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Page 4 of 12 Armstrong et al. Hepatoma Res 2021;7:18 I http://dx.doi.org/10.20517/2394-5079.2020.118

Pembrolizumab was also approved for second-line treatment of patients with HCC, based on the
KEYNOTE-224 phase II clinical trial. This trial demonstrated a pembrolizumab-induced ORR of 17.3%
(complete response, 1%; partial response, 16.3%) and stable disease in 44.2% of patients. The most
common treatment-related AEs were increased aspartate aminotransferase (AST) (7%), increased alanine
[46]
aminotransferase (ALT) (4%), and fatigue (4%) . The follow-up KEYNOTE-240 phase III trial confirmed
the benefits of pembrolizumab for second-line HCC. In this follow-up trial, 408 patients were randomized
in a 2:1 ratio to pembrolizumab [200 mg IV every 3 weeks (Q3W)] plus best supportive care (BSC) versus
placebo (Q3W) plus BSC for up to 35 cycles or until disease progression or unacceptable toxicity. The ORR
was 16.9% (95%CI: 12.7%-21.8%) for pembrolizumab vs. 2.2% (95%CI: 0.5%-6.4%) for placebo (nominal
one-sided P = 0.00001). Pembrolizumab responses were durable and had a median response duration
of 13.8 months (1.5-23.6). Although pre-specified statistical criteria were such that significance was not
reached, OS and progression-free survival (PFS) improved [(OS, 13.6 months vs. 10.6 months; HR = 0.78;
[47]
one-sided P = 0.0238); (PFS, 4.2 months vs. 3.8 months; HR = 0.78; one-sided P = 0.0209)] . Despite being
a statistically negative study, the results showed enough clinical benefit from pembrolizumab that justified
its approval in the second-line setting.

Despite positive results from the CheckMate 040 trial and subsequent FDA approval of nivolumab in the
second-line setting, a phase III frontline trial of nivolumab for patients with HCC failed to meet its primary
endpoints. The investigators of the phase III, international, multicenter CheckMate 459 trial randomized
743 treatment-naïve HCC patients to nivolumab (240 mg every two weeks) or standard sorafenib (400 mg
[48]
twice daily) . Nivolumab led to a better, but not statistically significant median OS compared to sorafenib
(16.4 months vs. 14.7 months; HR = 0.85; 95%CI: 0.72-1.02; P =0.0752). Therefore, nivolumab was not
approved in the frontline HCC setting. Median PFS was similar between the two groups, but the response
[48]
rate for nivolumab was higher than sorafenib (15% vs. 7%) . Although this trial was negative, based on
predetermined endpoints, the use of single-agent immunotherapy in the frontline showed a favorable
response in patients with advanced HCC, and the median OS for both groups was longer than that seen in
the SHARP trial. Interestingly, the median OS was 14.7 months in the sorafenib control arm, higher than
the 10.7 month OS observed in the original SHARP study.

COMBINATION IMMUNOTHERAPY AND TARGETED THERAPY
Anti-angiogenesis plus immunotherapy
The landmark IMbrave150 trial tested the combination of atezolizumab plus bevacizumab, and thereafter
solidified immunotherapy’s role in advanced HCC. Atezolizumab plus bevacizumab is the first therapy
to show improved PFS, OS and quality of life compared to sorafenib. The novel combination of PD-L1
inhibitor atezolizumab combined with VEGF inhibitor bevacizumab is thought to decrease angiogenesis,
[20]
decrease immunosuppression, promote T cell migration into the tumor and inhibit tumor growth .
This combination was initially studied in the phase Ib GO30140 trial, in which patients with untreated,
unresectable HCC (n = 119) were randomized to receive atezolizumab (1200 mg IV every 3 weeks) alone
or with bevacizumab (15 mg/kg IV every 3 weeks) until the development of unacceptable toxicity or loss
[49]
of clinical benefit . The 60 patients who received the treatment combination had better outcomes than
the 59 patients treated with atezolizumab alone. Atezolizumab plus bevacizumab had an acceptable side-
effect profile, and there was a significant improvement in the primary endpoint of median PFS compared to
atezolizumab alone: 5.6 vs. 3.4 months (1.9-5.2; HR = 0.55; 80%CI: 0.40-0.74; P = 0.011) .
[49]
The GO30140 trial seeded the global, open-label, phase 3 IMbrave150 trial, which randomized 501
treatment-naive advanced HCC patients (2:1) to receive either a combination of atezolizumab (1200 mg IV
every 3 weeks) plus bevacizumab (15 mg/kg IV every 3 weeks) or standard of care sorafenib (400 mg bid) .
[20]
After a median follow-up duration of 8.6 months, the results revealed an improved OS in the combined
[20]
therapy group (HR = 0.58; 95%CI: 0.42-0.79; P ≤ 0.001) . The OS rates at 6 months and 12 months were