Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Abstract Sorafenib and lenvatinib are approved for first‐line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first‐line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second‐line agents and provide practical guidance for selecting the best sequential treatment approach. The timing and sequencing of treatment switches are key to optimizing patient outcomes in advanced HCC, and decisions should be informed by reasons for discontinuation of previous therapy and disease progression. It is important not to switch too soon, because sequential treatment benefit may then be lost, nor should switching be delayed too long. Effectiveness, safety and tolerability, patient quality of life, route of administration, dosing regimen, drug class, molecular target and individual patients’ characteristics, including comorbidities, inform the selection of second‐line systemic treatment, independently of the aetiology of HCC, tumour stage and the response to previous treatment. Biomarkers predictive of treatment effectiveness are of great value, but currently biomarker‐driven patient selection is possible only in the case of ramucirumab. The approval of new combination therapies for advanced HCC in the first‐line setting will further increase the complexity of decision‐making. However, the important factors will remain the individual patient’s characteristics and preferences.


| INTRODUC TI ON
Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related mortality worldwide. 1 Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. 2 The treatment of HCC depends on the stage of the disease, usually based on the Barcelona Clinic Liver Cancer (BCLC) model, which considers factors that impact prognosis, such as tumour burden, liver function and performance status. 2,3 In In 2007, sorafenib, a multi-kinase inhibitor, became the first systemic therapy approved for first-line treatment of unresectable HCC in the EU and in the USA. 5,6 Approval of sorafenib was based on efficacy data from two randomized, double-blind, placebo-controlled, phase 3 trials in which sorafenib significantly prolonged overall survival (OS) vs placebo in patients with advanced HCC who had not received prior systemic treatment. 7,8 In 2018, the tyrosine kinase inhibitor lenvatinib was approved as an alternative to sorafenib for first-line treatment of advanced or unresectable HCC, 9,10 Table S1). [15][16][17][18][19][20][21][22][23] Regorafenib, a multi-kinase inhibitor, was the first agent to show a survival benefit over placebo in patients progressing on sorafenib and was approved for the treatment of advanced HCC after prior sorafenib treatment in the USA in April 2017 24 and in the EU in August 2017. 25 Approval for use after prior sorafenib treatment followed for cabozantinib (in the EU in November 2018 26 and in the USA in January 2019 27  ipilimumab, a human cytotoxic T-lymphocyte antigen 4-blocking antibody, was approved in the USA, in combination with nivolumab, for patients with HCC who have been previously treated with sorafenib, based on data from a phase 1/2 trial. 33 This rapid proliferation of second-line treatment options brings new hope for the treatment of advanced HCC. However, the approval of these new therapies creates complexity in the therapeutic landscape for treating clinicians, who need to understand the different risks and benefits associated with various systemic therapies so that they can choose the most appropriate treatment option for their patients. For example, regorafenib, cabozantinib and ramucirumab are indicated in advanced HCC for patients previously treated with sorafenib but not for patients previously treated with lenvatinib, for whom sorafenib is sometimes used as a subsequent treatment option. 34 An objective of this review was to describe factors for consideration by clinicians when assessing the evidence for the available second-line systemic agents and selecting the best sequential treatment strategy for their patients with advanced HCC.

| SUMMARY OF DATA FOR APPROVED S ECOND -LINE SYS TEMI C AG ENTS
To identify relevant evidence on second-line treatment options after sorafenib and lenvatinib in advanced HCC from phase 2 and phase covering trial design and efficacy outcomes, and safety/tolerability and health-related quality of life (HRQoL) respectively.

| Regorafenib
Regorafenib is an orally administered multi-kinase inhibitor that is structurally very similar to sorafenib but with a distinct target profile, including additional inhibition of fibroblast growth factor receptor kinases. 35,36 It was approved for the treatment of patients with HCC who have been previously treated with sorafenib on the basis of the results of the phase 3 RESORCE trial. 37 RESORCE was a randomized, double-blind, parallel-group trial that included 573 adult patients with advanced HCC and Child-Pugh liver function class A who tolerated sorafenib (≥400 mg/d for ≥20 days of the last 28 days of treatment) and who had documented radiological progression during sorafenib treatment. Patients were randomized 2:1 to regorafenib or placebo within 10 weeks of their last dose of sorafenib, with stratification by geographical region (Asia vs rest of the world), macrovascular invasion (yes vs no) and extrahepatic disease (yes vs no), AFP concentration (<400 vs ≥400 ng/mL) and Regorafenib also demonstrated statistically significant superiority to placebo in PFS, time to progression (TTP), objective response rate (ORR) and disease control rate (DCR) ( Table 2). Improvement in OS with regorafenib vs placebo was maintained across all preplanned subgroup analyses, and there was also consistent benefit in PFS and TTP. Regorafenib has also been found to be efficacious regardless of the pattern of progression on prior sorafenib 38 or the last sorafenib dose. 39 An exploratory analysis showed that OS from the start of sorafenib therapy was 26.0 months in patients switched to regorafenib and 19.2 months in patients switched to placebo. 39 The safety of regorafenib in HCC was found to be con-

| Cabozantinib
Cabozantinib is an orally administered tyrosine kinase inhibitor with activity against a broad range of targets, including VEGF receptor-2, MET, RET, AXL, FLT3 and c-KIT. 45

| Ramucirumab
Ramucirumab is an immunoglobulin G1 monoclonal antibody that targets the VEGF receptor-2 and is administered by intravenous infusion. Following a previous trial (REACH), in which benefit in comparison with placebo was only seen in a subgroup of patients with AFP ≥400 ng/mL, 23 The changes in AFP levels were associated with TTP and OS, and ramucirumab was found to increase time to AFP progression and radiographic TTP and to slow the rate of AFP increase during treatment. 62 Subgroup analyses of data pooled from REACH and REACH-2 have further confirmed the treatment benefit of ramucirumab in patients with advanced HCC who switched from sorafenib with elevated AFP, 63 including specifically in patients in Japan, 64 and regardless of aetiology of liver disease. 65 A post hoc analysis of data from REACH, REACH-2 and the pooled population found that treatment with ramucirumab increased OS vs placebo in all radiological progression pattern subgroups. 66  Ipilimumab is a monoclonal antibody that targets human cytotoxic T-lymphocyte antigen 4, and which is administered by intravenous infusion. It was recently approved by the FDA, in combination with nivolumab, for the treatment of patients with HCC who have been previously treated with sorafenib. As with nivolumab monotherapy, approval was based on the results of the single-arm phase 1/2 CheckMate 040 trial. With the ipilimumab plus nivolumab dosing regimen subsequently approved by the FDA, the overall ORR was 32% and the median duration of response was 17.5 months. The combination was also found to be generally well tolerated. 71   Route and schedule of administration are also important for many patients and may impact HRQoL and treatment adherence.

| Combination therapies under investigation (e.g. antiangiogenics/tyrosine kinase inhibitors plus immunotherapy)
There are strong rationales for combining ground-breaking immunotherapeutic agents with tyrosine kinase inhibitors or VEGF inhibitors. For example, it has been hypothesized that alleviating tumour hypoxia could be a valuable approach to improving the outcomes associated with current immunotherapies. Therefore, concurrent targeting of VEGF and its cognate receptors and immune checkpoints may be effective, and this hypothesis is now supported by pre-clinical and clinical data. For example, and as described above, atezolizumab (an immunotherapeutic agent targeting PD-L1) in combination with bevacizumab (an inhibitor of VEGF-A) has been found to offer improvements in OS and PFS vs sorafenib, in patients with unresectable HCC, who had not received prior systemic therapy. 14 It seems likely that atezolizumab plus bevacizumab will become the standard treatment in the first-line setting for patients with advanced HCC in the near future, fundamentally changing the current paradigm. It might be speculated that following resistance or intolerance to, or progression on atezolizumab plus bevacizumab, many clinicians will often use a current first-line treatment option, such as sorafenib or (off-label) lenvatinib, in the secondline setting. Cabozantinib may continue to be used in the secondline setting (off-label without prior sorafenib treatment) but that seems less likely for regorafenib, owing to the lack of data from patients who did not tolerate sorafenib, and ramucirumab, owing to similarities to bevacizumab (both being monoclonal antibodies that target VEGFs

| CON CLUS ION
There is limited evidence to support clinicians in choosing between approved second-line treatments for patients with advanced HCC, particularly in terms of sequencing. While product characteristics, and trial data on the efficacy, safety and tolerability and HRQoL outcomes associated with different treatment options can and should be used to inform the decision, until more data become available on current and new treatment pathways the single most important factor remains the individual patient, and their preferences should be closely considered.