Combining immunotherapy/targeted therapy with hepatic artery chemo-infusion in treating patients with advanced hepatocellular carcinoma

The treatment of hepatocellular carcinoma (HCC) is complex and difficult due to the heterogeneity of both interpatient and intratumoral presentation. In particular, a consensus for the most optimal treatment approach for advanced-stage HCC patients is yet to be determined and commonly used guidelines such as the Barcelona Clinic Liver Cancer (BCLC) recommend combination systemic treatment such as atezolizumab-bevacizumab as the first line therapeutic option for this patient population (1). The synergistic effect of combining an immune checkpoint inhibitor (ICI) and an anti-vascular endothelial growth factor (VEGF) was first brought to attention by IMbrave150, a global phase 3 randomized clinical trial that demonstrated better 1-year overall survival (OS) (67.2% vs. 54.6%) and median progression-free survival (PFS) (6.8 vs. 4.3 months) with atezolizumab-bevacizumab than sorafenib in unresectable HCC patients (2). Subsequent clinical trials investigating different combinations of tyrosine kinase inhibitors (TKIs) + ICI have reported varying results with some regimen (cabozantinib/atezolizumab, COSMIC-312) showing no significant improvement in OS and others (camrelizumab/apatinib, CARES-310) reporting significantly improved OS (22.1 vs. 15.2 months) and PFS (5.6 vs. 3.7 months) compared to sorafenib (3,4). Since the introduction of ICI + TKI, interest in novel therapeutic regimens has expanded to more aggressive triple combination treatment with locoregional therapy (LRT) + TKI + ICI. Promising results have been reported with triple therapy in advanced HCC; however, most completed studies have been retrospective in nature (5).

The present study in review, TRIPLET, is a prospective single-arm phase II trial conducted for 2 years at a single institution located in China aimed at investigating the combined efficacy of hepatic arterial infusion chemotherapy (HAIC-FOLFOX), camrelizumab, and apatinib. The study cohort consisted of 35 HCC patients classified within BCLC stage C, Child Pugh A/B, and Eastern Cooperative Oncology Group (ECOG) 0–1. All patients had HCC from hepatitis B virus (HBV) infection. Within the cohort, 16 (45.7%) of patients had Vp 3 or 4 portal vein tumor thrombosis and 5 (14.3%) had extrahepatic metastasis at the time of treatment. Patients underwent up to six cycles (21-days/cycle) of the triple combination regimen until unacceptable toxicities, disease downstaging for curative treatment, disease progression, or death occurred. The overall response rate (ORR) based on response evaluation criteria in solid tumors (RECIST) v1.1 was 77.1% and median OS was not reached at 24 months. The OS rates were 94.3% (6 months), 87.4% (12 months), and 65.0% (24 months). The median PFS was 10.38 months. Disease was controlled in 97.1% of the patients and 6/35 (17.1%) of the patients were down-staged to curative therapy (Table 1) (6).

Retrospective studies on triple therapy within the past several years have shown varying results. Majority of these studies reported slightly poorer outcomes compared to the present prospective study (7,8). Among the studies, the largest retrospective study consisting of 145 BCLC B/C patients who underwent triple therapy demonstrated ORR, disease control rate (DCR), and grade ≥3 adverse event rate at 57.2%, 89.7%, and 17.7%, respectively. Despite the poorer outcomes compared to the present prospective study, comparable downstaging rate to curative therapy at 18.6% and PFS at 9.7 months were seen (5). It is important to note that this retrospective study included BCLC B patients and patients who received all types of HAIC (FOLFOX/RALOX), TKI (sorafenib/lenvatinib/apatinib), and ICI (camrelizumab/sintilimab/tislelizumab), which is a common issue when comparing studies of HCC with varying patient population and treatment regimen. Several retrospective studies directly comparing triple therapy to alternative treatment regimens in BCLC C patients have demonstrated the positive synergistic effect of HAIC + TKI + ICI. When triple therapy was compared to monotherapy of lenvatinib (TKI), ORR and DCR were superior in triple therapy at 67.6% vs. 14.3% and 90.1% vs. 72.1%, respectively. PFS was also significantly improved with triple therapy at 11.1 vs. 5.1 months (7). Other similar retrospective studies reported superior overall outcomes with triple therapy when compared to dual therapy of TKI + programmed cell death protein 1 (PD-1), further highlighting the benefit of adding HAIC (8,9).

The merit of the present study is that it is one of the first prospective studies reporting data on the efficacy of triple therapy. This study was able to replicate the promising results seen by a recent single center prospective study of high risk HCC patients treated with a triple combination of lenvatinib, toripalimab, and FOLFOX-HAIC with median PFS (10.4 months) and median OS (17.9 months) (10). Another ongoing phase II, single arm clinical trial published comparable preliminary results to these two studies and further validated the efficacy of triple therapy in high-risk patients (11). One of the limitations of the current prospective studies is the lack of control arm. While these studies have demonstrated the safety and efficacy of triple therapy in advanced HCC patients, there is a need for randomized, prospective studies with control groups directly comparing the treatment regimen with current standard options, such as the ongoing clinical trials NCT05198609 and NCT05166239, to further understand the role of triple therapy (12,13). The second limitation is the study population primarily consisting of HCC patients secondary to HBV that make it difficult to extrapolate these study results to the West, where there is a noticeable shift in etiology of HCC from viral to non-viral (14,15).

The treatment of advanced HCC is complex and consensus on the best approach is widely debated. According to the BCLC guidelines, the recommended first line treatment of BCLC C patients remains systemic therapy due to the lack of high level of evidence for emerging novel regimens and approaches. In addition, the guidelines acknowledge the heterogeneity of HCC and advise patients to be treated in a highly individualized approach with consideration of the clinical, radiological, and biochemical profile of the patient, which is made possible at institutions through multidisciplinary care teams (1). The present study has shown clear synergistic effects with the addition of HAIC to ICI and TKI in certain populations; however further data are needed to elucidate the true beneficiaries as well as the optimal treatment protocol of triple therapy. In the West, the wide use of HAIC would not be feasible as it is less established compared to other modalities such as transarterial chemoembolization (TACE) or yttrium-90 transarterial radioembolization (Y90 TARE). These alternatives could potentially be the choice of LRT for triple therapy in the West because they are already commonly utilized for intermediate and advanced stage HCC and has been demonstrated to be effective in both viral and non-viral HCC (16). The quality of life and safety could be a major factor when choosing LRT modality, especially when used in combination with multiple systemic therapies. In the present study, patients had to undergo multiple >50 h HAIC sessions and treatment-related adverse events grade 3 or above was seen in 26/35 (74.3%) patients (6). In this regard, the use of Y90 TARE could be advantageous as it has been suggested by recent studies to have superior quality of life, safety profile, and time to progression compared to TACE (17,18). Furthermore, recent advances in Y90 TARE with the use of personalized dosimetry pioneered by the DOSISPHERE-01 trial has shown excellent results in BCLC C patients [69.6% partitioned volume imaging (PVI)], with OS 26.6 months and 36% downstaging to curative resection rate (19). Radioembolization reportedly has a synergistic effect with TKI and ICI by releasing neoantigens, increasing expression of negative T cell co-receptors, and increasing tumor infiltrating lymphocytes (20). Future directions should therefore involve a comparison of currently ongoing clinical trials of TACE and HAIC triple therapy with future planned clinical trials of Y90 TARE triple therapy, STRATUM (NCT05377034) and EMERALD-Y90 (NCT06040099) (21,22).

In summary, the present study further validates that the addition of LRT to TKI and ICI shows promising synergistic effects in advanced-stage HCC patients who can tolerate aggressive treatment regimens. However, prospective studies in this are limited and only represent data applicable to Asia. The shift in HCC etiology from viral to non-viral in the West poses further challenges and questions yet to be addressed. Additionally, the safety and tolerability of triple therapy remain a concern and barrier for patients considering this treatment approach. Therefore, there is an urgent need for further high evidence level investigation of triple therapy in this patient population to improve long-term outcomes, optimize therapy regimen, and ultimately increase conversion rates to curative therapy. Another topic of importance requiring further prospective research is the optimal approach to treating advanced-stage HCC patients who are ineligible for first line systemic therapy due to poor clinical function or have discontinued first line systemic therapy secondary to toxicity or HCC progression. Alternative therapies using a metronomic treatment approach with capecitabine have shown positive outcomes as an inexpensive, efficient, and safe second-line systemic therapy for such patients and could provide an opportunity for treatment in HCC patients ineligible for currently approved systemic therapies (23). As of now, advanced-stage HCC patients should be treated in a multidisciplinary, highly individualized approach with more aggressive treatment regimens reserved for carefully selected patients of favorable baseline characteristics.

Acknowledgments

Funding: None.

Footnote

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

Peer Review File: Available at https://cco.amegroups.org/article/view/10.21037/cco-23-159/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-23-159/coif). H.Y. received research funding for pancreatic cancer research from Guerbet LLC, support for Advisory Board from AstraZeneca, and honoraria for review from Techsomed. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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