Sangro Highlights Impact of Immunotherapy in HCC

October 3, 2018
Kelly Davio

Bruno Sangro, MD, discusses the current landscape for systemic therapies, new directions with immunotherapy, and the need for greater research into combination therapies for HCC.

Bruno Sangro, MD

The treatment paradigm for hepatocellular carcinoma (HCC) has advanced in recent years, however, the disease remains a challenging one to treat.

Research trends are now pointing to immune checkpoint inhibitors both alone and in combination as a promising new direction of for the treatment of HCC, explained Bruno Sangro, MD, during a presentation at the 12th International Liver Cancer Association (ILCA) Annual Conference, held in London, United Kingdom. The key will be determining which patients will be likely to benefit from this class of agents, he added.

At the meeting, Sangro, director of the liver unit and codirector of the hepatobiliary oncology area at Clínica Universidad de Navarra in Pamplona, Spain, discussed immunotherapy and immune-based biomarkers in liver cancer.

Immunotherapy has already entered the landscape. In September 2017, the FDA granted an accelerated approval to nivolumab (Opdivo) for the treatment of patients with HCC following prior sorafenib (Nexavar), regardless of PD-L1 status.

The approval is based on 154 patients enrolled in the phase I/II CheckMate-040 trial, in which the overall response rate by blinded independent central review was 18.2% per mRECIST criteria for those who had previously been treated with sorafenib. Now, the community is eagerly awaiting the results of the phase III CheckMate-459 trial (NCT02576509), which is comparing nivolumab with sorafenib in the frontline setting for patients with advanced HCC. Additionally, the randomized, multicenter, phase III HIMALAYA trial (NCT03298451) is looking at 4 treatment arms for patients with previously untreated, unresectable HCC with 2 regimens of durvalumab (Imfinzi) plus tremelimumab, durvalumab monotherapy, and sorafenib alone.

In an interview withTargeted Oncology, Sangro discussed the current landscape for systemic therapies, new directions with immunotherapy, and the need for greater research into combination therapies for HCC.

TARGETED ONCOLOGY:Please provide an overview of your presentation on immunotherapy and immune-based biomarkers in HCC.

Sangro:What we know is that, if you treat patients at the most advanced stages of the disease after sorafenib, the results in single-arm trials show that—compared with the behavior you would expect from placebo-treated patients—immunotherapy-treated patients survive much longer. That was the basis on which the FDA and other regulatory agencies worldwide have accepted nivolumab, which is an anti—PD-1 therapy, for the treatment of patients with advanced-stage HCC in the second-line setting.

Based on those results and the data we earlier produced with another anti—CTLA-4 inhibitor, tremelimumab, [which showed] in a much smaller trial that there was some activity there, the field has evolved to large phase III trials. [The results] in the first- and second-line settings for advanced disease have been challenging the standard of care, which is sorafenib for the first-line setting and best supportive care for the second-line setting. We are awaiting the results of these trials, which will be hopefully less than 1 year from now.

Eventually, this will change the treatment paradigm if these studies are positive. Even if they’re not, the knowledge of the activity of these agents in liver cancer has promoted the clinical development of combinations of immunotherapies and agents that we already know are active, such as sorafenib, lenvatinib (Lenvima), cabozantinib (Cabometyx), regorafenib (Stivarga), or ramucirumab (Cyramza).

The early things we know about some of these combinations are that they may be highly active. This has changed the whole spectrum of clinical development pathways. Now immunotherapy is not only tested in combination with the advanced patients, they are also tested as adjuvant therapies in those who have been resected or treated with percutaneous ablation and have a high chance of having recurrent disease, as they have different factors of poor prognosis.

Immunotherapy is now challenging the whole spectrum of stages in patients with HCC. The issue is, we know that there is a fraction of patients who respond very well, and these patients survive for a very long time. However, there is also a fraction of patients who seem to have no effect at all, and others in which the effect is difficult to illustrate or capture. Now, with 4 or 5 different drugs soon to be available, there is an absolute need to have markers that could identify patients who would benefit most from one therapy or another.

Unfortunately, we lack biomarkers for the available drugs…and biomarkers have produced conflicting results in other tumor types. What do we know now in HCC? We know very little, because only a fraction of information has been reported so far. The only thing we certainly know is that the presence of PD-L1 in the tumor cells does not correlate with better activity of the drug in patients who have such expression. In future clinical trials, we have to gather the samples that will allow us to learn and identify biomarkers that could help us in selecting patients for these kind of therapies.

TARGETED ONCOLOGY:What other areas of research would you like to see conducted?

Sangro:Of course, we always need more and more therapies. However, the most unmet needs now are more potent systemic therapies. The pathway to go is very likely combination therapies. We are there; the programs have started. It’s just a matter of time, but we will find more active combinations that will improve the patient benefit.

The second unmet need is [improving] the results of patients with earlier-staged disease, and there are also efforts to have combination therapies with locoregional treatments and adjuvant postresection or ablation.

The third unmet need is a method of selecting patients who are fit for one or another therapy, so the decision is evidence-based—not just the perception of a certain physician or the preference of a certain patient.

TARGETED ONCOLOGY:In looking at the current systemic therapeutic options, how do you choose a frontline treatment for patients with advanced HCC?

The situation is very clear. We do have sorafenib. We’ve been using this drug that has very consistently shown to prolong survival in patients with advanced tumors. We are familiar with the way the drug has to be handled, and this is the standard of care worldwide. Now we have lenvatinib, which has been proven to be noninferior, and has as distinct profile, but it is not too different from what we are used to with sorafenib.

The problem with lenvatinib is that we don’t have trials showing the efficacy of drugs following it. We cannot extrapolate the results from post-sorafenib treatments to post-lenvatinib situations, because lenvatinib has a unique tyrosine kinase inhibitor profile, and therefore the extrapolation cannot be made in a very straightforward manner.

Therefore, for first-line treatment: sorafenib. Lenvatinib can be an option, but one has to think [about] what will happen after the patient progresses through one drug or the other and put in some thought in advance.

TARGETED ONCOLOGY:What else is being explored in this landscape?

Sangro:The most relevant trend is expansion of the systemic therapy into stages other than the most advanced disease. We have to go back and see why that was the case. Thirty years ago, HCC tumors were either resectable or unresectable; most of them were unresectable. The evidence showed that a small faction of unresectable tumors benefited from locoregional therapies. However, because there was nothing there—because cytotoxic chemotherapy doesn’t work in HCC—these locoregional therapies were used for patients with tumor stages different from those in which the evidence was produced.

This space now is not empty. We have information about the benefit of treating patients with systemic therapy in the advanced setting. Now we have to rethink the limits. What is the border between patients who would benefit from locoregional therapy and those who would benefit from systemic therapy?

TARGETED ONCOLOGY:Are there ongoing studies that you are eagerly awaiting results of?

Sangro:Everyone is eagerly awaiting the results of CheckMate-459, which is comparing nivolumab and sorafenib as the first-line option for patients in the advanced stage, because that will be a major change if the trial results are positive.

It would certainly be a change anyway. If it’s negative, we will probably have an idea of what patients could benefit [from immunotherapy], and this will be the basis for future clinical development.


Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.J Clin Oncol. 2017;35 (suppl; abstr 4013).