Combinations in HCC Gaining Traction

Nadine Abi-Jaoudeh, MD

The standard of care for patients with intermediate stage hepatocellular carcinoma (HCC) is transarterial chemoembolization. But evidence suggests patients could derive more benefit from a combination of trans-arterial embolization with the experimental drug tirapazamine (SR-4233), says Nadine Abi-Jaoudeh, MD.

Tirapazamine is a hypoxia-activated agent, which suggests it would work well with embolization as embolization prevents blood flow to a designated area of the body, resulting in lower oxygen levels.

“This is promising,” says Abi-Jaoudeh, associate professor of Radiology at the University of California, Irvine. “We need more data, we need the prospective phase II to compare it with, but the fact is there could be better things out there for HCC than the chemoembolization.”

The safety and efficacy of this combination was evaluated in phase I escalation study, where patients were assigned to 1 of 5 cohorts according to dose. Out of 17 patients, the average number of lesions was 2.06 per patient and average tumor size was 32 mm. Additionally, average tumor burden per patient was 60 mm.

Results showed that the combination was well tolerated with were no dose limiting toxicities or serious adverse events reported.

OncLive: Please provide an overview of this study.

What are the preliminary findings of this study?

In an interview with OncLive during the 2017 International Liver Congress, Abi-Jaoudeh discusses the study of tirapazamine and transarterial embolization, as well as the promise of combinations in HCC.Abi-Jaoudeh: This was a feasibility and safety study to test the combination of tirapazamine and embolization for HCC. It was a classic 3+3 dose escalation study, meaning we start off at the lower dose and every time it was tolerated without any toxicity, we went up to a higher dose. We started off with an IV cohort at the request of the FDA, and then we moved to giving the tirapazamine intraarterially locally, combining it with the embolization. We went up to a dose of 20 mg/m2. We realized that this dose is very efficient and more than enough for what we need, which is why we stayed at that dose.The results are pretty impressive. Chemoembolization is recognized as one of the standard treatments for HCC, except it is a palliative treatment—complete response where you eliminate all of the live tumors was only about 15% of cases. In the intraarterial cohort with the tirapazamine study, we have been able to achieve an 82% complete response with the median complete response time at 211 days, making this a sustained complete response, which is very encouraging. The main purpose of this phase I was safety; there were no dose limiting toxicities and very few adverse events.

What has been the impact of tirapazamine in the HCC landscape?

We are moving toward a phase II study where we will go head-to-head with chemoembolization and patients will be randomized either conventional chemoembolization or the combination of tirapazamine plus embolization.It is funny, tirapazamine actually came out in the 1990s for non-small cell lung cancer and head and neck cancer, given intravenously. It had gotten an indication for those cancer types but it performed very poorly because it was administered alone and without sustained hypoxia, it does not really work that well.

Are there any other combinations that are particularly promising?

In HCC, tirapazamine has never been looked at—it was not its intended use when it was invented. This is kind of a new thing that we are doing, and the great thing with tirapazamine is that it is a hypoxia drug, meaning we are leveraging what we are doing. When we are doing chemoembolization, most cytotoxic therapies actually work better if the cell is oxygenated, but we are cutting off the oxygen by cutting off the blood supply with embolization. So, we are kind of working against each other there. With the tirapazamine embolization though, we are potentiating what we are doing—we are giving a drug that works when we cut off the blood supply and reduce the oxygen. I think one of the other combinations that might have promise in the territory of advanced HCC is combining locoregional therapy with immunotherapy. We know that nivolumab (Opdivo) is on the path to be approved in HCC, but also if you combine it with locoregional therapy such as ablation or chemoembolization, that locoregional therapy can act as a vaccine that stimulates the immune system. That response is then sustained with the immunotherapy, so the combined effect can be better than either of those therapies alone.

In advanced HCC, sorafenib (Nexavar) is the FDA-approved treatment, but I do not think it is enough. I think this is a place where immunotherapy, and combinations of immunotherapy and locoregional therapy, will flourish.

I was at the NIH before I joined the University of California, Irvine, and I was a part of a study that combined tremelimumab plus ablation and it had excellent results. We would ablate a tiny little lesion that is 1 cm on the left side while giving tremelimumab, and the lesions on the right side that were 10 cm would shrink to 5 cm.

I do think there is a huge space for combining immunotherapy in locoregional therapy in advanced HCC which is really, right now, almost an orphaned disease. There is sorafenib and that is about it.

Abi-Jaoudeh N, Fernando D, Nelson K, et al. Phase I dose escalating study of hypoxia-activating agent tirapazamine in combination with transarterial embolization in patients with intermediate stage hepatocellular carcinoma. Presented at: The International Liver Congress. Amsterdam, The Netherlands. April 19-23, 2017. Abstract #167550.

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