Optimizing Checkpoint Inhibitor Combinations in HCC


Ghassan Abou-Alfa, MD: Combining checkpoint inhibitors might have a quantitative value, especially because the immune system does not function in only 1 way but rather has different steps along the way. As such, an anti-CTLA-4 that can block the immune system part of lymph-node activity that will translate to further activation of the blockade in the tumor itself, which would be anti-PD-1, is a totally appropriate combination of therapy.

Combining checkpoint inhibitors is a very important aspect of the treatment for primary liver cancer, or HCC. If anything, the argument that an anti—CTLA-4 will activate the effect of the immune system on the lymph nodes and will activate further the effect of the immune system on to the tumor itself is a very reasonable approach. For that reason, currently a large clinical trial—which will actually be the largest ever clinical trial in regard to primary liver cancer, with close to about 1300 patients—will be looking into anti–CTLA-4, tremelimumab; versus anti–PD-1 therapy, durvalumab; versus the combination of the 2, durvalumab plus tremelimumab. Of course, there will be a comparison to the standard of care currently for first-line therapy, which is sorafenib.

Checkpoint inhibitors have really been driving a lot—not necessarily all, but a lot—of the data and efforts in regard to research in primary liver cancer, or HCC. On the other hand, everybody is trying to find out what could be a good combination of the checkpoint inhibitors with a certain TKI. If anything, there are different algorithms in that regard among which rationale is only example-based because there are too many of them. For example, c-MET inhibition plus a checkpoint inhibitor could be a very reasonable approach to consider based on some preclinical data in that regard.

The future of clinical trials in regard to checkpoint inhibitors is very promising. If anything, I put a lot of faith in this large and important study in the first-line setting for the combination of durvalumab plus tremelimumab, versus durvalumab, versus tremelimumab, versus sorafenib as well. This, of course, will come around the same time that the nivolumab versus sorafenib study has already completed accrual. Of course, we’re looking forward to its results.

However, short of looking at the checkpoint inhibitors from the standpoint of systemic therapy for advanced disease, we should not ignore the potential use in regard to local advanced disease. If anything, as I stated almost 10 years ago in one of the reports in the Journal of Clinical Oncology, the combination between local therapy and systemic therapy is not a divorce: it’s a marriage. If anything, the combination of an embolization, or of yttrium-90, plus a checkpoint inhibitor is definitely underway, and there’s definitely evidence in clinical trials that we’re looking forward to seeing the results of.

Transcript Edited for Clarity

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