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Page 8 of 10 Merle et al. Hepatoma Res 2020;6:60 I http://dx.doi.org/10.20517/2394-5079.2020.52
[10]
increased OS vs. placebo with a hazard ratio (HR) of 0.69 (95%CI: 0.55-0.87, P < 0.0001) . REFLECT
[11]
was a head-to-head comparison of lenvatinib and sorafenib, within a non-inferiority trial , but after trial
withdrawal, 33% and 39% of patients received potentially active medications against HCC, likely one of the
reasons why the OS of sorafenib improved from SHARP (10.7 months) conducted a couple of years before
[11]
[10]
2008 , towards REFLECT (12.3 months) conducted 10 years later [Table 3]. In the other 1L systemic
therapies with control arm, the same comments can arise from CheckMate-459 comparing nivolumab to
[20]
sorafenib . It was an open label trial, and at radiologic progression, patients were withdrawn and received
potentially active subsequent medications [Table 3]. That explains, at least in part, the high OS value in
the sorafenib arm (14.7 months), that maybe led to conceal the benefit of nivolumab (OS 16.4 months)
[20]
vs. sorafenib (HR 0.85 [95%CI: 0.72-1.02]; P = 0.0752) . The same conclusions can be drawn from the
[16]
IMBrave150 trial [Table 3] where OS under sorafenib was surprisingly high at 13.2 months, and the
atezolizumab/bevacizumab combination increased OS (not reached) vs. sorafenib (13.2 months) with HR
[16]
of 0.58 (95%CI 0.42-0.79, P < 0.0006) , the efficacy of the atezolizumab/bevacizumab combination being
high enough to prevent any concealing by the overestimated value of OS in the sorafenib arm.

However, operator experience acquired over time is also likely a relevant factor that has a
greater impact on OS in the sorafenib arms
In 2L setting, all control arms were placebo arms, also debatable due to post-withdrawal medications [Table 3].
In spite of the overestimated values of OS in placebo arms in 2L, regorafenib increased OS with HR of 0.63
[12]
(95%CI: 0.50-0.79, P < 0.0001) , cabozantinib improved OS with HR of 0.76 (95% CI 0.63-0.92, P < 0.005) ,
[13]
[14]
and ramucirumab improved OS with HR of 0.71 (95%CI: 0.53-0.95, P = 0.0199) . In the KEYNOTE-240
phase 3 study, the trial did not meet the statistical criteria for either of the dual endpoints (OS and PFS)
[18]
although pembrolizumab improved OS over placebo with HR of 0.78 (95% CI 0.61-0.99, P = 0.0238) , but
the placebo arm showed abnormally high OS value of 10.6 months, in part due to post-withdrawal trial
medication [Table 3].

CONCLUSION
For more than a decade, huge improvements have arisen in the systemic strategy of HCC therapy. The
coming 1L will associate atezolizumab and bevacizumab. Of course, a lot a work remains to be done to
improve this combination and find some strategies overwhelming primary or secondary resistances. Results
are soon expected from other 1L combinations in phase 3: pembrolizumab/lenvatinib (NCT03713593),
atezolizumab/cabozantinib (NCT03755791), durvalumab/tremelimumab (NCT03298451), and nivolumab/
ipilimumab (NCT 04039607). At the moment, there is also an urgent need for prospective controlled trials
to identify the best TKI therapy following progression under any ICI combination schedule. Sorafenib and
lenvatinib were the two possible 1L. Will they remain the gold standard after ICI combination schedule
failure? If yes, the subsequent TKIs after their own failure would likely remain regorafenib, cabozantinib or
ramucirumab, if not used in the prior ICI combination schedules of 1L. Only randomized controlled trials
will guide the future ways of research and draw the future therapeutic algorithms to improve more and
more the treatment of HCC.

DECLARATIONS
Authors’ contributions
Made substantial contribution to conception and design of the review article, and performed data analysis
and interpretation: Merle P, Subic M

Availability of data and materials
Not applicable.