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Page 2 of 10 Merle et al. Hepatoma Res 2020;6:60 I http://dx.doi.org/10.20517/2394-5079.2020.52

INTRODUCTION
Hepatocellular carcinoma (HCC) is a poor prognosis tumor ranking fourth as the leading cause of cancer
[1]
death worldwide, with about 841,000 new cases and 782,000 deaths annually inventoried in 2018 .
Due to the frequently silent clinical character and the low sensitivity of currently available diagnostic
biomarkers, HCC is commonly diagnosed at an advanced stage when curative treatments, i.e., surgical
resection, ablations, and liver transplantation, or radiologic palliative loco-regional therapies are not
[2]
feasible. Thus, these patients are eligible for systemic strategies . Until 2007, treatment options for
advanced HCC were lacking. No systemic cytotoxic chemotherapies, including new compounds loaded
[3]
onto nanoparticles , have ever shown to significantly improve overall survival (OS) of HCC patients.
[2]
Similarly, hormonotherapy and somatostatin analogs have failed to definitely benefit OS . The approval in
2007 of the first oral tyrosine kinase inhibitor (TKI) and antiangiogenic agent (AAA), sorafenib, and the
more recent development of other TKIs and immune checkpoint inhibitors (ICIs) as well, have completely
revolutionized the therapeutic paradigm for HCC. The perspectives for advanced HCC patients have
changed from palliative short-term mortality towards long-term survival expectations. Several drugs are
now available, and in this review, we will compare their efficacy with respect to OS and other surrogate
endpoints as well, keeping in mind that they are still controversial and their pertinence must be carefully
discussed. We will only focus on data emerging from positive phase 3 trials, and from those phase 1b/2
studies that led to an early US-FDA approval.

EFFICACY OF DRUGS: ENDPOINTS OF CLINICAL TRIALS
Clinical trials in HCC have been originally designed according to conventional biostatistical rules applied
in oncology trials , following the traditional linear model of cancer drug development in which drug
[4]
activity assessment occurs in randomized confirmatory phase 2 and 3 clinical trials with OS as the most
important endpoint for demonstrating clinical benefit. Nevertheless, OS has some disadvantages such as
the requirement for long follow-up time, the need for a high number of patients and the possibility to be
affected by sequential therapies administrated after tumor progression. The need to achieve a more rapid
development of new targeted antitumor agents led to the adoption of innovative clinical trial designs
and the identification of surrogate endpoints of survival such as progression-free survival (PFS), time to
progression (TTP) and objective response rate (ORR).

Objective response rate
ORR directly reflects the treatment antitumor activity and is usually defined as the sum of complete (CR)
and partial response (PR) rates. In HCC, ORR is measured according to Recist (Response Evaluation
[5]
Criteria In Solid Tumors) version and/or liver modified-Recist (mRecist) criteria . ORR has been
considered to be the primary endpoint for phase 2 studies dealing with local ablations or loco-regional
therapies studies in HCC where this endpoint is consistently associated with OS . Whereas with the
[6]
introduction of molecularly targeted treatments with TKIs, reliance on ORR needs to be reconsidered
because clinically significant survival advantages are reported despite faint ORRs. Of course, long-lasting
stable disease with the absence of progression is a beneficial characteristic, as death due to progression
would not occur. In contrast, ORR has shown to be a potentially promising endpoint to obtain clinical
[7,8]
benefit from some systemic drugs and in particular ICIs in HCC .

Although Recist 1.1 and mRecist criteria can both be used to assess ORR in HCC, Recist 1.1 remains the
gold-standard in phase 3 trials with systemic therapies. Of course, it is quite simple to apply Recist 1.1 after
liver resection or transplantation. In contrast, local thermoablations or loco-regional intra-arterial therapies
induce tumor necrosis, and thus, Recist 1.1 is not appropriate any more since it is unable to capture such
an effect since relying on size reduction and ignoring necrosis. That is the reason why the EASL introduced
[9]
criteria including the use of absence of contrast uptake in dynamic imaging to register response ,