Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future

Abstract

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.

FIGURE 1

Rationale for immunotherapy in adjuvant versus neoadjuvant setting for patients undergoing surgical resection. There are several benefits (green boxes) and limitations (red boxes) when considering a neoadjuvant approach (left side) versus an adjuvant approach (right side) to improve disease-free and overall survival in patients undergoing surgical resection. Potential end points for (neo)adjuvant trials are described at the bottom of the figure. Abbreviations: MoA, mechanism of action; PD-1, Programmed cell death protein-1; PD-L1, Programmed cell death protein ligand-1; TME, tumor microenvironment.

FIGURE 2

Complexities of neoadjuvant immunotherapy prior to liver transplantation. The potential benefits of immunotherapy before transplant to induce tumor responses and downstage patients to transplant must be weighed against the increased risk of allograft rejection, as these outcomes are mediated by the same mechanistic pathways of T-cell activation.