Page 10 - Read Online

Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58 Page 5 of 14

Table 1. Approved treatments for advanced HCC
Treatment Benefit Level of evidence Comments
Atezolizumab and ↑ survival 1A Non-curative treatment, superior to first line sorafenib
bevacizumab [78] In unresectable HCC, bevacizumab-atezolizumab has a better OS and PFS
compared to sorafenib
Improved OS with bevacizumab-atezolizumab at 6 months (84.8%) and 12
months (67.2%) vs. 72.2% and 54.6% respectively with sorafenib
PFS is longer with atezolizumab-bevacizumab (median 6.8 months) than
with sorafenib (median 4.3 months)
Most common grade 3 or 4 AEs: hypertension, AST increase, ALT increase,
fatigue, proteinuria, diarrhoea, decreased appetite, pyrexia
Nivolumab [67] No survival benefit 1A Treatment of advanced HCC previously treated with sorafenib
Durable ORR of 14%, median duration of response 17 months
Median OS as second-line therapy:15.6 months, non-curative
Well-tolerated
In front line setting vs. sorafenib did not show increase in OS (phase III
study)
Pembrolizumab [70] No survival benefit 1A Treatment of advanced HCC previously treated with sorafenib
Overall durable response rate of 17%, PFS 4.9 months, non-curative
treatment
Well tolerated
Nivolumab and ↑ survival 1A Treatment of advanced HCC after failure of sorafenib treatment
ipilimumab [68] Objective response 31%, median duration of response 17 months
Most common AEs: fatigue, diarrhoea, rash, pruritus, nausea,
musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting,
abdominal pain, dyspnoea, upper respiratory tract infection, arthralgia,
headache, hypothyroidism, decreased weight, dizziness
More than 50% of patients may require systemic steroids to manage AEs
Evidence-based classification adapted from the National Cancer Institute. 1 = Randomized controlled trial or meta-analysis; 2 = Non-
randomized controlled trial; 3 = Case series; A = Survival endpoint; B = Cause-specific mortality; C = Quality of life; D = Indirect
surrogates. OS: overall survival; AEs: adverse events; HCC: hepatocellular carcinoma; ORR: objective response rate; AST: aspartate
transaminase; ALT: alanine aminotransferase

In the open-label phase I/II CheckMate 040 trial, nivolumab was assessed as first-line therapy in patients
with advanced HCC. The protocol had three concurrent cohorts of patients, including non-viral infected,
HBV, and HCV infected advanced HCC. The results showed an ORR of 15%, a DCR of 58%, and a median
OS of 15.6 months in the dose-escalation phase. The six-month OS was 83%, the nine-month OS was
74%, and the median duration of response (DOR) was 17 months in the dose-expansion phase. The most
[76]
common treatment-related adverse events (TRAEs) were rash (23%) and pruritus (19%) . Hepatitis
flares were not reported. However, in the phase III randomized, double blind, multicentre CheckMate-459
trial, nivolumab failed to show statistical significance in OS benefit though there was a clear trend of
improvement in OS for patients treated with nivolumab compared to sorafenib [Table 1] . The viral
[77]
infection history of the patient population remains unclear. Nivolumab is also being studied in the phase
III CheckMate-9DX study as adjuvant treatment after curative therapy (surgery or ablation) for HCC in
patients with a high risk of recurrence compared with placebo (NCT03383458). Recent reports from the
combination of nivolumab and ipilimumab in patients with advanced or metastatic HCC showed an ORR
of 33% with an 8% complete response (CR) among a total of 49 patients. There was a median DOR of
17 months with TRAEs of grade 3 or higher in 34% of patients. Among the trial cohort, 57% had an active
HBV infection and 8% had an active HCV infection, and no evidence of viral hepatitis reactivation was
[68]
detected . Nivolumab and ipilimumab in the neoadjuvant setting (NCT03222076) have shown promising
preliminary results of 29% pathologic CR with 34% TRAEs (5 HCV-positive and 1 HBV infected patients
were reported).

Pembrolizumab is a recombinant monoclonal human antibody for human PD-1. A non-randomized,
multicentre, open-label phase II study (KEYNOTE-224) tested the efficacy and safety of pembrolizumab in
patients with advanced HCC as a second line treatment option, showing an ORR of 17% and a median OS
of 12.9 months. HCV positive (n = 26) and HBV positive (n = 22) patients did not have reactivation of viral