Immunotherapy on the Cusp in HCC

Tim F. Greten, MD

The promise of immunotherapy seen in other solid tumors is emerging in hepatocellular carcinoma (HCC), as well.

Results from the phase I/II CheckMate-040 trial were recently presented at the 2017 International Liver Congress (ILC), showing an objective response rate (ORR) by blinded independent central review of 14.5% with nivolumab in patients with advanced HCC who had been previously treated with sorafenib (Nexavar). The ORR was 19.3% by investigator assessment. The 12-month overall survival (OS) rate was 59.9% and the median OS was 16.7 months.

OncLive: What is the current status of immunotherapy in HCC?

What are some of the most promising immune-based therapies either in development or that you have seen in clinical trials?

In an interview with OncLive at the ILC, Tim F. Greten, MD, senior investigator, Thoracic and Gastrointestinal Oncology Branch, head, Gastrointestinal Malignancy Section, the National Cancer Institute, discussed the evolving role of immunotherapy in HCC.Greten: Basically, immunotherapy is a rapidly moving field in liver cancer. There are currently 3 published studies discussing the results from phase I and phase II studies that describe different immune checkpoint inhibitors. Currently, there is 1 large phase III trial testing a checkpoint inhibitor in combination with sorafenib in the first line. This whole field has really developed in the past 3 years.The one that is the furthest developed is nivolumab, which is being evaluated in a phase III study. There are multiple other checkpoint inhibitors which basically utilize the same mechanism of action. Then there are cell-based therapies, which are much more difficult to do, but there is little—but good—data for some of them.

Just like the questions with other entities, there are multiple different approaches, and there is a lot of interest in cell-based approaches but they are very very early ongoing right now.

What are the biggest challenges in applying these newer therapies in HCC?

CAR T-cell therapy is something that everyone is very excited about in the oncology field, but it has not been very successful in solid cancer. But, I know that it is being evaluated as a future possible therapy in HCC.The biggest challenge is basically our lack of knowledge. We just need to learn more about these therapies. HCC is different than many other cancers because of its underlying disease and the liver cirrhosis, and from an immune perspective—we do understand why immune checkpoint inhibitors work in some indications, but there are a lot of indications where they do not work.

Is there a valid argument for immunotherapy in HCC?

We have challenges from both sides—the HCC side and the specific disease of viral hepatitis, cirrhosis—and then there is the challenge of using the checkpoint inhibitor itself.There is a lot of data suggesting that immunotherapy is something valid in HCC. We know that this is an inflammation-induced cancer as viral hepatitis plays a big role, that is number 1.

What steps should be taken in the next 5 to 10 years to better understand this disease?

Is there anything that you would like to add?

There is a lot of preclinical data that suggests that immunotherapy may play a role. We know that even patients treated with conventional therapies, such as ablation, actually develop spontaneous immune responses. A third study was published showing that immune checkpoint inhibitors give a signal. That is all I want to say at this point because it is only really phase II data. But, all of these studies show a promising signal in HCC, so it is something to watch out for and see what the larger studies will bring.Science, science, science. You can argue all you want, but you need good data. I think the important thing is to conduct very good clinical trials and instead of banging your head against a wall, trying different forms of therapy until 1 works. The reality is a lot of the trial results in this disease are negative. That is something that we have to deal with—we need to make sure we learn enough from these negative studies. If you just learn that a negative study is negative, that is way too little. We can only advance the field if we learn from our mistakes.We are doing immunotherapy studies combining standard-of-care options, which are very specific in liver cancer. By that I mean ablative therapy, which play a big role. The majority of patients with HCC are actually treated by the interventional radiologist. So, if we find a smart way to combine that with an immune-based approach, I think that will be a big part of the future treatment.