Regorafenib plus nivolumab as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Multicenter phase 2 trial (RENOBATE).

415 Background: The immunomodulatory effect of regorafenib may enhance the anti-tumor activity of nivolumab in patients with uHCC. We report results from a phase 2 study of regorafenib plus nivolumab as first-line therapy in patients with uHCC. Methods: In this open-label, multi-center, single-arm study, patients with >19 years, ECOG PS 0 or 1, BCLC stage B or C, and no prior systemic therapy were eligible. Patients received intravenous nivolumab 480 mg, every 4 weeks, and oral regorafenib 80 mg daily, 3 weeks on/1 week off, every 4 weeks. Tumor response was evaluated per RECIST v1.1, every 8 weeks (fixed schedule). Primary endpoint was overall response rates (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), ORR per mRECIST, and safety profile per NCI-CTCAE v5. Results: A total of 42 patients were enrolled between JUL-2020 and JAN-2021. Median age was 61 years (range, 40-79), and 31 patients (73.8%) were male. Most patients had BCLC C stage (n=38, 90.5%) and hepatitis B virus infection (n=30, 71.4%). Extrahepatic metastasis was noted in 36 patients (85.7%) and baseline serum AFP levels were >400 ng/mL in 17 patients (40.5%). With median follow-up duration of 9.2 months (95% CI, 8.5-9.9 months), 21 patients were ongoing in this study. ORR per RECIST v1.1 was 31.0% (CR 1 [2.4%] and PR 12 [28.6%]), and ORR per mRECIST was 35.7% (CR 4 [9.5%] and PR 11 [26.2%]). Median PFS was 5.5 months (95% CI, 1.8-9.1 months) and median OS was not reached. The 6-months PFS and OS were 49.9% and 90.4%. Most common adverse events were hand-foot skin reaction (n=14, 33.3%), skin rash (12, 28.5%), and alopecia (10, 23.8%). Conclusions: Regorafenib plus nivolumab shows promising efficacy outcomes in uHCC. There was no unexpected safety signals and most of toxicities were manageable. Clinical trial information: NCT04310709.