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Page 8 of 17 Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24

Spartalizumab (anti-PD-1) + other agents
Spartalizumab is a human IgG4 mAb against PD-1 that is currently being studied in combination with
other drugs such as Sorafenib (NCT02988440), Capmatinib (c-Met inihibitor) (NCT02795429), NIS793
[40]
(anti-TGF-β) (NCT02947165) and FGF401 (fibroblast growth factor receptor 4 inhibitor) (NCT02325739) .
Other combinations
Several studies are ongoing for other combination of ICIs with molecular targeted agents such as
Nivolumab + Lenvatinib (NCT03418922), Nivolumab + Cabozantinib (NCT03299946), Nivolumab +
Bevacizumab (NCT03382886), Pembrolizumab + Regorafenib (NCT03347292), Pembrolizumab + Sorafenib
[28]
(NCT03211416), Avelumab + Axitinib (NCT03289533), and others .
There are ongoing early-phase studies with a combination of ICIs with other therapeutic agents such
as the DNA methyltransferase (DNMT) inhibitor Guadecitabine (NCT03257761), the anti-OX40 mAb
INCAGN01949 (NCT03241173), the anti-phosphatidylserine mAb Bavituximab (NCT03519997) and
[16]
others .

COMBINATION WITH LOCAL THERAPY
Strategies to improve the potential efficacy of ICIs in HCC are being investigated in several ongoing
clinical trials by including the addition of other conventional therapies such as TACE, RFA and other local
therapies. Radiotherapy has been demonstrated to provide synergistic effect in combination with PD-L1 or
CTLA-4 inhibitors [61,62] .

Nivolumab (anti-PD-1) + local therapy
Nivolumab in combination with TACE using drug-eluting beads is under study to assess the safety of this
[63]
combination in a phase I trial (NCT03143270) .

Pembrolizumab (anti-PD-1) + TACE
A phase I/II study of Pembrolizumab post TACE is evaluating safety and efficacy of the combination
[28]
therapy (NCT03397654) .
Tremelimumab (anti-CTLA4) + RFA or TACE
Tremelimumab was also examined in combination therapy with RFA or TACE to test if tumor necrosis
could induce antigenic stimulation and systemic immune response enhanced by immune checkpoint
blockade (NCT01853618) [16,64] . This study resulted in partial response in 5 patients (26%) out of 19 evaluable
patients and 12 patients (63%) had stable disease with time to progression 7.4 months and median overall
survival of 12.3 months [16,64] .

Other combinations with local therapies
In addition to above mentioned trials, there are several other clinical studies ongoing to assess the
combination of ICIs with local therapies including Nivolumab plus radioembolisation using yttrium-90
(NCT03033446), Durvalumab + Tremelimumab combined with radiotherapy (NCT03482102),
Pembrolizumab with the oncolytic viral preparation Talimogene Laherparepvec (NCT02509507) and
others [28,65,66] . These studies suggest another therapeutic option for treating chemoresistant cancer may
become available.

OVERCOMING THE LIMITATIONS OF IMMUNE CHECKPOINT BLOCKADE THERAPY
Despite the clinical success with immune checkpoint blockade therapy, there have been several
limitations. One of the major limitations of using ICIs is the associated significant adverse events from