Treatment Options Evolve in Nonresectable, Non-Transplantable Liver-Only HCC Paradigm

Mark Yarchoan, MD

Mark Yarchoan, MD

Patients with nonresectable, non—transplant eligible, hepatocellular carcinoma (HCC) that is only in the liver have limited treatment options. The most common treatment options in the frontline setting for these patients includes locoregional therapy and systemic therapy, said Mark Yarchoan, MD, at the 2019 International Society of Gastrointestinal Oncology Conference.

Transarterial chemoembolization (TACE), a locoregional therapy, is available for these patients, as well as other forms of locoregional therapy such as selective internal radiotherapy using yttrium-90 (Y90) resin microspheres. However, systemic therapies are increasingly under investigation for these patients. Up until recently, sorafenib (Nexavar) was the only systemic therapy available for patients.

Now, lenvatinib (Lenvima), a systemic therapy similar to sorafenib, is available for the treatment of HCC. This agent proved to be noninferior to sorafenib in a randomized phase III trial, but according to Yarchoan, the progression-free survival (PFS) appeared notably longer with lenvatinib.

The FDA has approved a number of other immunotherapeutic agents, such as nivolumab (Opdivo) and pembrolizumab (Keytruda); tyrosine kinase inhibitors (TKIs), such as regorafenib (Stivarga) and cabozantinib (Cabometyx). Combination therapy is also under investigation.

“We are also seeing a lot of clinical trials moving systemic therapy up in the treatment paradigm,” said Yarchoan. “Currently, systemic therapy is largely used in patients who are TACE-ineligible or have progressed after TACE, but we have a lot of studies now combining TACE with systemic therapy versus TACE alone.”

Combinations such as the angiogenesis inhibitor bevacizumab (Avastin) plus immunotherapy atezolizumab (Tecentriq), ipilimumab (Yervoy) plus nivolumab, durvalumab (Imfinzi) plus tremelimumab, and others are appearing now in clinical trials for the treatment of patients with HCC in both the first- and second-line settings.

In an interview withTargeted Oncology, Yarchoan, a medical oncologist at John Hopkins University, discussed the treatment options available for patients with liver-only HCC who are not eligible for surgery or transplant. He also highlighted the different treatment options that are under investigation now for patients with HCC in the first- and second-line settings.

TARGETED ONCOLOGY: What are the treatment options for patients with nonresectable patients with liver-only HCC who are not candidates for transplant?

Yarchoan:The most commonly used therapy for this group in the United States and around the world is locoregional therapy, such as TACE. That being said, I think there is rationale to consider systemic therapy as well. We have robust data that systemic therapy can prolong life.

TARGETED ONCOLOGY: What is the rationale for using systemic therapy in these patients?

Yarchoan:We know that systemic therapy is better than placebo in patients with HCC, and that applies to patients with both liver-only disease and extrahepatic disease. I think of systemic therapy as the default treatment for unresectable disease. By contrast, the evidence for using locoregional therapy at all is mixed. In fact, in 2011 a Cochrane review group looked at all of the studies ever done of TACE to see what effect TACE has on survival of patients with HCC. They found no evidence that TACE prolongs life in any way. So I would say that in contrast to common impressions, we don’t know that our default treatment for liver-only HCC helps patients live longer.

There have been 2 major head-to-head trials between systemic therapy and locoregional therapy with Y90. These trials were reported in 2017 and 2018, and both trials found similar survival with the standard of care at the time, which was sorafenib, versus Y90, although numerically overall survival (OS) was higher with sorafenib in both studies. I think that sorafenib should be considered the benchmark, and I would say Y90 failed to beat it and didn’t even meet what we would normally consider non-inferiority criteria in either study.

TARGETED ONCOLOGY: What are the other options that could be considered in this setting?

Yarchoan:This setting is certainly an evolving space, and there are patients for whom local therapies like TACE or Y90 can be considered. Other forms of radiation [therapy] may play a role in this area, as well. Systemic therapies, until now, have largely been sorafenib, but now we have many different drugs. Understanding where these new drugs fit into our evolving landscape is important.

TARGETED ONCOLOGY: Overall in the treatment landscape of HCC, what are the first-line options right now?

Yarchoan:For patients who require systemic therapy, we have 2 therapies that are approved in the frontline setting. One is sorafenib, which has been our default since 2007, and then we have a new drug called lenvatinib, which was shown to be noninferior to sorafenib in a randomized phase III study. Although some efficacy markers favored lenvatinib, lenvatinib does seem to have a higher response rate and a longer PFS. [The time to progression is] 2 to 3 times as long with lenvatinib as sorafenib, actually.

TARGETED ONCOLOGY: What are the second-line options for when these patients relapse?

Yarchoan:In the second-line, we have a number of options. Nivolumab and pembrolizumab are 2 anti—PD-1 immunotherapies that have been approved. They were approved based on single-arm phase II data, and there is a subset of patients who have nice responses with these drugs. Many patients tolerate them quite well, but unfortunately, the recent data in HCC has been somewhat disappointing with anti–PD-1 therapy. Pembrolizumab had a, technically, negative phase III study versus placebo in the second-line setting. Although it was statistically significant in favor of pembrolizumab in terms of OS, there was some crossover, and there was some strange co-primary endpoint of PFS and OS. I think where PD-1 therapy fits in the evolving landscape of HCC remains unclear.

We also have 2 TKI therapies. One is called regorafenib and was approved in patients who tolerated sorafenib, which may be a distinct group of patients. We also have cabozantinib, another multikinase TKI, which, like regorafenib, showed OS benefit over placebo. We also have another targeted therapy, ramucirumab (Cyramza), which was approved in a biomarker-selected patient that have elevated alpha-fetoprotein (AFP).

TARGETED ONCOLOGY: What is the current role for ramucirumab in HCC?

Yarchoan:Ramucirumab is an interesting targeted therapy. It was first studied in a large phase III study versus placebo, and the study was technically negative. There was no statistically significant survival benefit of ramucirumab over placebo, but when the data was looked at, there was some signal for improved survival in the patients with elevated AFP. However, there was no benefit to ramucirumab over placebo in patients without elevated AFP. The drug company, in this case, went and did a whole new phase III trial selected for patients with elevated AFP, and the study was positive with regard to OS. However, the survival benefit is quite small.

TARGETED ONCOLOGY: Looking at all these different options in the second line, how do you decide what is the best next option for your patients?

Yarchoan:I don’t think there is a single correct answer for any particular second-line therapy in HCC. These treatments are evolving, and we need more data because many of these agents were studied at a time when all we had was sorafenib in the first-line. I do think immunotherapy will continue to play some role in the treatment of HCC because there is a group of patients who do extremely well with anti—PD-1 therapy. Some of them can have disease control for years, which we have never seen before.

That being said, most patients do not respond to anti—PD-1 therapy, so I consider anti–PD-1 therapy for patients who progress on first-line therapy and are reluctant to go back on a TKI because of issues with toxicity. Sometimes, they need a break. I consider anti–PD-1 therapy a chance to give patients that great response, recognizing that only 15% to 20% of patients at best will fall into that group. If they don’t benefit, I stop the therapy quickly.

Multikinase TKIs remain as the default therapy for the second-line setting. We have regorafenib and cabozantinib. These are both multikinase TKIs, and they both have robust phase III data with similar OS benefit and hazard ratios. I think that regorafenib is structurally similar to sorafenib, it just has a single extra fluoride. Patients tolerate regorafenib very similarly to sorafenib, so if a patient has done very well with sorafenib, I will consider regorafenib, but if the patient hasn’t done well with sorafenib, I often switch to cabozantinib in the second-line therapy because I think of it as being a different compound.

Ramucirumab numerically seems to improve OS and PFS a bit less than some other second line options, but it is often well tolerated. Again, we have no head-to-head trials, so we don’t know for sure which second line therapy is most effective and which subsets of patients benefit more from which drugs. We need more studies, but I think that ramucirumab can be a good option for patients with elevated AFP who want something usually well tolerated.

TARGETED ONCOLOGY: How do you see this treatment landscape evolving over the next decade?

Yarchoan:We have a lot of drugs now that are approved or show activity in HCC. I think we have major unanswered questions about sequencing these drugs and also about whether there are rational combination therapies. In the next year to 2 years, we will see an amazing amount of phase III data with a lot of different drug combinations. Drugs to watch out for would be bevacizumab and atezolizumab, which is the combination of a targeted therapy targeting VGEF with immunotherapy. We will also hear some additional data on lenvatinib plus pembrolizumab, so this is a multikinase TKI plus immunotherapy. I think there will be more drug combinations similar to this, combining a targeted therapy with an immunotherapy. Because the results with immunotherapy monotherapy have been disappointing, I think these combination trials will be very important in potentially establishing a distinct role for immunotherapy in the treatment of HCC.

At the same time, since the results with anti—PD-1 therapy have been underwhelming as monotherapy, there is an effort now to combine PD-1 therapy with anti–CTLA-4 therapy. The 2 combinations to watch are durvalumab plus tremelimumab and then somewhat behind that is ipilimumab plus nivolumab. Ipilimumab/nivolumab had very impressive phase II data that were recently presented, showing about a 32% response rate. The responses appear to be quite durable, so these data have given us hope that the combination of CTLA-4 plus PD-1 may be much more effective than PD-1 by itself in HCC.

Finally, I think we will need better biomarkers to understand which patient should get what therapy. So far, we are in a 1-size-fits-all treatment paradigm with HCC, with the exception of high AFP for ramucirumab. We don’t know who are the patients that are responding to immunotherapy, or are there patients that would benefit more from cabozantinib versus regorafenib or vice versa in the second-line setting? These are important questions that we need to [address].

All of our drugs right now have been studied mostly in the frontline setting or the second-line setting, but many of our patients are surviving longer than ever before. Some of them need third-line treatment options, and what a lot of us have done is we have taken drugs that have been studied in the second-line and are using them in the third-line, but we don’t have strong evidence to do this.

TARGETED ONCOLOGY: Where do you see systemic therapy fitting into the treatment landscape down the line?

Yarchoan: