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Page 8 of 13 Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21

therapy. Grade 3 and 4 adverse events included diarrhea (20%), palmar-plantar erythrodysesthesia (15%) and
[57]
thrombocytopenia (15%). More than the half of patients (59%) required at least one dose reduction .

In the randomized, double-blind, parallel-assignment, placebo-controlled phase 3 trial (CELESTIAL), 707
subjects with HCC were randomized according to a 2:1 ratio to receive cabozantinib at 60 mg daily (n = 470)
[58]
or placebo (n = 237) . All the patients presented ECOG performance status of 0 or 1, Child-Pugh score of
A, and resulted progressed or intolerant to at least 1 prior systemic therapy for advanced HCC. Worth to
be mentioned is that 28% of subjects received two prior systemic therapies regimen, therefore CELESTIAL
study enrolled also patients receiving cabozantinib as third line of treatment. The primary endpoint OS
resulted significant favorable to cabozantinib: 10.2 months compared with 8.0 months with placebo,
representing the 24% reduction in the risk of death (HR 0.76; 95% CI 0.63-0.92; P = 0 .0049). The PFS with
cabozantinib was 5.2 months compared with 1.9 months for placebo, corresponding to the 56% of reduction
in the risk of progression or death with the targeted therapy (HR 0.44; P < 0.0001). In the subgroup analysis
of patients receiving only prior sorafenib, the median OS was 11.3 months with cabozantinib compared with
[58]
7.2 months for placebo (HR 0.70) .

In the treatment arm resulted an increased number of patients discontinuing due to treatment-related
adverse events, in particular the most common grade 3/4 adverse events with cabozantinib resulted
hand-foot skin reaction (17% vs. 0% in placebo arm), hypertension (16% vs. 2%), increased aspartate
aminotransferase (12% vs.7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). In addition, cabozantinib
arm presented a higher incidence of grade 5 adverse events; in fact, 6 patients died due to hepatic failure,
esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism,
and hepatorenal syndrome. The median duration of exposure resulted in 3.8 months and 2 months in
[58]
cabozantinib and placebo arms respectively . Notably, the discordance registered between PFS and DoE
in the active arm versus the placebo one could be explained by the significant higher incidence of adverse
events in the cabozantinib group that could have been led to an earlier treatment discontinuation, reflecting
probably a not easy management of toxicities.

Nivolumab
Nivolumab in HCC was investigated in the CheckMate-040 trial, a multicenter, open label phase I/II
study conducted from November 2012, to August 2016 in adults (≥ 18 years) with histologically confirmed
advanced HCC with or without hepatitis C or B (HCV OR HBV) infection. A previous sorafenib treatment
[59]
was allowed . The study enrolled 48 patients in a first dose-escalation phase and 214 patients in a
subsequent dose-expansion phase. Primary endpoints were safety and tolerability for the escalation phase
and objective response rate (evaluated by RECIST version 1.1) for the expansion phase.

In the escalation phase, patients received 0.1 to 10 mg/kg of IV nivolumab every 2 weeks. Nivolumab 3 mg/kg
[59]
every 2 weeks was chosen for the dose expansion phase . The confirmed overall response rate assessed by
blinded independent central review was 14.3% (22 of 154 patients), with 3 complete responses (1.9%) and
19 partial responses (12.3%). Response duration ranged from 3.2 to more than 38.2 months; 91% of those
patients had responses of 6 months or longer and 55% had responses lasting 12 months or longer.

Common adverse reactions occurring in more than 20% of patients included fatigue, rash, musculoskeletal
pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain,
arthralgia, upper respiratory tract infection, and pyrexia. Differently for the safety profile previously
described in nivolumab label, patients of CheckMate-040 reported a higher incidence of elevations in
transaminases and bilirubin levels: treatment-emergent grade 3 or 4 AST was observed in 27 (18%) subjects,
grade 3 or 4 ALT in 16 (11%) patients, and grade 3 or 4 bilirubin in 11 (7%) patients. Immune-mediated
[59]
hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients .