Triple combination of hepatic arterial infusion chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors for treatment of advanced hepatocellular carcinoma: more robust evidence is still needed
Editorial Commentary

Triple combination of hepatic arterial infusion chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors for treatment of advanced hepatocellular carcinoma: more robust evidence is still needed

Mohammad Saeid Rezaee-Zavareh1, Ju Dong Yang2,3,4

1Middle East Liver Diseases Center, Tehran, Iran; 2Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence to: Dr. Ju Dong Yang, MS, MD. Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8900 Beverly Blvd., Los Angeles, CA 90048, USA; Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8900 Beverly Blvd., Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8900 Beverly Blvd., Los Angeles, CA 90048, USA. Email: judong.yang@cshs.org.

Comment on: Zhang TQ, Geng ZJ, Zuo MX, et al. Camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and hepatic artery infusion chemotherapy for hepatocellular carcinoma in Barcelona Clinic Liver Cancer stage C (TRIPLET): a phase II study. Signal Transduct Target Ther 2023;8:413.

Keywords: Hepatocellular carcinoma (HCC); immune checkpoint inhibitors (ICIs); tyrosine kinase inhibitors (TKIs); hepatic arterial infusion chemotherapy (HAIC); Barcelona Clinic Liver Cancer (BCLC)

Submitted Dec 16, 2023. Accepted for publication Sep 14, 2024. Published online Oct 14, 2024.

doi: 10.21037/cco-23-155

Hepatocellular carcinoma (HCC) is a leading cause of cancer incidence and mortality around the world. Under the Barcelona Clinic Liver Cancer (BCLC) staging classification, HCC with portal vein tumor thrombosis (PVTT) or extrahepatic metastasis is categorized as advanced cancer. Patients are recommended to receive systemic treatment, including multi-target tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) (1).

Hepatic arterial infusion chemotherapy (HAIC) has been used in the management of intermediate or advanced HCC cases with PVTT as a traditional treatment intervention in some Asian countries, such as Japan, South Korea, etc. (2-4). However, due to a lack of sufficient evidence, this approach is not endorsed by the guidelines of the European Society of Liver Diseases and the American Association for the Study of Liver Diseases (5). Using different catheter techniques (continuous perfusion chemotherapy via Hepatic Arterial Chemotherapy Kit or with disposable catheterization), HAIC as a locoregional treatment, can directly administer different chemotherapy agents into the tumors via the hepatic artery. These cytotoxic chemotherapy agents include epirubicin, doxorubicin, 5-fluorouracil (5-Fu), gemcitabine, and platinums which are used alone or in combination, each of which has different safety and efficacy profiles and are used in different countries (6). FOLFOX regimen for HAIC consisting of oxaliplatin, fluorouracil, and leucovorin was proposed by Chinese researchers (7). A 2022 meta-analysis with the inclusion of six studies (five nonrandomized and one randomized controlled trial) has shown that HAIC may be superior to transarterial chemoembolization (TACE) in the management of patients with unresectable HCC. Although there was no significant difference in 2-year overall survival between study groups, objective response rate (ORR) and disease control rate (DCR) have been significantly better in the HAIC group than in the TACE group. Serious adverse events (AEs) have been less in the HAIC group than in the TACE group (3). Furthermore, HAIC has been proposed as a cost-effective treatment approach compared to TACE for Chinese HCC patients with large unresectable tumors (8).

Patients with BCLC C HCC especially with PVTT have poor prognosis and are considered a difficult-to-treat population. Therefore, different studies (mainly retrospective cohort studies or single-arm clinical trials) have evaluated the effect of HAIC in dual or triple combination therapy with TKIs and/or ICIs (5,6). Several recent meta-analyses have shown that compared to sorafenib alone, HAIC with or without sorafenib may lead to a better OS, progression-free survival (PFS), and ORR among HCC cases (9-12). A meta-analysis of five RCTs and two observational studies has demonstrated that compared to sorafenib alone, the combination of sorafenib with HAIC can be associated with significantly better survival and more tumor response among advanced HCC cases but also with more grade 3/4 AEs including leukopenia, neutropenia, thrombocytopenia, and anemia and also gastrointestinal events (12). Another meta-analysis has shown better efficacy in terms of OS, PFS, complete and partial response rates, ORR, and DCR for HAIC compared to sorafenib for HCC cases with PVTT (9). However, these conclusions are based on a few clinical trials and cohort studies. In addition to sorafenib, the effectiveness of lenvatinib has been also investigated with HAIC for the treatment of advanced HCC cases. In a cohort study of 349 patients with propensity score matching, it has been determined that compared with lenvatinib alone, dual combination therapy of lenvatinib and HAIC is associated with higher one-, two-, and three-cumulative OS. Also, the rate of AEs has been similar between study groups (13). Dual combination therapy with HAIC has not been limited to TKIs. The retrospective assessment of a combination of HAIC with anti-PD-1 inhibitors (nivolumab, pembrolizumab, toripalimab, sintilimab) in comparison with HAIC has been conducted among 229 advanced HCC cases. The results indicated a superior survival benefit and tumor response for the combination therapy (14). Several retrospective studies have assessed the safety and efficacy of triple combination therapy of HAIC, TKIs, and ICIs for advanced HCC cases (15,16). A recent meta-analysis, evaluating nine retrospective cohort studies from China, has concluded that compared with TKIs alone and TKIs with ICIs, triple combination therapy with HAIC, TKIs, and ICIs is associated with better survival benefits (OS and PFS), ORR, and DCR (15). In addition to retrospective studies, triple combination therapy with lenvatinib, toripalimab, and HAIC for high-risk advanced HCC patients has been assessed in a single-arm phase 2 trial, showing acceptable safety and efficacy profiles, which should be confirmed in phase 3 trials (17). Such promising results from the phase 2 single-arm trial have been reported for the combination of HAIC, sintilimab, and a bevacizumab biosimilar (IBI305) (18).

Recently, another single-arm phase 2 trial from China has been published in the journal Signal Transduction and Targeted Therapy assessing the efficacy and safety of triple combination therapy of FOLFOX-HAIC (six cycles of oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, and fluorouracil at 2,500 mg/m2), camrelizumab (200 mg intravenously every 21 days), and apatinib (250 mg orally and daily) for the management of 35 treatment-naïve advanced HCC patients (19). ORR, as primary outcome, has been assessed every 6 weeks using contrast-enhanced computed tomography or magnetic resonance imaging, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary outcomes include modified RECIST-based ORR, DCR, time to response (TTR), median duration of response (DoR), PFS, and OS. Quality of life was also an exploratory objective. The authors reported ORR based on the RECIST and modified RECIST criteria as 77.1% [95% confidence interval (CI): 59.9–89.6%] and 88.6% (95% CI: 73.3–96.8%), respectively, which was higher compared to what was reported previously for camrelizumab and apatinib (20). DCR, TTR, median DoR, and median PFS were 97.1% (95% CI: 85.1–99.9%), 2.66 months (95% CI: 2.10–2.89), 7.52 months (95% CI: 4.83–12.52), and 10.38 months (95% CI: 7.79–12.45), respectively. Median OS is unreached, and 6-, 12-, 18-month PFS rates were 85.0%, 34.2%, and 22.8%, while OS rates were 94.3%, 87.4%, and 65.0%. Despite an initial decline in quality of life during the first four treatment cycles, it subsequently improved, aligning with disease control. Overall, the triple combination therapy has been well tolerated. They made some modifications to enhance patients’ tolerability and reduce liver toxicity. Specifically, apatinib and camrelizumab were initiated on day 8 in the first HAIC cycle and on day 4 in the second HAIC cycle, respectively. Additionally, a lower dose of oxaliplatin (85 mg/m2 instead of 130 mg/m2) was used, and it was administered alongside an analgesic to minimize subsequent abdominal pain. They reported 13 cases with serious AEs, with a decreased platelet count observed in 14.3% of cases, representing the most common serious AE. Additionally, they noted decreased lymphocyte and neutrophil counts in 37.1% and 34.3% of patients, respectively, as the most frequent grade ≥3 treatment-related AEs (TRAEs), consistent with the results from the RESCUE study for using camrelizumab combined with apatinib (20) in which grade ≥3 TRAEs and serious AEs had been reported in 77.4% and 28.9% of cases respectively. In this study, 16 patients had PVTT of Vp 3 (n=8) or 4 (n=8), 10 had a tumor size of ≥10 cm, and five had extrahepatic metastasis. Based on the subgroup analysis, the authors have shown that triple combination therapy might be beneficial even in high-risk HCC patients. Additionally, as previous studies have pointed to the possible role of HAIC as a downstaging tool (21,22), in this study, the authors reported that six patients could undergo curative therapy (five with resection and one with ablation) after receiving triple combination therapy.

This study adds to the body of evidence proposing better survival benefits and tumor responses for triple combination therapy using HAIC compared to dual or monotherapy. A meta-analysis published in 2023 attempted to assess the safety and efficacy of HAIC + TKI/ICI (group C), HAIC alone (group B), and ICIs + other systemic therapies (group A) among advanced HCC patients. The longest median PFS (months) for groups C, B, and A was estimated as 9.37 (95% CI: 6.81–11.93), 7.45 (95% CI: 6.45–8.46), and 5.92 (95% CI: 5.31–6.54), respectively. No significant difference in OS was reported, likely due to OS events not being reached during the follow-up in several included studies. Evaluation of grade 3 AEs showed no significant difference between group C and the other groups (23).

This study was a single-arm trial without a control group and with a relatively low sample size with a mean age of 46 years in which the background etiology for all included HCC cases was hepatitis B virus infection. To obtain more robust evidence and overcome different biases, RCTs with longer follow-up time, proper randomization, and with active or placebo control groups including HAIC with or without systemic therapies are needed. Although the general safety profile of treatment with TKIs and ICIs has been well established (24). adding HAIC to these combinations might lead to deterioration of liver function, potentially leading to worse survival outcomes. This emphasizes the need for running prospective trials comparing the triple combination of HAIC, TKIs, and ICIs with the double combination of TKIs and ICIs (like atezolizumab/bevacizumab as the standard systemic treatment for advance HCC), which have demonstrated very promising efficacy and safety (25). Furthermore, inherent difficulties in preparing for the treatment of HAIC (insertion of a port to access the hepatic artery, maintenance of the port in the hepatic artery, and local complications) should be carefully evaluated in future investigations (6).

Table 1 summarizes registered phase 3 or 4 clinical trials (ongoing) assessing the impact of HAIC, combined with TKIs and ICIs, on advanced HCC patients. Prior evidence confirmed the impact of HCC etiology and patients’ age on the treatment outcome. Therefore, new RCTs should be performed on HCCs with different background etiologies, different age groups, and from different geographical regions. An additional consideration is the variation in regimens and protocols for HAIC across different studies, involving diverse medication types, dosages, durations, cycle numbers, and routes of administration. This aspect should be addressed in future research, wherein a focus on comparing the safety and efficacy profiles of various dual and triple combinations with HAIC, and their impact as first or second-line treatment regimens for different HCC populations, is necessary. Only with such level of evidence, they can be recommended in the international guidelines for different or at least a subset of the HCC population.

Table 1

Registered phase 3 or 4 clinical trials evaluating the impact of HAIC, combined with TKIs and ICIs, on advanced HCC patients

Trial registration code Study design Estimated enrollment number & status Study groups Main inclusion criteria Primary outcome
Intervention Control
NCT05313282 Phase 3/randomized/parallel assignment/open label 140/recruiting HAIC + apatinib + camrelizumab Apatinib + camrelizumab No prior systemic therapy; Child-Pugh <6; ECOG score <2; BCLC: C PFS
NCT05198609 Phase 3/randomized/parallel assignment/open label 214/recruiting HAIC + apatinib + camrelizumab Apatinib + camrelizumab No prior systemic therapy; unresectable HCC or progression after surgery or locoregional therapy; patients with PVTT OS
NCT05250843 Phase 2–3/randomized/parallel assignment/open label 90/recruiting TACE/HAIC + lenvatinib + sintilimab (neoadjuvant) Liver resection No previous anti-HCC therapy; Child-Pugh <7; ECOG score: 0–2 RFS
ChiCTR2300073434 Phase 2–3/randomized/parallel assignment 118/recruiting HAIC + lenvatinib + pembrolizumab followed by surgery Surgery Child-Pugh <7; ECOG score: 0–2; BCLC: C 3-year OS
ChiCTR2100046555 Phase 4/randomized/parallel assignment 154/recruiting HAIC + regorafenib + PD-1 inhibitors (camrelizumab, nivolumab, pembrolizumab) Regorafenib + PD-1 inhibitors (camrelizumab, nivolumab, pembrolizumab) Previously treated with TKI; BCLC: B or C; Child-Pugh: A or B; ECOG score <2 Disease remission rate
ChiCTR2200061735 Cluster randomization/open label 134/not yet recruiting ALPPS + PD-1/PD-L1 inhibitor + lenvatinib + HAIC PD-1/PD-L1 inhibitor + lenvatinib + HAIC No previous anti-HCC treatment; unresectable HCC; Child-Pugh <7; ECOG score <2 Tumor resection rate and ORR
ChiCTR2300071146 Phase 3/single arm 97/recruiting TACE/HAIC + bevacizumab and sintilimab No previous anti-HCC treatment; ECOG score <2; BCLC: C; Child-Pugh: A or B PFS, ORR

HAIC, hepatic arterial infusion chemotherapy; TKI, tyrosine kinase inhibitor; ICI, immune checkpoint inhibitor; HCC, hepatocellular carcinoma; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; PFS, progression-free survival; PVTT, portal vein tumor thrombosis; OS, overall survival; TACE, transarterial chemoembolization; RFS, recurrence-free survival; PD-1, programmed death-1; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; PD-L1, programmed death-ligand 1; ORR, objective response rate.

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-23-155/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-23-155/coif). J.D.Y. reports that he provides a consulting service for AstraZeneca, Eisai, Exact Sciences, Exelixis, Fujifilm Medical Sciences, and Gilead Sciences. 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Rezaee-Zavareh MS, Yang JD. Triple combination of hepatic arterial infusion chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors for treatment of advanced hepatocellular carcinoma: more robust evidence is still needed. Chin Clin Oncol 2024;13(5):77. doi: 10.21037/cco-23-155

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