Precision combination therapies: shaping the future management of advanced hepatocellular carcinoma?

With an increasing incidence and high incidence-mortality index, hepatocellular carcinoma (HCC) is a significant global health problem. Modeling predicts that there will be 1.3 million deaths annually by 2040 (1). Less than a quarter of patients with cirrhosis undergo HCC surveillance (2) and consequently, over 60% of HCC cases are advanced at diagnosis (3). While there are a variety of surgical and locoregional modalities for liver-isolated disease with limited intra-hepatic burden, therapeutic options for locally advanced and metastatic HCC remain limited. There is currently no established role for conventional systemic chemotherapy in the HCC treatment algorithm, owing to poor objective response rates and significant treatment-related toxicities in clinical trials. Furthermore, given the heterogeneity of HCC, biomarkers to improve the management remain elusive.

The mainstay of systemic therapy for advanced HCC is combination immunotherapy and anti-angiogenic therapy in the form of atezolizumab plus bevacizumab (4). Updated data from the IMbrave150 study demonstrates a 6-month margin in median overall survival (OS) when comparing atezolizumab plus bevacizumab with sorafenib (19.2 vs. 13.4 months) and reaffirms the difference in progression-free survival (PFS) between groups (6.9 vs. 4.3 months) (5). About 60% of trial participants demonstrated extrahepatic spread of HCC at baseline; it is unclear whether the median OS and PFS in this group was significantly different to the rest of the cohort. Subgroup analyses of participants with main portal vein tumor thrombus assigned atezolizumab plus bevacizumab have demonstrated significantly lower median PFS and OS (5.4 and 7.6 months, respectively) (6).

He et al. performed an exploratory single-arm phase II study assessing the combination of lenvatinib (a tyrosine kinase inhibitor), toripalimab (a PD1 inhibitor), plus FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil) systemic chemotherapy in individuals with high-risk HCC, which included participants with extrahepatic metastasis and high intrahepatic tumor burden (7). FOLFOX has previously demonstrated survival benefits in advanced HCC when used in hepatic artery infusions in combination with systemic therapy (8). Combination therapy aims to capitalize upon synergistic effects of the different lines of therapy without excess accumulation of treatment toxicities. For example, chemotherapy has been shown to stimulate a sensitizing effect upon tumor cells to immunotherapy (9), while the vascular remodeling effect of tyrosine kinase inhibitors has contributed to success in inhibiting HCC growth when combined with immunotherapy (10). The primary outcome of this study was PFS at 6 months. An important secondary objective was the use of tumor biopsy tissue to identify potential biomarkers based on single-nucleus RNA sequencing (snRNA-seq) profiles.

This Chinese study enrolled 30 participants who were typical of an Asian population with hepatitis B virus (HBV) as the predominant etiology (97%) and a majority male population (90%). All participants were classed as Child-Pugh A, however, only 13 (57%) had cirrhosis. All participants had advanced HCC with a median tumor diameter of 10.2 cm and 25 (83.3%) participants had major vascular invasion. A total of 11 (37%) participants completed six cycles of treatment and only 10% went onto maintenance therapy with lenvatinib and toripalimab. The authors reported a 6-month PFS of 66.7% and a median PFS of 9.7 months [95% confidence interval (CI): 2.9–16.6], which was superior to the historical results of atezolizumab plus bevacizumab combination therapy in the IMbrave150 study as well as that of various single and combination chemotherapy regimens in past randomized control trials (11,12).

Previous chemotherapy-based trials are summarised in Kim et al.’s review (13), but the use of chemotherapy for advanced HCC has largely declined since the SHARP (14) and Asia Pacific (15) trials for sorafenib. Previously, the combination of doxorubicin and sorafenib had also shown promise in phase II trials but did not result in any improvement in PFS or OS compared to sorafenib monotherapy in a randomized phase III trial (16). Aside from atezolizumab plus bevacizumab, various other combination therapies have been explored in phase III trials, such as durvalumab (PD-L1 inhibitor) plus tremelimumab (CTLA-4 inhibitor), cabozantinib [anti-vascular endothelial growth factor (anti-VEGF)] plus atezolizumab, and lenvatinib plus pembrolizumab (PD1 inhibitor), the findings of which have been collated in a recent network meta-analysis (17). The myriad of ongoing phase III trials for unresectable HCC, as recorded by Ntellas et al. (18), explore varying combinations of an immune checkpoint inhibitor (ICI), anti-VEGF, and kinase inhibitor therapy, with or without transarterial chemoembolization, but none of these trials currently include systemic chemotherapy.

These findings need to be put in context. The cohort largely consisted of Asian males with HBV, which makes these results less generalizable to other populations. It is important to note that a low proportion of participants had cirrhosis; preserved liver function is a positive prognostic marker for better OS. The participants were also younger with a median age of 45 vs. 64 years in the IMbrave150 study, who would have fewer co-morbidities and be more likely to tolerate systemic therapy, demonstrating why it is problematic to compare outcomes against historical controls. A better comparison would have been with a concurrent control arm of similar demographics receiving standard-of-care treatment or even comparison to other contemporary trials with better-matched controls. However, the majority of recent phase III trials evaluating frontline systemic therapies have included participants with a mean age of over 60 years and also recruited for a wider range of HCC aetiologies in comparison to He et al. (17). Nonetheless, the inclusion of patients with high intrahepatic tumor burden and major vascular invasion is atypical compared to published trials and should be commended. The median OFS and PFS rates achieved with the combination therapy in this study certainly rival the results of many of the frontline combination therapies included in Fulgenzi’s network meta-analysis, but again it is difficult to directly compare the results of this exploratory phase II trial to these larger randomized controlled trials (RCTs). Currently, this therapy would not be recommended as first-line treatment but does provide interesting data for salvage regimens in advanced HCC.

It should be noted that only 11 (37%) participants completed six cycles of chemotherapy and 23 grade 3–4 treatment-related adverse effects were reported, most frequently relating to chemotherapy-induced hepatotoxicity and myelotoxicity. Overall, 16 (53%) participants had to discontinue one arm of therapy during the trial and 5 (17%) participants were discontinued. The use of FOLFOX in advanced HCC has previously been associated with greater than 40% prevalence of grade 3–4 treatment-related adverse effects (11). Fulgenzi et al.’s network meta-analysis has found that ICI plus anti-VEGF treatment, and double ICI treatment confers a lower rate of treatment toxicities in comparison to ICI plus kinase inhibitor regimens (17). While the rates of treatment adverse effects and discontinuation in this trial are not unexpected, it is worth emphasizing that HCC patients who suffer severe toxicities experience a significant detriment to their quality of life over their remaining months. Again, there would have been value in a standard of care arm to evaluate how the toxicity profile of this treatment approach directly measures up against the current standard of care, and whether this is balanced out by a definite survival advantage.

He et al. should be commended on their exploratory analyses of snRNA-seq profiles as a biomarker of response to the treatment regimen. Cellular heterogeneity is a key characteristic of HCC with significant variation within the tumor, between tumors, and between individuals. Compared to bulk sequencing, single-cell, and snRNA-seq techniques provide superior analysis of diverse cell types at a finer resolution and elevate our understanding of the tumor microenvironment. Specifically, the snRNA-seq technique has demonstrated better performance in profiling a higher number of hepatocyte clusters (19). Future precision medicine approaches using either tissue or liquid biopsies, particularly in the context of intermediate of advanced HCC, could identify biomarkers to improve treatment allocation, monitor treatment response and determine prognosis (20). Using biopsies from six participants, three responders and three non-responders, He and colleagues identified CFHR4⁺ and AKR1C2⁺ malignant hepatocyte subsets that predicted a worse response to therapy. Both these subsets were associated with altered metabolic pathways, which could impact response to combination systemic chemotherapy. Furthermore, these tumor subsets expressed immune-related signatures, which were also associated with reduced immune cell populations potentially leading to immune therapy resistance. This precision medicine approach should be further developed, particularly related to first-line immune therapy.

Ultimately, many novel combination therapies for HCC have shown promise in phase II studies but have not proven effective in larger RCTs. Where chemotherapy is involved, navigating narrow therapeutic indices in patients with impaired hepatic function has proven to be a demanding challenge, manifesting in unacceptable levels of treatment toxicity in phase III trials. Promising contemporary combination therapies have also yielded disappointing results in phase III RCTs, as was the case for cabozantinib plus atezolizumab vs. sorafenib (21), and the underlying reasons for this are still being contested. Whether this iteration of lenvatinib, toripalimab, and FOLFOX chemotherapy is an exception to the rule remains yet to be seen, but future phase III trials including a standard of care arm could quantify the specific benefit of systemic chemotherapy and determine whether it outweighs the harms of cumulative toxicity. Currently, this therapy cannot be recommended.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-52/coif). The authors have no conflicts of interest to declare.

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