Expert Recognizes Expansion of HCC Treatment Options During Liver Cancer Awareness Month

David J. Pinato, MD, PhD

Following the approval of the first systemic therapy, sorafenib (Nexavar), in 2007, the treatment landscape of hepatocellular carcinoma (HCC) has been enriched by a number of first- and second-line therapeutic options, including tyrosine kinase inhibitors (TKIs) and immunotherapy agents.

The second agent approved in this setting for patients with HCC was lenvatinib (Lenvima), which joined sorafenib as a frontline treatment option. In the second-line setting, several treatments have also been approved by the FDA, including regorafenib (Stivarga) and cabozantinib (Cabometyx). Ramucirumab (Cyramza) was also approved in the second line for treatment of patients with HCC who have alpha fetoprotein (AFP) of ≥400 ng/mL.

Combination regimens also appear promising in this treatment landscape. Atezolizumab (Tecentriq) plus bevacizumab (Avastin) received FDA approval for the frontline treatment of patients with advanced HCC. The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) also appears promising in the second-line setting as well.

Although having so many new treatment options available for patients with HCC makes for an exciting era in the paradigm, clinicians must now face the challenge of selecting the appropriate treatment for each patient. More research is necessary to determine biomarkers that could guide clinicians in their treatment decision-making process, but other challenges remain in the field that will need to be overcome as the landscape continues to evolve.

In an interview with Targeted Oncology, David J. Pinato, MD, PhD, clinical senior lecturer in medical oncology, clinician-scientist, and consultant medical oncologist in the Department of Surgery and Cancer at Imperial College London, reviewed how the treatment landscape of HCC has evolved over the years and the challenges that clinicians and researchers currently face in the field.

TARGETED ONCOLOGY: What is the typical prognosis like for patients with HCC?

Pinato: The prognosis of patients with HCC is strongly dependent on a number of factors, and I think the most important 1 is the stage. We now have a codified staging for patients with HCC, which is the Barcelona Clinic Liver Cancer (BCLC) algorithm has been around for now 20 years, and it basically tells us that the prognosis of patients with liver cancer is dictated by the radiological spread of the disease by the underlying liver function by the same terms, so things like the performance status of these patients, and the prognosis of patients also strongly depends on treatment. I think that's 1 of the biggest advantages of this particular stratification on the basis of not just the baseline features but also the type of treatments that are linked with each particular stage, so patients that can be cured of HCC are the ones with very limited disease and the ones that are receiving radical therapy, such as liver transplant, which is a curative treatment of both cirrhosis and HCC. For those whose survival can be measured in years, [we've seen] up to 10-year survival figures with very, very low chances of post-operative relapse around 15% or even less in people who are optimally selected, so things like the Milan criteria definitely made a difference in this space.

The prognosis becomes shorter as we navigate throughout the staging system. In patients with intermediate-stage HCC, the modern expected survival should exceed 24 months, so unfortunately, these are patients that will not be cured from the disease, that sooner or later unfortunately, will die, and that, however, it can be targeted with very effective palliative treatments, so that can extend the quality and improve the quantity of life as well.

The area of high unmet need in the past decade has been advanced-stage HCC. Traditionally, the prognosis of these patients has been very poor, with an overall survival that still a few years ago, when the first drugs were approved for HCC, was not superior to 10 to 12 months in general. Now what we're seeing is that with the expansion of novel molecular therapies, both in the first and in the second line, this has been an area of great advantage for the patients with HCC because we're seeing survival expanding even further.

TARGETED ONCOLOGY: How has the treatment landscape for HCC evolved over the last decade or so?

Pinato: Ten years ago, we were in a very different place compared to now. We only had 1 molecular therapy, sorafenib, which, although it has been a ground breaking discovery for patients with liver cancer who had never been served by the positive effects of chemotherapy or other targeted therapies in the year prior 2007 when the SHARP trial was published, molecular therapy with sorafenib has been limited in terms of efficacy. On average, we could think about the given survival extension of patients on sorafenib by about a couple of months.

Over the past 10 years, we have seen significant changes in first-line treatment, first with the advent of lenvatinib, a drug that has been shown to be noninferior to sorafenib and therefore has led to different choices in terms of treatment for patients with HCC. Not all patients were in fact able to tolerate sorafenib, so the idea of having something dissimilar from it certainly improve the situation. However, most recently, we have had the approval of second-line therapy, so for example, regorafenib was the first, then cabozantinib, followed by ramucirumab for a sub-selected population of patients with higher AFP levels. Most recently we've seen immunotherapy, although only in the FDA territory with nivolumab and pembrolizumab as single-agent therapies.

The key advantage, especially in the past year or so, has been the final demonstration that sorafenib was not really invincible as a first-line molecular therapy, but that could be the subject of novel advancements, so that sort of primate of sorafenib and TKIs in general could be challenged by combination immunotherapy. Most recently, we have seen the approval of atezolizumab and bevacizumab in the first-line treatment of patients with advanced HCC but also very interesting data from combination immunotherapy in the second line, for example, with ipilimumab and nivolumab. The future holds lots of debates, sometimes even a lot of confusion for some of the people that are involved in the care of these patients, but certainly a much better outcome for patients with advanced HCC.

TARGETED ONCOLOGY: Could you elaborate more on the current treatment options that are available?

Pinato: If we focus on patients with advanced disease as we speak at the moment, I think TKIs are still heavily diffused throughout the world as a first-line treatment option, but as I said before, the advent of atezolizumab/bevacizumab, in particular, is challenging this particular concept of TKIs as a universal choice in patients with advanced HCC. I think this is an area of expansion. Some of the countries in Europe have access to atezolizumab/bevacizumab through expanded access schemes, so the ability to prescribe these therapies is still limited and is probably more prominent in the United States or within the FDA territory. This is shifting the landscape.

What we would like to see in the future is see disruptive changes also in the early and intermediate stages of disease. We have had no approvals and no positive trials in the intermediate stage for over 2 decades now, so the standard of care has always been TACE, as there have been a number of failures, for example, in radioembolization, and that particular segment of the BCLC algorithm, which has been a big disappointment, and even more so in early-stage HCC where there is evidence of adoptive cell therapy with cytokine-induced killer (CIK) cells from a Korean trial. Again, I'm not sure how this can be felt as being a universally available option, but certainly most of the drugs, including TKIs, in the early stage setting have failed to prove a survivor benefit. At the moment, a lot of changes have happened in the advanced stage, as we said before, but hopefully even more changes as we go along.

TARGETED ONCOLOGY: What are the new therapeutic options or treatment strategies that are looking promising right now?

Pinato: There is a lot of emphasis on anti-PD-1/PD-L1, and anti-CTLA4 agonists, which is a potential for combination that has been shown to be bioactive in HCC with response rates that are in the double-digits and toxicity that are not universally felt as being a barrier in terms of delivering patients with HCC, where we have impaired liver function, and I think we still have to see whether or not these combinations will be proven as bringing a survival benefit to patients with advanced liver cancer.

Other combinations are the ones between PD-1/PD-L1 backbone and TKIs, and it does make sense as a choice, so we know that TKIs are active in HCC and some of them such as, for example, pembrolizumab and lenvatinib, have been shown to have a synergistic efficacy in terms of having a very high proportion of response rates. The problem with this, as well as other combinations, for example, atezolizumab and cabozantinib, is the fact that toxicity can be significantly higher, and therefore other options that have been shown to have survival benefits, such as atezolizumab/bevacizumab in first-line, are quite competitive. Atezolizumab/bevacizumab serves a population of patients that is fairly well selected for the risk of bleeding, which is a key concern in patients who are receiving bevacizumab, but at the same time, the toxicity profile for that regimen appears to be fairly tolerable.

There are lot of different options, so I guess 1 of the unmet needs is the fact that, as a clinician myself, I'm really not very much guided in terms of which potential options to use in the future. The key here is that we lack biomarkers that can help us understand a bit more about who should be getting 1 treatment versus another.

TARGETED ONCOLOGY: What other challenges remain in this space right now?

Pinato: Long-term survivorship in patients with heavy disease burden and intermediate or advanced disease is probably 1 of the key challenges, so we are seeing that the current therapies have revolutionized the treatment algorithms, which is great. What is still not fully understood is whether there is an option for, for example, immunotherapy to lead to long-standing immune control of the disease and therefore increase the chances of long-term survivorship in these patients, which is something that we have seen in other disease areas such as, for example, melanoma, a relatively incurable diagnosis for most of the patients, where whether there is this plateauing of the curves in a proportion of patients that respond to therapy.

Another key challenge is to integrate these novel systemic agents across the board and maybe not just trying to think about survival extension. We're trying to think about increasing the chances of curing patients with liver cancer. We still have to remember that patients with HCC overall considered for whatever stage they present, their 5-year overall survival rate is still at the moment is less than 10%, so even if we are able to catch the disease early and offer potentially radical treatment, for example, after resection, 70% to 80% of the patients with relapse, and the same is true for radiofrequency ablation. We have to insist a lot on delivering better curative treatment for these patients, so that more can benefit from from long-term survivorship.

TARGETED ONCOLOGY: How do you see the field evolving in the next 5 years?

Pinato: I think the field of HCC in the next 5 years will be fairly confused. We were used to a certain level of uniformity in the treatment guidelines, which is a comfort sometimes for clinicians because it's easy to make decisions. Decisions are sort of streamlined on the basis of strong evidence, and they're tight protocols. I think those times are gone, and we have to consider the fact that having a choice amongst multiple treatments is not necessarily a disadvantage but a great advantage for the patients because it means that different therapies, even though they might not be all available during the same pathway of care, they will at least be equally valid alternatives. Maybe not all of them will be characterized by the same probability of response, the same probability of achieving good survival figures, good long-term survivorship, as we said before, but I think it would be very important that clinicians maintain a fairly individualized approach so that they do not forget the role as clinicians and as leaders of the oncological pathway and in a disease that is as tough as liver cancer, we have to always consider multidisciplinary management because a lot can be done by surgery alone, a lot can be done by interventional radiology, a lot can be done by systemic therapies, and even potential radiotherapy in some patients. However, I think it's the combination of all these techniques and the combination of all the different types of expertise that makes the overall survival increase in these patients.

TARGETED ONCOLOGY: As we recognize how far we've come in the field during Liver Cancer Awareness Month, what message would you like to share with your colleagues?

Pinato: The key message for me in this Liver Cancer Awareness Month is a message of engagement. I think all of us should be more mindful of the dynamic changes in the therapeutic landscape of liver cancer, and we should take pride in what we have achieved so far but also recognize that a lot more work has to be done. As a medical oncologist, I have been 1 of the few of my generations perhaps to be deeply interested about the fact that HCC is a tough disease, and it does require a lot of effort to be understood and to be able to be confident in terms of how to treat it. This has to change. I think we have to be able to train the next generation of physicians or allied healthcare professionals that will develop an active interest in HCC. This will sadly be an oncological diagnosis that will maintain an increasing incidence. We are seeing this across the board from epidemiological studies, so unfortunately, it will stay with us for longer, and we need to toughen up in terms of considering all the best treatment options. We need to work together [to address] an area of unmet need [in oncology].