Combination checkpoint inhibition, angiogenic inhibition and hepatic artery infusion chemotherapy for disease control of advanced hepatocellular carcinoma

The Barcelona Clinic Liver Cancer (BCLC) (1) Stage C cases of hepatocellular carcinoma (HCC) are advanced due to portal venous involvement and/or extrahepatic spread not amenable to surgical treatment or chemo-embolization (TACE) alone. The advent of checkpoint inhibitors and anti-angiogenic agents in combination, notably atezolizumab and bevacizumab (IMBRAVE 150 Trial) (2), have significantly improved progression-free survival (PFS) in these advanced cases. There have also been trials involving nivolumab (CheckMate 459 Trial) (3), Sorafenib or lenvatinib, transarterial chemo-embolization combined with systemic therapy. Ultimately, the most beneficial combination of these newer treatments still lacks head-to-head comparison. Another recent trial of PD-1 inhibition with VEGF-2 inhibition combined camrelizumab and apatinib (CARES-310 trial) (4) in these advanced, unresectable HCC cases. The result of CARES-310 showed an overall risk reduction (ORR) of 25.4% and a median PFS of 5.6 months. The authors of this TRIPLET phase II study (5) have combined the modest results of the CARES-310 trial and added in hepatic artery infusion chemotherapy (HAIC) using systemic FOLFOX (5-FU, leucovorin, oxaliplatin) (Table 1).

In the current treatment strategy in BCLC Stage C, the first line therapy has become a combination of atezolizumab and bevacizumab which has had post-hoc analysis showing 19.2 months overall survival (OS) compared to previous first line sorafenib 13.4 months (P<0.0009). In the CARES-310 trial the OS was even higher up to 22.1 months. The main adverse events include hypertension, transaminitis, hypoalbuminemia and thrombocytopenia. Since the advent of the SHARP trial with sorafenib, all trials in advanced HCC have focused on a combination of tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), anti-angiogenic (VEGF inhibitors) and HAIC or a combination of several. Of these trials over the last 20 years, there have been 6 favorable trials in advanced BCLC B and C HCC (6). There have been several small studies that have shown a better tolerated safety profile for HAIC (most commonly FOLFOX) compared to TACE as mentioned in this TRIPLET study (5). Of these, the most significant was the [SoraHAIC Trial (7)] combination of sorafenib with HAIC FOLFOX showing medial OS 13.37 vs. 7.13 months for sorafenib alone (P<0.001). Especially, when there is diffuse disease in the liver TACE is less effective and with tumors >7 cm TACE is less effective at controlling tumor burden (8). Therefore, the role of HAIC in combination with ICI+VEGF inhibition seems to be promising.

The TRIPLET trial (5) had enrolled 35 patients, all with hepatitis B viral infection and >90% with high risk features for recurrence. They were selected appropriately as prior meta-analysis shows ICI drugs work best in viral etiology advanced HCC, while anti-VEGF inhibitors are effective against all etiologies. HAIC with FOLFOX with its control of tumor burden and favorable side effect profile also was well selected in this patient population. The trial was able to report on PFS at 10.38 months (95% CI: 7.79 to 12.45), with the 6-, 12-, and 18-month PFS rates of 85.0%, 34.2%, and 22.8%, respectively. The median OS was not yet reached at the time of reporting. Interestingly this three target approach was effective at showing good median OS so far the 6-, 12-, and 24-month OS rates were 94.3%, 87.4%, and 65.0%, respectively. More profound was the 17% of patients that were downstaged to BCLC stage A and were resected with curative intent after treatment (⅚ resected and ⅙ ablated).

The strengths of this study were in keeping with prior positive trials, showing good disease control in all advanced BCLC Stage C cases, with the ability to convert a significant proportion to resectable disease, which achieves the best control of disease with R0 resection. The other very interesting finding reported is up to 77% partial response compared to the best case 1st line treatment according to the IMBRAVE 150 study at 27.3%. The overall PFS also was 10.38 months compared to 6.8 months, between TRIPLET and IMBRAVE 150, respectively. The limitations of the study were the short-term follow-up, and the small number of patients which could contribute to results that don’t reach statistical significance without larger cohorts. There is also the question of a control arm in this study which would either include or not include HAIC FOLFOX to perform adequate randomization. The side effect profile is also reported as tolerable but >35% of patients had Grade 3 or 4 adverse events related to cytopenia, transaminitis and requirement of steroid infusions. This study will have to add a control arm with a larger cohort of patients to account for confounders such as the side effects from chemotherapy as well as the side effects from immunotherapy in separate arms. A follow-up on the current cohort in the TRIPLET trial with disease-free survival and OS would also help provide an update on the composite endpoints of the study.

In conclusion, this study is promising at identifying advanced HCC cases at high risk of recurrence and decreased PFS and OS. The control of disease and the ability to downstage disease as shown is very promising at challenging the paradigm of operable or inoperable disease. It also challenges the issue of transplantable candidates with the ability to downstage disease in this population. A larger randomized controlled study would provide potentially a different algorithm for multi-target responsive advanced HCC and promises to be a very fluid landscape in treatment of this complex disease.

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-23-149/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-23-149/coif). The authors have no conflicts of interest to declare.

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