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Armstrong et al. Hepatoma Res 2021;7:18 I http://dx.doi.org/10.20517/2394-5079.2020.118 Page 5 of 12

84.8% (95%CI: 80.9-88.7) and 67.2% (95%CI: 61.3-73.1) respectively, in the atezolizumab-bevacizumab
group; and 72.2% (95%CI: 65.1-79.4) and 54.6% (95%CI: 45.2-64.0) respectively, in the sorafenib group. The
median PFS was longer with the atezolizumab-bevacizumab combination than with sorafenib [6.8 months
(95%CI: 5.7-8.30) vs. 4.3 months (95%CI: 4.0-5.6); stratified HR for progression or death, 0.59; 95%CI:
0.47-0.76; P < 0.001]. Secondary outcome findings included an ORR by RECIST 1.1 of 27.3% in the
atezolizumab-bevacizumab group versus 11.9% in the sorafenib group (95%CI: 7.4-18.0; P <0.001), and an
ORR by hepatocellular carcinoma-specific mRECIST of 33.2% (95%CI: 28.1-38.6) versus 13.3% (95%CI:
[20]
8.4-19.6; P < 0.001) . The study also explored quality-of-life outcomes utilizing the EORTC QLQ-30
questionnaire. Results showed that a combination of atezolizumab plus bevacizumab delayed the time to
deterioration compared to sorafenib (11.2 months with the combination vs. 3.6 months with sorafenib;
HR = 0.63; 95%CI: 0.46-0.85). The most commonly seen combination therapy grade 3 or 4 AEs were
hypertension (15.2%), elevated AST (7%) and elevated ALT (3.6%). Although this landmark trial led to
the approval of atezolizumab plus bevacizumab as a frontline treatment for individuals with unresectable
or metastatic HCC and meaningfully changed the advanced HCC treatment landscape, this therapy is
not suitable for every patient. The trial excluded those with Child-Pugh B and C, Eastern Cooperative
Oncology Group (ECOG) 2 or greater, a history of autoimmune diseases, coinfections with HBV and HCV,
[20]
and untreated esophageal or gastric varices that accompanied bleeding or were at risk of bleeding .
TKI plus immunotherapy
The focus on drug development in HCC over the past decade has utilized targets in the VEGF receptor
(VEGFR) signaling pathway, including monoclonal antibodies as discussed above and TKIs with success.
Studies of the combination of TKIs with immunotherapy are ongoing and preliminary results are
promising.

Combination immunotherapy regimens currently being investigated include lenvatinib plus pembrolizumab,
[50]
tested in a recent phase 1b trial (n = 100) . Lenvatinib, a multikinase inhibitor, is approved for frontline
HCC treatment, and pembrolizumab has accelerated approval in the second-line setting. The results from
this phase 1 trial revealed a side effect profile similar to that of each drug alone; the most common grade
3 AE was hypertension. Three treatment-related deaths occurred, which were related to acute respiratory
distress syndrome, intestinal perforation and liver failure. The response rate was 36% when using RECIST
[50]
and 46% when using modified RECIST . Median OS was 22 months (95%CI: 20.4-not yet reached), and
the median PFS was 8.6 months (95%CI: 7.1-9.7). This combination regimen is undergoing investigation in
the phase 3 LEAP-002 trial (NCT03713593), which has completed accrual, and results are pending.

Another anti-PD-L1 and multi-targeted TKI combination, penpulimab plus anlotinib, went under clinical
study in China. The phase Ib/II open-label multicenter trial tested the combination of penpulimab and
anlotinib in 31 patients with unresectable HCC. Results demonstrated an ORR of 24% (NCT04172571), and
the most frequent treatment-related AEs included AST (35.5%) and ALT (29%) elevation, fatigue (22.6%),
[51]
thrombocytopenia (19.4%), increased bilirubin (19.4%) and rash (16.1%) .
Studies are ongoing to explore the novel combination of atezolizumab plus cabozantinib, an oral TKI
that targets the VEGFR, MET and AXL family, in the treatment of patients with advanced HCC. The
combination was tested in a phase I trial that included patients with advanced HCC and various other
malignancies. The study found no grade 4 or 5 AEs on treatment with cabozantinib (40 mg daily) plus
[52]
atezolizumab (1200 mg IV every 3 weeks) . Combination cabozantinib plus atezolizumab is also being
compared to sorafenib treatment of patients with advanced HCC in the phase 3 global, randomized open-
[53]
label COSMIC-312 study (NCT03755791) . The primary endpoints are PFS by RECIST and OS.