Sequencing Challenges Impact the Management of Advanced Hepatocellular Carcinoma

Mehmet Acke, MD

A number of treatment options are available for patients with hepatocellular carcinoma (HCC), but little data remains to support sequencing approaches in the second and later lines of treatment. Treatments currently available for advanced-stage disease include targeted therapies and immunotherapeutic agents.

The targeted therapies available include multikinase inhibitors sorafenib (Nexavar), regorafenib (Stivarga), lenvatinib (Lenvima), ramucirumab (Cyramza), and cabozantinib (Cabometyx). The immunotherapy options are checkpoint inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda).

Sorafenib, lenvatinib, and the combination of atezolizumab plus bevacizumab are the frontline options, while regorafenib, cabozantinib, ramucirumab (for patients with alpha-fetoprotein [AFP] > 400), nivolumab, pembrolizumab, and the combination of nivolumab and ipilimumab make up the second line and beyond settings.

Other treatment options are also emerging for the treatment of patients with advanced HCC. These include the combination of nivolumab plus cabozantinib with or without ipilimumab (Yervoy) for treatment in the first and second lines, lenvatinib plus pembrolizumab in the first line, and durvalumab (Imfinzi) plus tremelimumab in the second line.

A number of unanswered questions remain in this treatment landscape, including how to sequence these agents appropriately. Other unanswered questions include the lack of biomarkers, immunotherapy-resistance, and the use of novel agents in earlier lines of treatment, as well as in the adjuvant and neoadjuvant settings.

In an interview with Targeted Oncology, Mehmet Akce, MD, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, discussed the treatment options available for patients with advanced HCC and how he would go about sequencing these treatments in his practice.

TARGETED ONCOLOGY: What are the current treatment options for advanced HCC?

Akce: For advanced HCC at the present time, the currently approved therapies in the first line include atezolizumab and Bevacizumab combination, lenvatinib, and sorafenib. In the second-line and beyond, the approved therapies, at the present time include regorafenib, cabozantinib, ramucirumab for patients more than AFP of 400, single-agent nivolumab, pembrolizumab, and the nivolumab and ipilimumab combination. In the third-line setting, cabozantinib could be included because the trial that studies cabozantinib allowed patients to receive up to 2 prior lines of therapy. These are all the approved therapies.

TARGETED ONCOLOGY: With these agents that we have available, what are still the key challenges with treating this disease?

Akce: The second-line therapies were all studied after sorafenib, but none of them have really been studied after the other 2 first-line therapies, particularly atezolizumab and bevacizumab. We don't have evidence based approaches to support our treatment choices for sequencing of therapy, and keep in mind, many of the oral agents have similar targets, which makes it challenging because for example, if you failed lenvatinib in the first line, we don't have data about the sequencing of other agents since all those agents were studied after sorafenib. This is 1 of the biggest challenges, and other challenges include lack of biomarkers to predict response and when the disease is refractory to immune checkpoint inhibitor. We don't have data about how to come up with the next line of therapy, other than maybe cabozantinib, which was studied in up to 2 lines of prior therapy in the CELESTIAL study (NCT01908426), and even in that trial, if you look in detail, patients who received an investigational agent in the treatment arm was 13% versus the placebo arm of 8%. There were some patients who received doxorubicin, for example 5% in the cabozantinib and 4% in the placebo arm, and according to the publication, only 3% in the cabozantinib arm and 1% in the placebo arm received prior anti-PD-1 therapy. The investigational agents are not listed here, so probably some of them also got immunotherapy, but again, that's not a very detailed evidence.

TARGETED ONCOLOGY: Can you discuss the 3 emerging agents in the space? What data have we seen with them that are encouraging?

Akce: As far as the emerging options go, we do have some data about nivolumab and cabozantinib combinations plus or minus ipilimumab, which recently was shown to have 17% overall response rate with the doublet and 26% with the triplet regimen. There's also data with durvalumab and tremelimumab with 25% overall response rate. In the lenvatinib plus pembrolizumab trial with 104 patients, overall response rate was 36% and 88% disease control rate, but keep in mind, lenvatinib and pembrolizumab versus lenvatinib plus placebo trial is still pending results. That's the phase 3 randomized trial. Those are some of the options, but multiple ongoing trials are looking into combining the systemic therapy options with liver-directed therapy or radiation options. We are still waiting on those trials.

TARGETED ONCOLOGY: How do you go about treating patients with advanced HCC?

Akce: My approach to first-line treatment of HCC in the advanced setting starts with utilization of the atezolizumab/bevacizumab combination based on the IMbrave150 trial. However, looking at the inclusion and exclusion criteria of the trial, I would caution use of this combination in patients who have untreated varices because the trial required the varices to be treated if they had any, and patients with a prior history of very serious bleeding in the last 6 months were excluded, so we don't really have safety to support this combination in these 2 groups of patients. I restrict this to very good liver function, and if the patient doesn't have any of those red flags, I would feel comfortable to utilize atezolizumab and bevacizumab as a first-line agent because it is superior to sorafenib in the first line.

As I noted, not every patient might be suitable for this combination, and as far as lenvatinib goes, it's a very good option for someone with Child-Pugh A, but keep in mind, the trial specifically excluded patients with main portal vein invasion and the liver tumor occupying more than 50% of liver, so that is something to keep in mind. As far as the sorafenib goes as a first-line agent, there are some retrospective data in liver dysfunction studies that are showing reasonable safety for sorafenib up to Child-Pugh B7 as an underlying liver dysfunction because in clinical practice, not everyone would have child Pugh A. We need to be cognizant about the patients with Child-Pugh B7/B8, which we don't really have data for at this moment. That's why as a first-line agent, if those 3 agents are not applicable because of the reasons that I mentioned, then based on the CheckMate040 trials, nivolumab arm in Child-Pugh B7/B8 patients, that provides some evidence to be able to utilize nivolumab as a first-line agent in this patient population if we are not able to use the other 3 agents. Again, the first-line treatment with sorafenib versus nivolumab was negative in the first-line trial, which we are still waiting for the full publication.

This is my first-line approach with 3 main agents and the backup agent with nivolumab single agent. For my approach for second-line therapy, the data we have is all post-sorafenib. If someone progressed while they were on sorafenib and they tolerated it well, I think regorafenib is a very good second-line agent because this trial specifically restricted patients who progressed on sorafenib. However, the rest of the trials in the second line and beyond included both sorafenib progressive or tolerant patients. From that regards, regorafenib seems to be a good choice. Another choice could be ramucirumab, particularly in patients with AFP more than 400, and nivolumab/ipilimumab is also a good option. Pembrolizumab is a second line agent, so although it could be considered, I would like to caution you that the placebo control trial was negative for primary end points. I tend to utilize either immunotherapy-based approaches in the second line, I tend to utilize the nivolumab/ipilimumab combination or nivolumab because of that negative first-line study, which was the KEYNOTE-240.

When it comes to patients who are treated with atezolizumab and bevacizumab in the first-line setting, or lenvatinib, we don't really have data to support how to sequence the subsequent therapies. Cabozantinib, on the other hand, since it included up to 2 lines of prior therapy, which included few of the patients with immunotherapy-based therapies, could be a good second- or third-line choice in that scenario as well. The rest of the patients, for example, if someone progressed on atezolizumab and bevacizumab, would you consider nivolumab and ipilimumab combination? We don't know because that comes to immunotherapy-resistant patient population, so whether you would want to utilize this regimen or you would want to utilize one of the other TKIs, that is not evidence-based. I use clinical judgment, so for example if someone progressed on atezolizumab/bevacizumab, you probably would want to utilize 1 of the TKIs, like cabozantinib or regorafenib, in that setting.

TARGETED ONCOLOGY: What is the biggest area of unmet medical need for advanced stage disease?

Akce: I would bring up 2 very important areas of unmet need. The first is how are we going to treat patients with immunotherapy-resistant disease? The second equally important question is how to best sequence these available agents. Another maybe third key question would be, how can we incorporate these agents into earlier stages of HCC as well as the adjuvant and neoadjuvant setting?