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Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24 Page 7 of 17

Ipilimumab (anti-CTLA4) + Nivolumab (anti-PD-1)
Since its FDA approval in 2011 for advanced melanoma, Ipilimumab (anti-CTLA4) has also been approved
for renal cell carcinoma in combination with another ICI, Nivolumab (anti-PD-1), based on CheckMate
[40]
214 [53,54] . In HCC, there are four ongoing trials combining Ipilimumab with other ICIs . The first study
is the combination therapy of Ipilimumab and Nivolumab for HCC patients before liver resection
[40]
(NCT03682276) . The second study is also a combination therapy with Nivolumab as neoadjuvant therapy
[40]
for HCC (NCT03510871) . A third study compares the combination of Ipilimumab and Nivolumab versus
Nivolumab alone in resectable HCC (NCT03222076) . The fourth study also compares combination of
[40]
Ipilimumab and Nivolumab with Nivolumab alone in terms of safety and tolerability, after external beam
photon stereotactic body radiotherapy in patients with unresectable HCC (NCT03203304) .
[40]
Tremelimumab (anti-CTLA4) + Durvalumab (anti-PD-L1)
A phase I/II clinical study including combination of Tremelimumab (anti-CTLA4) and Durvalumab
[55]
(anti-PD-L1) in 40 HCC patients reported a response rate of 25% and manageable toxicity profile .
Currently, a phase III study of combination therapy including various dosage regimens of Durvalumab
and Tremelimumab versus Sorafenib is ongoing to compare the efficacy of these therapeutic approaches
[56]
(NCT03298451) . Similar combination therapy of Tremelimumab and Durvalumab is being studied in a
phase II trial in HCC patients previously treated with Sorafenib (NCT02519348) .
[52]
Other ICI combinations
Besides CTLA-4, other immune checkpoint molecules such as TIM-3 and LAG-3 are also being examined
[52]
in combination with PD-1/PD-L1 blockade therapy . There are ongoing clinical studies with combination
of anti-TIM3 antibody LY3321367 with anti-PD-L1 antibody LY3300054 (NCT03099109), anti-LAG-3
antibody REGN3767 with or without the anti-PD-1 antibody REGN2810 (NCT03005782) .
[16]

NON-IMMUNE-BASED COMBINATION TREATMENTS WITH ICIS
The effects of ICI therapy in HCC could be enhanced when combined with non-immune-based therapies
such as chemotherapy with the aim to improve anti-tumor efficacy and survival in HCC.

Atezolizumab (anti-PD-L1) + Bevacizumab (anti-VEGF)
Atezolizumab is a human IgG1 mAb against PD-L1 which is being studied in combination with
Bevacizumab (anti-VEGF antibody) in several clinical studies [57,58] . A phase I study of Atezolizumab and
Bevacizumab as combination therapy reported a tolerable safety profile and promising response rates
[58]
in patients (NCT02715531) . Another phase III trial is ongoing for combination of Atezolizumab and
[57]
Bevacizumab with 480 patients with advanced or metastatic HCC (NCT03434379) .

Pembrolizumab (anti-PD-1) + Lenvatinb (multikinase inhibitor)
Pembrolizumab (anti-PD-1) in combination with Lenvatinib (a multikinase inhibitor) is currently being
[59]
compared with Lenvatinib plus placebo as first-line treatment option in 750 HCC patients (NCT03713593) .
The combination therapy of Pembrolizumab and Lenvatinib reported a 42% response rate and median
progression free survival of 9.69 months in HCC patients as per results presented at the ASCO
2018 [28,57] . Another study is also ongoing with combination therapy of Pembrolizumab and Lenvatinib
[16]
(NCT03006926) .

Camrelizumab (anti-PD-1) + Apatinib (TKI)
Camrelizumab (SHR-1210) is an anti-PD-1 antibody, which in combination with Apatinib, a TKI, has been
reported at the ASCO 2018 meeting in a phase I trial with 18 HCC patients to demonstrate a response rate
[60]
of 38.9% and a median progression free survival of 7.2 months (NCT02942329) .