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modest increase in survival in the sorafenib groups compared to placebo controls, the objective response
rates of < 2.0% were also very low. However, toxicities have been considerable, with many patients requiring
dose reduction, variable drug “holiday” or drug discontinuation. Toxicities include hand-foot syndrome,
[29]
rash, diarrhea and fatigue, most commonly, but also hypertension, nausea and leukopenia .
Several large phase III trials comparing sorafenib with newer agents have failed to successfully meet their
planned end-points, including trials of brivanib, linifanib, sunitinib. A randomized phase II trial with
sorafenib vs. erlotinib plus bevacizumab likewise failed to show superiority for the comparison arm with
respect to sorafenib. The onlyrecent exception thus far, is the recently FDA-approved lenvatinib (below)
phase III trial.

Several attempts to improve on sorafenib therapy by combining it with other agents or with TACE or SIRT,
have been recently made. However, results have so far been minor at best [30,31] . Sorafenib was also evaluated
[32]
as an adjuvant therapy to resection in the STORM trial, but also without added benefit to surgery alone .

Lenvatinib (lenvima)
FDA has just (Aug 2018) approved lenvatinib for first line therapy of advanced or metastatic HCC, based on
a randomized controlled phase III REFLECT trial, comparing lenvatinib 8 or 12 mg daily with sorafenib
[33]
400 mg twice daily . Median OS was 13.6 months for lenvatinib and 12.3 months for sorafenib. The trial
demonstrated that lenvatinib was noninferior (but not statistically superior) to sorafenib for OS, which was
the primary endpoint (HR 0.92; 95% CI 0.79-1.06). The overall response rate was higher for lenvatinib than
for sorafenib (41% vs. 12% per modified RECIST and 19% vs. 7% per RECIST 1.1). Patients with main trunk
PVT were excluded from this trial. The commonest toxicities in the lenvatinib-treated patients (≥ 20%) were
hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain
and palmar-plantar erythrodysaesthesia. It is a multi-tyrosine kinase inhibitor of VEGFR1-3, FGFR 1-4,
rearranged during transfection (RET), receptor tyrosine kinase (KIT, also called CD117 and stem cell factor
receptor) and PDGFR.

Thus, current first-line therapies for previously untreated HCC, include TACE, SIRT, sorafenib and
lenvatinib [Table 2]. The initial choice has been conventional chemoembolization (TACE) or more recently
SIRT, especially in the presence of PVT and excellent liver function. However, in the presence of 5 or more
lesions or bilobar lesions, it is reasonable to consider Sorafenib or Lenvatinib as initial therapy, especially in
the presence of serum bilirubin levels > 2.5 mg/dL, in light of the known hepatotoxicity of both TACE and
SIRT.

Current second line therapies
Regorafenib (stivarga)
Regorafenib is a multi-kinase inhibitor of VEGFR1-3, tyrosine kinase with immunoglobulin-like and EGF-
like domains 2-unlike sorafenib, PDGFRβ, FGFR, c-KIT (stronger than sorafenib), RET, BRAF, BRAFV600
and RAF-1. It is the first agent to provide survival benefit in the second line, after failure of sorafenib
[34]
and has recently been FDA-approved as a second line therapy. The phase III RESORCE study was for
HCC patients who had progressed on sorafenib, but not failed due to toxicity, and it improved OS with
a HR of 0.63 (P < 0.0001); the median OS was 10.6 months for regorafenib vs. 7.8 months for placebo and
the disease control rate was 65.2% vs. 36.1% (P < 0.001). Regorafenib was administered at 160 mg daily for
3 weeks, with a subsequent rest week. The commonest grade 3 or 4 treatment-emergent events were 15%
hypertension in the regorafenib group vs. 5% in the placebo group, 13% hand-foot skin reaction/palmar-
plantar erythrodysaesthesia for regorafenib vs. 1% in the placebo group, 9% fatigue for regorafenib vs. 5% in
the placebo group, with 3% diarrhea for regorafenib vs. none for placebo. Thus, these data differ from the
sorafenib SHARP trial results in which few patients had objective responses, suggesting that regorafenib
(fluoro-sorafenib) is a more potent agent than sorafenib. Toxicities were similar for regorafenib and sorafenib,