a phase 1 study in advanced solid tumors. This study evaluates the safety and efficacy of RP2 combined with atezolizumab (atezo) + bevacizumab (bev) as second-line therapy in patients (pts) with unresectable advanced HCC or RP2 combined with durvalumab (durva) in pts with unresectable advanced BTC after first-line chemotherapy is discontinued. Methods: This is an open-label, multi-cohort, phase 2 trial (NCT05733598; RP2-003). For the HCC cohort (n = 30), pts receive RP2 combined with atezo + bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor ≥1 cm (longest diameter), Child-Pugh class A, ECOG performance status of 0–1, and progression on 1 prior systemic treatment (anti–PD-1/PD-L1 as immediate prior therapy). Key exclusion criteria include untreated/incompletely treated esophageal or gastric varices with bleeding or high bleeding risk and macroscopic invasion of the tumor into any major blood vessels or main bile ducts. Pts receive intratumoral (IT) RP2 every 2 weeks (Q2W) until the 4 th dose, then Q3W thereafter. Bev is given IV at 10 mg/kg Q2W with the 1 st dose of RP2, then 15 mg/kg Q3W starting with 4 th dose and thereafter; atezo is given IV at 840 mg Q2W for 2 doses starting with the 2 nd dose of RP2, then 1200 mg Q3W thereafter. For the BTC cohort (n = 30), pts receive IT RP2 Q2W combined with durva 1500 mg Q4W after combination chemotherapy is discontinued. Pts must be on a combination of gemcitabine, platinum-containing chemotherapy, and a checkpoint inhibitor for ≥12 weeks and have documented stable disease or partial response on ≥2 scans. Pts with mismatch repair deficiency/microsatellite instability-high tumors are excluded. For both cohorts, the primary endpoint is overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include safety, ORR per RECIST 1.1 modified for use in HCC (HCC cohort only), duration of response, complete response rate, progression-free survival, and overall survival. Clinical trial information: NCT05733598 .