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

be done with considerable cautioun. However, the long duration of tumor response under atezolizumab/
bevacizumab combination as discussed above in “ORR” paragraph, was clearly of huge importance to
[16]
impact on the long median OS (not reached) , whereas the quite similar PFS under lenvatinib was
[11]
associated with a much lower OS (13.6 months) . Unfortunately, the duration of response under lenvatinib
has not been assessed, although it is likely shorter than under ICIs and similar to those of other TKIs [Table 1],
[12]
for instance 3.5 months with regorafenib . This difference in OS cannot be explained by the disease
[16]
control rate (DCR by Recist 1.1) since very similar in both trials (74% for atezolizumab/bevacizumab vs.
[11]
72.8% for lenvatinib ) [Table 1].
PFS by Recist 1.1 for monotherapies of ICI gave values around 4 months (3.0-4.9) [17-20] , quite similar to
[12]
[11]
those of TKIs such as sorafenib (3.6 months) and regorafenib (3.4 months) . PFS seems to be better
with cabozantinib (5.2 months) , but worse with ramucirumab (2.8 months) , which supported a poor
[14]
[13]
prognosis subpopulation. When available, TTP was in accordance with PFS. It is important to underline
that ICI monotherapy responders have a long duration of response [Table 1], but the number of responders
was too low in the trials to have a significant impact on median PFS or median TTP, and finally on median
OS. Differences on PFS/TTP/OS cannot be explained by different DCRs [Table 1] since they were quite the
[16]
[8]
same between ICI and TKI schedules: atezolizumab/bevacizumab (74%) , nivolumab/ipililumab (50%) ,
[11]
nivolumab (55%-64%) [19,20] , pembrolizumab (61%-62.2%) [17,18] , lenvatinib (72.8%) , sorafenib (59-71%) [10,11] ,
[13]
[12]
regorafenib (66%) , and cabozantinib (64%) .
Overall survival
Overall survival (OS), defined as the time from randomization to death, is a direct measure of clinical
benefit to a patient and the gold standard primary endpoint to evaluate the outcome in oncologic clinical
trials. OS is easily measured, unambiguous, objective, not subjected to researcher bias and it is used by the
international authorities worldwide for cancer drug approval. OS is the primary endpoint recommended
for all phase 3 studies in HCC. When selecting endpoints in HCC clinical trials, it must be also considered
that OS is impacted by liver failure due to both the end stage natural history of underlying chronic liver
disease and the HCC loco-regional spread, which in turn promotes liver failure and leads to death. Thus,
if the treatment aims to reduce HCC-related death (i.e., the endpoint is cancer-related death), but the
competing mortality from progressive liver failure is high in both the active treatment and in the control
arms, the risk ratio will be reduced and the required sample size increases. Thus, phase 3 studies in HCC
require a larger sample size to include competing risk analysis and assess cancer-related deaths as compared
to OS evaluation.

In the present review, regarding OS [Table 3] and taking into account potential confounding factors that
may influence the median OS, atezolizumab/bevacizumab therapy has not reached median OS so far
[16]
taking into account that the median follow-up is only 17 months , the nivolumab/ipilimumab combination
[20]
(22 months) , nivolumab (16.4 months) , pembrolizumab (12.9-13.9 months) [17,18] , lenvatinib (13.6 months) ,
[8]
[11]
[13]
[10]
[12]
sorafenib (10.7 months) , regorafenib (10.6 months) and cabozantinib (10.2 months) , while worse
[14]
with ramucirumab (8.5 months) due to the poor prognosis assessed subpopulation . The 1L or 2L design
of the trials does not impact much the spontaneous OS of patients since in the placebo arms of randomized
controlled trials, median OS is quite the same in 1L or 2L for HCC patients eligible for systemic therapies
with ECOG PS status 0-1 and Child-Pugh A liver functions. Indeed, OS of placebo arms seems similar in
[27]
1L phase 3 trials (7.9 months in SHARP , 8.5 months in SEARCH ) by comparison to 2L/3L phase 3 trials
[10]
[12]
[18]
[13]
(7.9 months in RESORCE , 8 months in CELESTIAL , 10.6 months in KEYNOTE-240 , 8.2 months
in BRISK-PS , 7.3 months in EVOLVE-1 , 7.6 months in REACH , and 9.1 months in METIV-
[28]
[21]
[29]
[30]
HCC ).
The control arm and subsequent therapies administered after trial withdrawal are of prominent importance.
Indeed, OS in HCC randomized controlled trials depends on the target population, the parameters assessed