Future Directions of HCC

Stephen L. Chan, MD: In terms of systemic therapy for liver cancer, it has advanced a lot in the past 5 years. First, we know that apart from TKI [tyrosine kinase inhibitor], we can use the immune checkpoint inhibitors. In the past 2 to 3 years, we have learned that as a monotherapy, PD-1 may not be as useful in terms of prolonging the overall survival as we think. The direction of the developing systemic therapy for liver cancer is more toward the combinational treatment. The combination of the atezolizumab and the bevacizumab is 1 of the first combinations, in my opinion, that has been shown to improve the overall survival of the patients.

I imagine that in 1 or 2 years, we will have an increasing number of the studies and the combinations of the different systemic therapies: PD-1/CTLA4, PD-1 with another VEGF, PD-1 with TACE [transarterial chemoembolization], and more combinations. This is a key to the future in terms of the development of systemic therapies. Another important direction is developing the systemic sequences. As mentioned, we have 8 or even 9—or in the future more than 10—different drugs being approved or demonstrated to be useful in HCC [hepatocellular carcinoma]. But how do we sequence them? Will we combine them and put into the freezer? Together, or do we give 1 drug after the other? This will be an important topic for us to study in the future. All this will be important for improving the outcome of HCC patients.

Masatoshi Kudo, MD, PhD: I’m very interested in the adjuvant setting where there are 4 ongoing trials: pembrolizumab monotherapy, nivolumab monotherapy, durvalumab-bevacizumab combination, and atezolizumab-bevacizumab combination therapy, plus no therapy after resection or ablation. The most important program is after curative. Even after curative treatment like resection or ablation, the recurrence rate is very high in cases of HCC. The recurrence rate at 1 year is more than 35%, 2-year recurrence rate is 50%, and 5-year recurrence rate is 50%. For that recurrence we perform the treatment, and during that treatment course we perform TACE. During that treatment course, liver function is deteriorated. In the real cure, the unmet need is suppressing the recurrence after curative therapy. In that sense, we are awaiting those adjuvant setting results.

Regorafenib plus pembrolizumab is also a good combination. Regorafenib is a relatively toxic agent, but they reduced the dose and changed the treatment. Usually, it’s an 80-mg tablet or a 160-mg tablet. Usually, a full dose of regorafenib is very toxic, but low-dose regorafenib can modulate the tumor and immune microenvironment, and pembrolizumab can work well in that combination. The antitumor effect of regorafenib is also good. Regorafenib-pembrolizumab combination therapy is promising.

Amit Singal, MD, MS: With the advances we’ve seen in the systemic therapy space, it’s exciting for our patients with advanced-stage HCC. Equally exciting is the way these systemic therapies and the immune checkpoint inhibitors are being applied to earlier stages of disease. We see a lot of combination trials looking at immune checkpoint inhibitors being combined with locoregional therapies, chemoembolization, radioembolization, but we’re now also seeing these applied in the neoadjuvant or adjuvant setting. We’ve seen some early data in the neoadjuvant setting, where immune checkpoint inhibitors induced responses in a sizable number of patients undergoing resection. The hope is that that would translate into improved recurrence-free survival and overall survival after ablation or resection.

Equally exciting is the fact that these therapies can apply across or may apply across the entire spectrum of disease, and thereby increase survival across the board. As we do so, it’s important to recall that transplant plays a critical role for our patients with early stage disease. One of the things we also have to consider is the safety of these immune checkpoint inhibitors in somebody who can be down staged or falls within transplant criteria.

Some of the other interesting data that we’re starting to get a sense of as we move forward was presented earlier this year, looking at the Mount Sinai experience of patients who had received immune checkpoint inhibitors prior to transplant. The Mount Sinai experience is about 10 patients who received immune checkpoint inhibitors prior to transplant, variable doses, variable time to come into these variable agents. Overall, the early data coming out of this experience suggested that these patients can do OK. They did not note significantly higher rates of rejection or bad outcomes in their early outcomes of patients post-transplant. It’s going to be important that we have increasing data in this setting. But if we see this, it will be exciting that we could safely and with increased reassurance consider immune checkpoint inhibitor therapy earlier in the stages of disease, and this may completely transform the landscape of HCC if these other trials are positive as well.

One other thing that we have to consider when we think of HCC is that we’ve seen, once again, notable advances in the advanced-stage setting. But when we think of overall survival across the spectrum of HCC disease, the best survival continues to be at that early stage setting and with the application of curative therapies. When we think of how we can best improve prognosis for HCC patients, to reduce HCC-related mortality, it continues to be with increased implementation of HCC screening programs so we can identify patients at an early stage. If we find those patients at an early stage, it is critical that we refer those patients for curative therapies, once again highlighting the importance of multidisciplinary care and incorporation of transplant hepatologists, transplant surgeons, and surgical oncologists, so we can apply curative therapies if patients are found at an early stage disease.

Unfortunately, I do see people in my clinical practice who are treated outside, found at an early stage, who received noncurative palliative therapies. Although these can improve survival, they don’t yield the same survival that we see with curative therapies. So it’s very important that we refer these patients to curative therapy if and when possible.

Transcript Edited for Clarity