Page 124 - Read Online

Gomaa et al. Advanced HCC: current and potential therapies

investigated and showed encouraging results in phase years, and demonstrated 72% OS rate at 6 months
II studies. Currently several phase III studies evaluating with durable responses across all dose levels and HCC
combination of multiple targeted agents for treatments cohorts (ORR:15%, DCR: 65%), with manageable AE
of advanced HCC are ongoing. profile. These responses were observed regardless of
viral hepatitis infection status. In the expansion phase,
In a phase III study, the combination of sorafenib and nivolumab was well tolerated in patients with HBV and
the EGFR-TKI erlotinib in advanced HCC (SEARCH HCV related HCC. [48] OS rates for all patients at 6 and 9
study) did not significantly improve survival over months were 82.5% and 70.8%, respectively. Disease
sorafenib alone. [14] Similarly, the combination of the stabilization was observed in patients who previously
mTOR inhibitor everolimus with sorafenib did not progressed on sorafenib, 91 of 204 patients (45%) had
improve the efficacy of sorafenib in patients with reduction in tumor burden and 45 (22%) had ≥ 30%
unresectable or metastatic HCC. [44] reduction in tumor burden compared to baseline. [48]
A phase III trial evaluating nivolumab vs. sorafenib as
Refametinib, an oral mitogen-activated protein kinase first-line treatment in patients with advanced HCC is
(MEK), or mitogen-activated protein kinase (MAPK)/ ongoing (Checkmate-459, NCT02576509).
ERK kinase] inhibitor, combined with sorafenib,
improved survival in patients with advanced stage Cytotoxic-T-lymphocyte-antigen (CTLA)-4 blockade
HCC (DCR: 43%, TTP: 122 days, OS: 290 days) could be an efficient alternative in advanced HCC. In
with patients with rat sarcoma (RAS) mutations a phase II study, the CTLA-4 inhibitor tremelimumab
experiencing the best clinical response. However, showed partial response rate 17.6%, DCR 76%, TTP
grades 3 and 4 adverse events were reported in about 6.5 months. [49] However, 45% of patients experienced
80% of cases. [45] An ongoing trial is evaluating the grade-3 aspartate aminotransferase and alanine
combination in patients with unresectable or metastatic aminotransferase elevations. Studies exploring
HCC with RAS mutation (NCT01915602). combinations of these agents in a randomized, second-
line setting are ongoing. A phase II study is currently
Clinical trials of sorafenib in combination with the evaluating the PD-L1 inhibitor durvalumab and
transforming growth factor receptor beta (TGF-β) tremelimumab alone or in combination for patients with
inhibitor galunisertib (LY2157299), the mTOR inhibitor unresectable HCC who progressed on, are intolerant
temsirolimus, and the histone deacetylase (HDAC) to, or refused treatment with sorafenib (NCT02519348).
inhibitors vorinostat and resminostat are currently
ongoing. Systemic chemotherapy
Cytotoxic agents as 5-fluorouracil, cisplatin,
Immune therapy for HCC doxorubicin, gemcitabine, capecitabin, epirubicin or
Programmed cell death ligand 1 (PDL-1) are expressed combined regimens showed a low response rate (<
on HCC tumor cells. These interact with PD-1 receptors 10%) with slight improvements in OS. [50,51] Cisplatin,
on activated T cells, leading to their inactivation, thus interferon, doxorubicin, and fluorouracil (PIAF) in
enhancing tumor-cell survival. Blocking the PDL-1- combination showed favorable results in a phase II
PD-1 receptor interaction increases tumor necrosis. [46] study. In a phase III study, PIAF combination compared
to doxorubicin alone demonstrated no significant
Nivolumab is a fully human IgG4 monoclonal antibody difference in OS (8.67 vs. 6.83 months) or in ORR
inhibitor of the programmed death-1 (PD-1) receptor (20.9% vs. 10.5%). [51] Patients treated with the PIAF
that restores T-cell-mediated antitumor activity. regimen experienced higher rate of myelotoxicity
Treatment with nivolumab has extended survival in compared with doxorubicin.
multiple tumor types, and it is approved for metastatic
melanoma, metastatic non-small cell lung cancer, The lower effect of doxorubicin in HCC is assumed to
advanced renal cell carcinoma, Hodgkin lymphoma, result from multidrug resistance (MDR) mechanisms.
and recurrent or metastatic squamous cell carcinoma Doxorubicin-Transdrug (DT), a nano-particle
of the head and neck. [47] formulation of doxorubicin, has been shown to enter
HCC cells by diffusion, by passing the MDR proteins,
Nivolumab was evaluated in a multiple ascending- and demonstrated higher intracellular concentration
dose, phase I/II study in patients with advanced-stage and effectiveness than doxorubicin. [52] A phase III
HCC, refusing, intolerant, or progressing on sorafenib multicenter, randomized, controlled trial comparing
with preserved liver function (CTP score up to B7) the efficacy and safety of IV infusions of doxorubicin-
(Checkmate-040 trial). [48] Patients received intravenous transdrug in patients with advanced HCC after failure
nivolumab 0.1-10 mg/kg every 2 weeks for up to 2 or intolerance to sorafenib (ReLive Study) is ongoing

116 Hepatoma Research ¦ Volume 3 ¦ June 15, 2017