Immunotherapy has revolutionized the treatment landscape for advanced HCC, resulting in prolonged response and improved survival. With these results, a pressing question arises: what is the optimal treatment following first-line immunotherapy? Despite the benefits of immunotherapy, most patients will experience disease progression within six months and will require subsequent therapies. International guidelines recommend second-line multi-kinase inhibitors following progression on immunotherapy
however, this recommendation is primarily based on expert consensus rather than high-quality evidence. Nevertheless, real-world data indicate that these agents demonstrate similar efficacy and safety when used as first-line treatments. Conversely, it remains unclear whether continuing immunotherapy after progression is beneficial. In some cases, adding anti-CTLA-4 as salvage therapy has shown effectiveness. Molecular-directed therapies have also been tested, showing some initial promise, but further data is needed to confirm the benefits of this approach. Emerging evidence suggests that patients experiencing oligoprogression may benefit from local or locoregional therapies while continuing immunotherapy. In this review, we will discuss treatment strategies following progression after first-line immunotherapy.