Editorial: Regorafenib Plus Nivolumab in Advanced Hepatocellular Carcinoma—A Step Toward Mechanism‐Guided Second‐Line Therapy

The therapeutic landscape of advanced hepatocellular carcinoma (HCC) has evolved rapidly, yet effective second-line options remain limited. Current evidence supports the use of tyrosine kinase inhibitors (TKIs), including regorafenib, cabozantinib, and ramucirumab, which were developed and evaluated in post-sorafenib settings [1-3]. However, none have been explicitly validated following first-line immune checkpoint inhibitor (ICI)-based therapies [1-5]. The GOING trial, an investigator-initiated phase I/IIa study, explored an innovative add-on strategy: sequential administration of regorafenib followed by nivolumab [6]. This design leveraged the ability of regorafenib to induce immunogenic cell death and enhanced antigen presentation, with subsequent programmed death-1 (PD-1) blockade by nivolumab to counteract immune escape [7]. Safety, the primary endpoint, was manageable. Although adverse events were universal, discontinuation rates were modest (9%), and severe treatment-related events occurred in less than one-third of participants. Importantly, feasibility was demonstrated in both sorafenib-pretreated and atezolizumab plus bevacizumab–exposed cohorts. Efficacy signals were also noteworthy. The median overall survival reached 20 months, extending to 25 months in sorafenib-progressors, with nearly half alive at 3 years. These outcomes compared favourably with historical benchmarks from RESORCE and CheckMate 040 [1, 2], though caution is warranted given the single-arm design. The GOING trial underscores the value of investigator-driven research, highlighting mechanism-guided sequencing rather than simultaneous combination. While larger randomised studies are still needed, these findings support the add-on strategy of regorafenib plus nivolumab as a promising second-line option, particularly for patients progressing on sorafenib. By contrast, outcomes were less favourable in patients previously treated with atezolizumab plus bevacizumab. Several second-line strategies after failure of ICI-based regimens have been reported from real-world data, post hoc analyses, and select prospective studies, largely based on phase I/II in design [4, 5]. A recent retrospective study suggested that nivolumab plus ipilimumab may retain clinical activity even after prior ICI-based combinations, including atezolizumab plus bevacizumab, though data remain limited in this small cohort [8]. Notably, this regimen is associated with higher rates of immune-related adverse events compared with PD-1 monotherapy; therefore, careful patient selection and close monitoring are critical. Additionally, hepatic arterial infusion chemotherapy has shown promising survival outcomes in selected cohorts after failure of atezolizumab plus bevacizumab, particularly among Asian populations [9, 10]. In conclusion, second-line therapy for advanced HCC should be individualised, considering performance status, liver function reserve, prior treatment response and toxicity, and specific patterns of disease progression. Ongoing investigations are evaluating innovative strategies, including ICI–TKI combinations, chimeric antigen receptor (CAR) T-cell platforms, and targeted agents against molecular drivers such as fibroblast growth factor 19 and glypican-3. Continued clinical trials, complemented by real-world evidence, will be pivotal to refine treatment algorithms and optimise outcomes. Furthermore, advancing knowledge of resistance mechanisms and the tumour microenvironment in patients progressing after ICI-based therapies remains critical to guide rational drug development. Yuan-Hung Kuo: writing – original draft. Chao-Hung Hung: conceptualization, writing – review and editing. The authors have nothing to report. This article is linked to Sanduzzi-Zamparelli et al. paper. To view this article, visit https://doi.org/10.1111/apt.70578. The authors have nothing to report.