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Page 4 of 10 Merle et al. Hepatoma Res 2020;6:60 I http://dx.doi.org/10.20517/2394-5079.2020.52
[8]
[16]
former. In those, comprising atezolizumab/bevacizumab and nivolumab/ipilimumab combinations,
durations of response were long-lasting (median not reached and 17.5 months, respectively) as well as with
[20]
[18]
ICI monotherapies (median 23.3 months with nivolumab , 13.8 months with pembrolizumab ), and
unfortunately not determined with lenvatinib .
[11]
ORR might be a surrogate endpoint of drug efficacy in some cases. In phase 1/2 trials with ICIs, ORR by
[7]
Recist 1.1 seemed to deeply correlate with OS of patients treated either with nivolumab monotherapy
or with the nivolumab/ipilimumab combination . In both cases, tumor responders (CR + PR) had the
[8]
best OS [median non-reached (NE-NE) for both cases]. Patients in progression disease (PD) did not
seem to have any benefit on OS by comparison to well known patients randomized in the placebo arms
in controlled trials [8.9 months (7.3-13.4) and 8.3 months (6.6-10.8), respectively]. Intermediately, stable
diseases (SD) had better but not striking data [16.7 (13.8-20.2) and 14.5 (8.4-29.6), respectively]. However,
[16]
it has not been assessed so far in the atezolizumab/bevacizumab phase 3 trial or other kind of ICI plus
AAA combination in phase 1/2 studies, whether ORR has the same predictive value on the outcome of
HCC patients. Furthermore, no data on the field are available regarding the correlation between ORR by
mRecist and OS of HCC patients treated with ICIs.

These observations do not seem so evident with TKIs, which have the disadvantage of resulting in very
[11]
low levels of ORR except for lenvatinib . ORR (and TTP) have been suggested as potential surrogate
endpoints for OS in advanced HCC with brivanib [21,22] , and seemed to be confirmed with sorafenib and
lenvatinib in REFLECT [11,23] . However, a weak correlation was reported between ORR, TTP/PFS and OS in
SHARP with sorafenib , and with regorafenib in RESORCE [12,24] . In this later study, since ORR was rather
[10]
low either by Recist 1.1 (2%) or mRecist (10%), a bootstrap approach was applied to simulate 10,000 trials
of patients with advanced HCC from RESORCE (n = 573), and the mean simulated results were calculated.
A Pearson correlation was calculated between estimated median OS and estimated ORR for regorafenib
and placebo arms separately. The Pearson correlation of log-rank test statistics was calculated comparing
regorafenib and placebo. The Pearson correlation of log-rank test statistics comparing the two arms for
OS was used and the Cochran-Mantel-Haenszel test statistic used to compare the two treatment arms for
ORR. Finally, a weak correlation between median OS and ORR was found for regorafenib and placebo
in RESORCE, indicating that mRecist/Recist 1.1 ORR may not be a reliable surrogate endpoint for OS in
patients with advanced HCC. The same observation was found for TTP in this study.

In summary, ORR could be as a good surrogate marker for OS in HCC patients under lenvatinib or ICI
therapy, which give high levels of ORR, whereas it is more complex, debatable and doubtful for drugs
with low level of ORR such as sorafenib and regorafenib, keeping in mind that this research has not been
performed so far for cabozantinib and ramucirumab.

Progression-free survivals and/or time to radiologic progression
In HCC, progression-free survival (PFS) is frequently used in phase 2 trials. PFS is a composite endpoint
that includes: (1) radiologic progression as defined by Recist 1.1 or mRecist; and (2) death due to tumor
progression or the terminal natural history of the underlying chronic liver disease. In general, regulatory
agencies prefer PFS to TTP for drug approval because the former endpoint may be better correlated with
[25]
OS . However, in HCC, PFS might not be reliable because death resulting from the natural history
of cirrhosis might confound the detection of potential benefits from effective drugs. The risk of bias in
detection of potential benefits from effective antitumor drugs due to death related to liver failure despite
a relevant antitumor response can be avoided using restrictive inclusion criteria for evaluation of liver
[25]
function .

[26]
Time to radiologic progression (TTP), on the other hand, is a pure radiologic endpoint , and requires
repeated radiologic measurements to capture relevant differences between groups that can be missed if the