Page 39 - Read Online

Page 6 of 10 Carr. Hepatoma Res 2019;5:3 I http://dx.doi.org/10.20517/2394-5079.2018.113

[37]
trial was reported , showing that in sorafenib resistant patients, cabozantinib treatment resulted in longer
OS than for placebo patients. Median OS was 10.2 months with cabozantinib and 8.0 months with placebo
(HR for death, 0.76; 95% CI 0.63-0.92; P = 0.005), and the objective response rates were 4% for cabozantinib,
but less than 0.4% for placebo, respectively (P = 0.009). 16% of patients discontinued cabozantinib due to
treatment-related adverse events (palmar-plantar erythrodysesthesia, hypertension, fatigue, diarrhea and
increased aspartate aminotransferase), compared to 3% of patients on placebo. Given that the phase III trial
also included patients receiving cabozantinib as third line therapy, this opens the possibility for the potential
for third line therapies in patients with resistant HCC or who are intolerant to other therapies.

Ramucirumab (cyramza)
Ramucirumab is an anti-angiogenic VEGFR-2 antagonist that binds and blocks VEGF-A, VEGF-C and
VEGF-D. In a phase III placebo-controlled trial (REACH) in second line on sorafenib failure patients,
no significant survival differences were found between ramucirumab and placebo. However, meaningful
improvement was observed in a patient subgroup with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL, HR
= 0.67, P = 0.006; median OS 7.8 months for ramucirumab vs. 4.2 months for placebo controls. Therefore, a
subsequent phase III randomized trial was performed (REACH-2), in a biomarker-selected HCC patients,
[38]
having AFP levels of > 400 ng/mL . In patients with baseline AFP ≥ 400 ng/mL, a significant survival
benefit was found in patients treated with ramucirumab compared with placebo and was coupled with a
trend in patient-focused outcome benefits. The only grade 3 toxicity was hypertension and hyponatremia in >
[39]
5% of the patients. In a Japanese sub-analysis , the median OS was 12.9 months for the ramucirumab arm (n
= 45) and 8.0 months for the placebo arm (n = 48) (HR 0.621; 95% CI 0.391-0.986; P = 0.0416). In patients with
a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm
(n = 20) and 4.3 months for the placebo arm (n = 22) (HR 0.464; 95% CI 0.232-0.926); P = 0.0263). Objective
response rates were 11% for the ramucirumab arm and 2% for the placebo arm (P = 0.0817). Ramucirumab is
currently being considered for approval by the FDA.

Thus, 3 agents are currently FDA-approved for second line therapy, namely regorafenib, nivolumab
and cabozantinib. However, in 2019 ramucirumab may also be approved in this same setting. How does
one choose the optimal sequence for using these agents? In addition, for liver-only HCC patients who
have failed chemoembolization and who have preserved liver function, may also be suitably treated with
radioembolization. Given the high response rates for regorafenib, this is an attractive agent for use in this
setting, but its use is also associated with considerable toxicities. The RESOURCE trial on which its approval
was based, did not include patients who were sorafenib-intolerant in the first line setting. Thus, the use of
regorafenib in the second line setting may be limited to a subset of patients. Cabozantinib and ramucirumab
are also multikinase inhibitors, with similar toxicities to both sorafenib and regorafenib. Therefore, patients
whose tumors have failed chemoembolization and/or radioembolization might be most suitably offered
nivolumab at the time of writing, due to its different toxicities and even higher responses. New approvals
are likely however, for other immune checkpoint inhibitors and/or their combinations with other agents and
these recommendations will then need to be reconsidered.

EXTRA-HEPATIC METASTASIS AND PVT
Metastasis is the single most important cause of morbidity and mortality in most solid adult tumors. HCC
may be an exception, as patients usually die of their liver failure, either from tumor growth and parenchymal
liver destruction, or from the underlying and liver disease that caused the HCC to arise, regardless of the
presence or absence of metastasis. HCC with extra-hepatic metastasis may even constitute a distinct HCC
[40]
subset, and is associated with less cirrhosis than other HCC . While systemic therapy is mainly chosen
[41]
in this circumstance , an argument can also be made to initially treat the main disease in the liver.
Regardless, several studies with systemic chemotherapy or multikinase therapy have shown no survival
benefit in this situation.