Masatoshi Kudo, MD, PhD: Regarding the PD-L1 plus CTLA4 procedure, the rationale is that CTLA4 can recruit the dendritic cells and activate T cells efficiently in the lymph nodes in the priming phase. The activated T cells infiltrate the tumor. At the tumor, the CTLA4 regular 3T cells, there is also expressed CTLA4. CTLA4 inhibits the regular 3T cell, so microenvironment is changed to chroma-immunosuppressive. At the same time PD-L1 blocks the PD-1/PD-L1 axis. In other words, tumor invasion activates T-cell effect. I think it’s a rationale of such combination.

Minsig Choi, MD: Some recent development is combination therapy in the frontline treatment for liver cancer. There are emerging data from different clinical trials. One of them is the HIMALAYA study, which looked at nivolumab and tremelimumab combination. It’s just like the nivolumab-ipilimumab combination looking at anti–PD-1 plus a CTLA4 antibody, trying to see if those have a superior clinical outcome compared with just a single-agent PD-1 or CTLA blockade.

The phase 3 trial in the HIMALAYA study was completed, and we are eagerly awaiting the results. The recent results has been the combination of atezolizumab with Avastin, which showed that there was a definite clinical superiority when you do these types of combinations.

Now we were a part of the LEAP-002 study, which was looking at lenvatinib and pembrolizumab combinations. I have seen some patients of mine doing very well on this combination, having good clinical response to this treatment. I think the future will be the combination strategy looking at different TKIs [tyrosine kinase inhibitors] plus immune checkpoint inhibitors, and there are currently multiple studies going on. The COSMIC-312 study with cabozantinib and the atezolizumab study, LEAP-002, just completed its clinical trial core, so in the next 6 to 12 months we’ll be seeing a lot of combination strategies for the treatment of liver cancer. If these are positive, the first-line treatment from TKIs would be changed to combination strategies.

Transcript Edited for Clarity