HCC Treatment Paradigm Evolves Rapidly, Abou-Alfa Says During Liver Cancer Awareness Month

Ghassan K. Abou-Alfa, MD

The treatment landscape of hepatocellular carcinoma (HCC) focuses on the role of precision medicine with the approval of several targeted therapeutic options, such as tyrosine kinase inhibitors (TKIs). In the frontline setting, the mainstay of treatment has been the TKI sorafenib (Nexavar), but this agent has been joined by lenvatinib (Lenvima) with its FDA approval in 2018. The options in the second-line setting include regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza).

The treatment landscape continues to evolve as well. Checkpoint inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), have demonstrated promising activity, both as single agents and in combination with other therapies, as treatment of patients with HCC. Several of these combinations have received FDA approval in this space. Newer targeted therapies are also under evaluation, targeting different pathways in patients with HCC.

While the addition of these agents to the armamentarium has been exciting for the HCC treatment paradigm, challenges remain in understanding how to sequence these therapies in order to optimize outcomes in patients with HCC. In effort to improve the survival outcomes of patients with HCC, a greater understanding of the tumor immune microenvironment is warranted.

In an interview with Targeted Oncology, Ghassan K. Abou-Alfa, MD, from the Memorial Sloan Kettering Cancer Center, discussed the evolution of the liver cancer treatment landscape and recognizes some of the most important advances in the field during Liver Cancer Awareness Month.

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

Abou-Alfa: This has been an incredible past few years in regard to liver cancer, and we're very thrilled and happy to see how things are evolving. Sadly, liver cancer remains a very serious problem worldwide, and there is continued increased incidence, and if anything, sadly, the number of patients that can have a cure from surgery, radiofrequency ablation, or transplant remain limited, and that's why the prognosis will be very dependent on what we will discover as treatments in local settings or in the advanced setting.

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

Abou-Alfa: The landscape for the treatment of HCC has evolved markedly, especially in the last few years. As we all know, we've been very dependent on the local therapy because there was no evidence of any systemic therapy that can help enhance survival. This changed markedly with the advent of sorafenib as a TKI that showed an improvement in survival compared to placebo, and if anything, we remained dependent on sorafenib for almost close to a decade, until new advances came in to play among other TKIs. Checkpoint inhibitors, even though there was a lot of promise with them, did not fare well as single agents, but for sure in combination, they've been doing extremely well.

TARGETED ONCOLOGY: Do you want to elaborate more on the current treatment options that are available?

Abou-Alfa: The current treatments that are available for patients with need for systemic therapy is dependent on many choices. They jump from 1 choice to almost 8 choices now. In the first-line setting, we have sorafenib and lenvatinib, both TKIs which are quite effective. We also have a new advancement, which is the combination of atezolizumab plus bevacizumab in the first-line setting.

In the second-line setting, we have regorafenib with a condition of prior sorafenib exposure. We have cabozantinib in second and third line. We have ramucirumab with a conditional need for a high AFP of more than 400 at baseline. We have nivolumab as a single agent, ipilimumab (Yervoy) plus nivolumab, and also pembrolizumab as a single agent. As we can see, this landscape evolved quite a bit, and of course, with the advent of new therapies, a lot of confusion came into play. A lot of clarity is needed in regard to how you line up those therapies, how you treat patients, what follows what, and this is something that is still evolving.

TARGETED ONCOLOGY: What new therapeutic options or treatment strategies are under evaluation now that look most promising?

Abou-Alfa: I have no doubt that the understanding of combination therapy has been very positively welcomed based on some of the data among which for example, the atezolizumab and bevacizumab, and the other is, for example, pembrolizumab and lenvatinib. We have also seen the durvalumab (Imfinzi) plus tremelimumab and the combination of ipilimumab plus nivolumab. Now, these are not to be looked at as one size fits all or of the same subject as they are totally different. If anything, what we're trying to do is to help enhance the anti-PD-1/anti-PD-L1 activity at the cell membrane level. We need some enhancers from higher in the chain of command, and we understand that between the cancer cell and the lymphocytes, there are a lot of things that can occur.

The anti-VEGF, which is applicable for the bevacizumab and atezolizumab, is 1 that happened right above that applicability at the cell membrane level. The anti-FGF activity will go 1 step higher, and this is going to be applicable, for example, for pembrolizumab and lenvatinib. By the way, I'm giving examples here, but there are many variants of the different things. At the lymphocyte level is the anti-CTLA4, which is, for example, illustrated by the tremelimumab plus durvalumab at the cell membrane level. As you can see, this kind of higher chain of command can reduce on the degeneracy as such to ensure that we have an activation of the immune activity. Of course, we're waiting for a lot of data to come up as well.

TARGETED ONCOLOGY: What are the biggest challenges that remain in this field?

Abou-Alfa: Despite all the excitement that we're hearing about new therapies, we have to remember and recognize that the biggest challenge that remains for the patients as far as what they are asking for is the needed cure. If anything, the current variation of this subject and the enhancement of survival to be more than 2 years, by all means we're very happy about, but we need to cure.

I think the component that we need to focus on is, who are the patients that are responding to therapy? Are they dependent on certain etiology? Certain ethnicity, certain specific demographics? It seems not. We looked at that, and we spoke about it multiple times. Other colleagues did discuss it as well, and we didn't see that difference. The question is in the tumor immune microenvironment. That is what we have to work on. It's time to look into the tumor immune microenvironment.

TARGETED ONCOLOGY: How do you see the field evolving over the next five years?

Abou-Alfa: The field is evolving for HCC super well, and if anything, for the first time we're seeing more interest by our young colleagues in training that are seeking an interest in HCC, and we're very excited to see that. By all means, I welcome everybody to join on those very important efforts. There were very, very few, like you can count them on 1 hand, and now there are many amazing colleagues all over the world who are interested in this disease, and we're very excited to see that. By all means, this is going to be evolving fast and steadily, and I definitely would look very positively to a further improvement in outcome for patients.

TARGETED ONCOLOGY: This month, October is Liver Cancer Awareness Month, so as we recognize how far we've come in the field, what kind of message would you like to share with your colleagues?

Abou-Alfa: October is Liver Cancer Awareness Month. It's most important to remember that because sadly, sometimes it's forgotten. We have to remember and recognize that any of us can be at risk for liver cancer. It has happened because of different etiologies, as we all know. The 4 drivers of them is Hepatitis B, although thankfully, immunization is definitely trying to reduce on that incidence but nonetheless, we know very well that in many parts of the world immunization is not yet available; Hepatitis C, despite that we have the advent of therapy for this, anyone who had this might develop HCC because of the lack of benefit or at the same time necessarily have available therapy; alcohol remains readily present and relevant to development of HCC, maybe to a lesser extent with regard to the regular age group, but definitely we're seeing it at younger age group, which is very concerning and very scary; and lastly, non-alcoholic fatty liver disease, morbid obesity and diabetes, which, sadly, are things that we're very concerned in our community about.

We have to recognize, as I mentioned, that all of us are prone to any of those, and as such, we have to be very open and very cognizant and make sure we're very supportive for our patients. They are not really a certain exceptional rarity. They are living among us, and they are us.