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Combinations of immune checkpoint inhibitors
Patients who were previously treated for HCC in the second-line with nivolumab plus ipilimumab had very
durable responses, and consequently, the combination underwent accelerated approval in this treatment
setting. In the CheckMate 040 trial, 148 pretreated patients were randomized to one of the 3 therapeutic
arms: Arm A entailed 1 mg/kg nivolumab plus 3 mg/kg ipilimumab, each administered every 3 weeks for
4 doses, followed by nivolumab 240 mg every 2 weeks; Arm B comprised 3 mg/kg nivolumab plus 1 mg/kg
ipilimumab, administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks; and
Arm C comprised 3 mg/kg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. The dosing
regimen in Arm A demonstrated the best responses [ORR, 32% (8% complete response, and 24% partial
[54]
response)], and an additional 18% had stable disease. The median OS in this cohort was 23 months .
In the ongoing, randomized, phase 3 CheckMate 9DW trial, patients with HCC are being treated with
ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) on a three-week cycle for a total of 4 doses, after which
nivolumab is administered at a straight dose of 480 mg every four weeks as maintenance therapy. The
investigators aim to compare the response of these patients with those receiving sorafenib or lenvatinib in
the frontline setting. The primary endpoint is OS (NCT04039607). This trial is still ongoing, and the results
are not yet available.

The dual anti-CTLA4 and PD-1/PD-L1 axis therapy combination durvalumab plus tremelimumab was
[55]
evaluated for safety and efficacy in a phase I/II study by Kelley et al. Of the 40 HCC patients enrolled,
93% were Child-Pugh class A, 30% were treatment naïve, 27% had hepatitis B, and 23% had hepatitis C. The
response rate to therapy was 15%, and the most common any-grade AEs included fatigue (20%), increased
ALT (18%), pruritus (18%) and increased AST (15%). Following this trial, the phase III HIMALAYA study
(NCT03298451) was initiated [55,56] . The study included the following arms: combination tremelimumab plus
durvalumab; durvalumab alone; and sorafenib. Additional combination immune checkpoint clinical trials
are still underway and exploring a combination of anti-PD1/PD-L1 with novel targeted agents including
anti-LAG-3 (NCT03005782, NCT01968109), anti-TIM3 (NCT03099109), anti-IL-6, and anti-TIGIT in the
Morpheus-Liver trial (NCT04524871). As shown in Figure 1 [57-66] , Tables 1 and 2.

USE OF IMMUNOTHERAPY IN INTERMEDIATE STAGE HCC
As discussed above, the role of immunotherapy in advanced HCC is somewhat established, with many
more agents and their combinations still under investigation. However, the benefits of immunotherapy in
intermediate HCC remain unknown. Current treatment for intermediate HCC includes local therapies
such as RFA, TACE, transarterial radioembolization (TARE) and microwave embolization. In current
practice, the failure of local therapy, including resection, is due to the development of micrometastases
that escape therapeutic death, and produce new lesions and spread of HCC [67-69] . Utilizing immunotherapy
along with local therapies in intermediate stage HCC is hypothesized to reduce micrometastasis, leading
to improved response and survival. The local therapies destroy tumor tissue, causing necrosis and release
of tumor-associated antigens [70,71] , stimulating the immune system and, in the case of TARE, contributing
to the abscopal effect (antitumor response in metastases that are distant to the irradiated tumor) [72,73] .
However, checkpoints are also activated by this antigen release, which promotes tumor immunoevasion
and immunoresistance. Hence, the novel combination of immune checkpoint blockade with local tumor-
[74]
destroying therapies is hypothesized to result in a robust tumor-fighting response . Emerging clinical
trials evaluating local therapy plus immune checkpoint treatment are underway. One phase II trial is
randomizing 128 patients between Y-90 TARE alone and Y-90 TARE followed by the combination of
atezolizumab and bevacizumab (NCT04541173). The primary endpoint is PFS by RECIST. Secondary
endpoints include AEs, PFS, time to progression and ORR, all assessed by the modified RECIST; and OS.
Another phase II trial explored the administration of Y90-RE to patients with intermediate-stage HCC
combined with nivolumab (NCT03033446). This trial enrolled 40 patients, and 36 were evaluable, all of