Liver cancer is the 5th most common cancer in men and 9th among women (1). In 2020, almost 900,000 new cases were registered across the globe with 830,200 people died from this disease (1). Hepatocellular carcinoma (HCC) is a primary malignant liver tumour with the higher incidence and mortality in Asia as compared to Western countries (2). Despite the availability of various therapies, the prognosis and survival of patients with advanced HCC remains poor (3). Until recently a multi-kinase inhibitor sorafenib was a first line standard of care (SoC) for patients with advanced HCC with the median overall survival (OS) of 10.7 months (4). Immune-checkpoint inhibitors (ICIs) have touted a new era in clinical oncology and already changed treatment paradigms for multiple solid malignancies (5) including advanced HCC (3). ICIs target unique inhibitory checkpoint molecules on immune and tumour-infiltrating myeloid cells, thus promoting the proper differentiation of cytotoxic T cells and disabling tumour cells to escape from immunosurveillance (Figure 1) (6). In 2020, the combination of programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab + inhibitor of vascular endothelial growth factor (VEGF) bevacizumab was approved as a superior first line therapeutic option for patients with unresectable HCC (7). Single-agent ICI pembrolizumab targeting programmed cell death 1 (PD-1) has recently received an accelerated approval from US Food and Drug Administration (FDA) for second-line treatment (8). Recently, Qin et al. reported the outcomes of the phase 3 Keynote-394 trial (NCT03062358) comparing single agent pembrolizumab to placebo as second line therapy in sorafenib or oxaliplatin experienced patients with advanced HCC from Asia (9).
NCT03062358 (9) is a randomized, double-blind, phase 3 trial that recruited patients with advanced HCC across 41 hospitals in mainland China, Republic of Korea, Malaysia, Taiwan and Hong Kong to receive second line pembrolizumab 200 mg (group A) or placebo (group B) intravenously every 3 weeks in combination with the best supportive care. Eligible patients had Barcelona Clinic Liver Cancer (BCLC) stage B and/or C, life expectancy of >3 months and Eastern Cooperative Oncology Group (ECOG) 0 or 1. Notably, n=236 (78.7%) and n=124 (81%) in groups A and B respectively were positive for hepatitis B. All recruited patients had documented radiographic progression or intolerance after being treated with sorafenib [n=272 (90.7%) in group A and n=139 (90.8%) in group B] or oxaliplatin-based chemotherapy [n=28 (9.3%) and n=14 (9.2%) in groups A and B, respectively]. The primary endpoint was OS. The secondary endpoints were (I) objective response rate (ORR) defined by response evaluation criteria in solid tumours (RECIST) version 1.1, (II) duration of response (DOR) and (III) disease control rate (DCR).
In total, n=453 were enrolled to this trial with n=300 and n=153 into groups A and B, respectively. Median age in both groups was 54 years old with n=257 (85.7%) and n=126 (82.4%) were male in groups A and B respectively. Firstly, the results reported that median OS was significantly higher in group A [14.6 months (95% CI: 12.6 to 18)] than in group B [13 months (95% CI: 10.5 to 15.1)], respectively [hazard ratio (HR): 0.79, P=0.0180]. Secondly, the ORR was significantly higher in the group A [13.7% (95% CI: 10% to 18.1%)] as compared to the group B [1.3% (95% CI: 0.2% to 4.6%) respectively, P=0.0001]. The DCR was 52.7% and 47.7% in groups A and B, respectively (with no tested significance). In the pembrolizumab group n=6 (2%) reached complete response (CR) and n=32 (10.7%) had partial response (PR) by the time of final analysis. In comparison, only n=1 (0.7%) had CR and n=1 had PR in the placebo group. Finally, treatment-related adverse events (TRAEs) occurred in n=200 (66.9%) and n=76 (49.7%) of patients in groups A and B respectively. Only patients (n=3) treated with pembrolizumab experienced grade 5 TRAEs. It is worth noting that only n=4 (1.3%) from group A experienced immune-mediated hepatitis. This finding may be linked to the impact of pre-existing hepatitis B infection on immune tolerance, potentially leading to a reduced risk of immune-mediated hepatitis and toxicity in general.
Single agent pembrolizumab is a recent addition to a second line therapeutic arsenal for advanced HCC. The phase 3 of Keynote-394 study confirmed that second line pembrolizumab provided significantly higher OS, progression-free survival (PFS) and ORR in Asian patients with advanced HCC as compared to placebo. Superior efficacy of pembrolizumab was also observed in global patient populations (8), although Keynote-240 reported higher ORR [18.3% (95% CI: 14% to 23.4%)] (8). Nonetheless, the question remains if pembrolizumab can provide better efficacy than current SoC kinase inhibitors regorafenib, cabozantinib or ramucirumab. These drugs have also proven more effective compared to placebo and were introduced into clinical practice within the previous decade (10). Regorafenib is a recommended strategy in patients progressed on first line sorafenib in both European (10) and Asian (11) populations. While ethically difficult, a head-to-head comparison of pembrolizumab to current SoC kinase inhibitors would be essential to elucidate the best therapeutic option after sorafenib progression. It will be also intriguing to investigate if pembrolizumab can provide better efficacy for patients based on their extrahepatic spread, macrovascular invasion, or hepatitis B/C infection. The availability of such data will enable a more precise categorisation of currently approved treatment regimens, leading to improved decision making by hepatologists and oncologists.
Another important question that needs to be addressed is which second line therapy more suitable for patients who progressed on first line atezolizumab + bevacizumab. Given that atezolizumab targets the PD-L1, should we opt for another ICI such as pembrolizumab or switch to a drug with completely different mechanism of action, such as regorafenib? Additional clinical trials are required to address this concern, particularly regarding the safety profiles of those regimens. Since nearly 67% of patients experienced TRAEs following pembrolizumab treatment (9), it is critical to elucidate whether the toxicity would be even more pronounced in patients who received prior ICI therapy.
The ongoing exploration of ICI therapy in HCC is continuing and there is a high anticipation for the upcoming findings of certain trials (NCT04696055, NCT05101629) as they will provide crucial insights into the efficacy of combining pembrolizumab with kinase inhibitors for second line treatment. This data will help to determine if the combinatorial approach can provide the best therapeutic outcomes in patients progressed on first line ICI-based therapy. Even though these trials are single arm their results may further inform the clinical decision making. Finally, pembrolizumab has emerged as a new second line therapeutic alternative for advanced HCC in global patient populations. While its efficacy looks encouraging, further research is needed to investigate its safety profile, particularly with respect to biomarkers. With the constant advancement of science, there is a hope that pembrolizumab and/or other emerging targeted therapies will improve outcomes and quality of life of HCC patients in near future.
Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. 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://cco.amegroups.com/article/view/10.21037/cco-23-44/coif). DS reported travel grant from Cancer Institute NSW and conference travel support from SPHERE Cancer Clinical Academic Group. GA reported honoraria from AbbVie, Gilead and Gore. The authors have no other conflicts of interest to declare.
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