Triplet regimen with camrelizumab plus apatinib in combination with hepatic artery infusion chemotherapy (HAIC): a new treatment paradigm for select patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma?

In 2020, primary liver cancer was reported to be the third leading cause of cancer-related death worldwide with hepatocellular carcinoma (HCC) being the dominant histology, comprising up to 85% of cases (1). Major risk factors for HCC vary based on region with over two-thirds of HCC cases in China being attributed to hepatitis B virus (HBV) infection (2). While the incidence of liver cancer has begun to plateau in the recent birth cohorts in China, it remains a major health concern (3). The Barcelona Clinic Liver Cancer (BCLC) staging system, last updated in 2022, incorporates cancer stage, performance status and liver function (4). Despite trends suggesting improvement in outcomes over the last several years (5), the 5-year overall survival (OS) for patients with BCLC stage C HCC is 6% (6).

With the advent of immune checkpoint inhibitors (ICIs) and targeted therapies, there have been significant advancements in HCC treatment landscape over the past decade (7). Combining programmed death-ligand 1 (PD-L1) inhibitors with vascular endothelial growth factor (VEGF) blockade augments intra-tumoral T-cell infiltration resulting in increased efficacy (8). This synergistic effect has translated into statistically significant improvement in OS in phase III studies as evidenced initially in IMbrave150 which combined atezolizumab and bevacizumab (9) followed by CARES-310 which combined camrelizumab and apatinib (10) with sorafenib as the control arm in both trials. This has resulted in approval of camrelizumab, an anti-programmed cell death 1 (anti-PD-1) antibody in combination with apatinib, a VEGF receptor 2-targeted tyrosine kinase inhibitor (TKI) as well as atezolizumab, an anti-PD-L1 antibody in combination with bevacizumab, a monoclonal antibody targeting VEGF-A, as first-line treatment options for patients with unresectable/advanced stage HCC in China.

Amongst locoregional treatment options, ablation, radiation, transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are feasible options based on clinical factors in patients who are not candidates for curative surgery. Hepatic arterial infusion chemotherapy (HAIC) is another locoregional treatment option, well-described in Asia for HCC. HAIC allows for direct delivery of chemotherapy into the arterial supply of the tumor and minimizes systemic toxicities through first-pass effect in the liver. In a phase II trial, which enrolled 49 patients with BCLC stage C HCC to receive HAIC with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX-HAIC), demonstrated an acceptable toxicity profile, an overall response rate (ORR) of 29% and a 12-month survival rate of 55% (11). The treatment regimen used in this study was modified FOLFOX6 (mFOLFOX6), which included a 3-hour infusion oxaliplatin at 130 mg/m², a 2-hour administration of leucovorin at 200 mg/m², a bolus dose of fluorouracil at 400 mg/m² and a 46-hour delivery of fluorouracil at 2,400 mg/m², repeated every 3 weeks. Subsequently, mFOLFOX6-HAIC was compared to sorafenib in a phase III trial and yielded a higher median OS (mOS) of 13.9 versus 8.2 months, respectively (12).

In order to improve efficacy even further, there have been studies combining locoregional therapies including HAIC, TACE, and TARE with systemic therapies (13-15). He et al. have previously shown a significant improvement in OS with combining sorafenib and FOLFOX-HAIC (oxaliplatin at 85 mg/m², leucovorin at 400 mg/m², a bolus dose of fluorouracil at 400 mg/m² and a 46-hour delivery of fluorouracil at 2,400 mg/m²) referred to as the SoraHAIC group, where the mOS was 13.4 months compared with sorafenib alone where the mOS was 7.1 months, in patients with HCC and portal vein invasion (13). Of note, this study used a lower dose of oxaliplatin and a higher dose of leucovorin compared to mFOLFOX6. EMERALD-1 was a global phase III trial that showed a statistically significant improvement in median progression free survival (mPFS) to 15 months with combining durvalumab and bevacizumab with TACE compared to 8.2 months with TACE alone, in patients with unresectable HCC (16). Another ongoing clinical trial is evaluating the safety and efficacy of combining TARE with atezolizumab and bevacizumab in this patient population (17).

Building on the synergistic anticancer effects of chemotherapy with TKIs and ICIs, Lai et al. conducted a phase II study combining lenvatinib (multi-receptor TKI), toripalimab (humanized immunoglobulin G4 (IgG4)/kappa PD-1 monoclonal antibody) and FOLFOX-HAIC in patients with unresectable BCLC stage C HCC with Child-Pugh class A liver function. This study showed an ORR of 64% and a mPFS of 10.4 months (18). VEGF blockade/ICI combination with HAIC can increase chemotherapy delivery via promoting vascular normalization (19) and chemotherapy in turn can help recover immunosurveillance resulting in an improved immune response (20). The study-at-hand was designed to evaluate the efficacy of FOLFOX-HAIC in addition to an approved first line regimen of camrelizumab and apatinib in BCLC stage C HCC patients in China (21).

The study is a prospective, single-arm, open-label phase II clinical trial which enrolled 35 treatment-naïve patients over a period of approximately 2 years. All patients had HBV-related HCC with Child-Pugh class A liver function only. Majority of the patients were male, which is representative of the gender distribution globally (22). More than 50% of patients were less than 50 years of age, which is younger than the peak age of HCC incidence in most regions worldwide (23). The protocol included up to 6 cycles of mFOLFOX7-HAIC (2-hour infusion oxaliplatin at 85 mg/m², a 2–3-hour administration of leucovorin at 400 mg/m², and a 46-hour delivery of fluorouracil at 2,500 mg/m²) administered every 21 days in combination with apatinib 250 mg daily, taken orally, beginning on day 8 of the initial HAIC cycle and camrelizumab 200 mg, every 3 weeks commencing on day 4 of the second HAIC cycle. Since HAIC allows for direct delivery of fluorouracil through the artery into the tumor, the investigators eliminated the initial bolus dose as it was not required to reach a systemic steady-state concentration and instead used a higher dose of infusion fluorouracil at 2,500 mg/m² compared to 2,400 mg/m² in the SoraHAIC study (13). The median number of completed HAIC cycles was 6, which was the maximum allowed per the protocol. Nineteen patients (54%) required dose interruptions and 4 patients (11%) discontinued treatment due to adverse effects. Twenty-six (74%) of patients experience grade ≥3 to treatment-related adverse events (TRAEs), most commonly cytopenias and deterioration in liver function, which most patients were able to recover from. In terms of quality-of-life analysis, there was a transient decline in global health status and functioning within the first four cycles of treatment which subsequently stabilized.

The ORR was 77% and the disease control rate (DCR) was 97%, which was consistent across all subgroups including patients with tumor size ≥10 cm, multiple tumors, and high degree of portal vein thrombosis. The high ORR and DCR did translate into a mPFS benefit of 10.4 months and a 65% survival rate at 2 years. While not ideal to perform cross-trial comparisons, this is an improvement from historical controls using TKI + ICI blockade combination alone where the mPFS is known to be 6 months (9,10). The mOS in this study had not been reached at time of publication. Another key finding in the study was that 6 patients were able to be downstaged and receive curative therapy, including 5 patients who underwent R0 resection, and 1 patient who underwent curative ablation.

The strength of the present study is that it is the first study to demonstrate the safety and efficacy of mFOLFOX7-HAIC in combination with an established first line regimen of camrelizumab and apatinib in patients with BCLC stage C HCC. The high response rate and improvement in mPFS from historical control is encouraging and more likely to translate into a survival benefit compared to a previous study which evaluated FOLFOX-HAIC in the postoperative adjuvant setting and did not find a survival benefit compared to surgery alone, possibly due to availability of other treatment options available at progression (24,25). Another encouraging finding in the study was the downstaging of 6 patients to receive curative therapy. While specific details regarding clinical factors for these patients were not provided in the publication, it could be a valuable exploratory endpoint to evaluate in the ongoing phase III study (NCT05313282).

Although the study reports promising results with first line mFOLFOX7-HAIC in combination with camrelizumab and apatinib, there are several limitations that need to be considered. While the protocol allowed for Child-Pugh score of ≤7, all patients enrolled had a Child-Pugh score ≤6 and 91% of patients had a Child-Pugh score of 5. Therefore, the safety and efficacy of this treatment regimen in BCLC stage C HCC patients with Child-Pugh class B7 cannot be established. While the compliance with HAIC was impressive in this study, this regimen does require repeat hospital admission and transarterial administration of chemotherapy every 3 weeks. Additionally, all patients in this study had HBV-related HCC. Both these factors make the applicability of this regimen questionable in the western population, where this procedure is not standard and HCC is more frequently associated with metabolic syndrome, hepatitis C and chronic alcohol consumption.

In summary, Zhang et al. (21) reported the first phase II study demonstrating the safety and efficacy of first line mFOLFOX7-HAIC in addition to camrelizumab and apatinib in BCLC stage C HCC patients in China. The numerical improvement in mPFS and survival rate at 2 years warrant a phase III clinical trial to further evaluate the efficacy of this regimen, which is currently ongoing (NCT05313282). There are ongoing trials that are evaluating the efficacy of combining other systemic therapies with HAIC (NCT04135690, NCT05029973, NCT06201065, NCT05617430) as well as other locoregional therapies (NCT05332821, NCT05550025, NCT05320692) in advanced stage HCC in China. Results from these studies will not only be essential in establishing efficacy of different treatment combinations but also in identifying potential factors that could help tailor therapy and providing more personalized care.

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-24-22/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-24-22/coif). M.A. serves as consulting or advisory role in Eisai, Ipsen, Exelixis, GSK, QED, Isofol, Curio Science, AstraZeneca, Genentech, Incyte, Taiho and participates in researches of Bristol-Myers Squibb-Ono Pharmaceutical (Inst), Xencor (Inst), Merck Sharp & Dohme (Inst), Eisai (Inst), GSK (Inst), Bayer (Inst), Relay (Inst), ProDa BioTech (Inst), Exelixis (Inst), AstraZeneca (Inst). A.C. receives consulting fees from Curium, Ipsen, TerSera, Novartis, Seneca. The other authors have no conflicts of interest to declare.

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