Optimal Sequencing Key Next Step for HCC Paradigm

Anthony B. El-Khoueiry, MD

For more than a decade, clinical trials of therapies for patients with hepatocellular carcinoma (HCC) had a negative pattern, and sorafenib (Nexavar) was the sole FDA-approved agent in the space.

However, over the last year, the pipeline has grown to include positive data that have led to meaningful changes in the first- and second-line settings, said Anthony B. El-Khoueiry, MD.

For example, in August 2018, the FDA approved lenvatinib (Lenvima) as a first-line treatment for patients with unresectable HCC, based on data from the phase III REFLECT trial. The study showed that lenvatinib was noninferior to sorafenib in the frontline setting, which was the established first-line standard of care. Median overall survival (OS) was 13.6 months on the lenvatinib arm compared with 12.3 months for those who received sorafenib.

In terms of progression-free survival (PFS), lenvatinib and sorafenib were associated with a median PFS of 7.4 months and 3.7 months, respectively. Toxicity data were comparable in the 2 arms, El-Khoueiry added.

Regorafenib (Stivarga) and nivolumab (Opdivo) are both FDA approved in the second-line setting. Moreover, agents such as cabozantinib (Cabometyx), pembrolizumab (Keytruda), and the combination of bevacizumab (Avastin) atezolizumab (Tecentriq), among others, have also shown promise in this field. El-Khoueiry explained that the next step is determining how to sequence these agents and which patients will derive the most benefit from them.

OncLive: What is the evolution of HCC treatment?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, El-Khoueiry, an associate professor of clinical medicine at University of Southern California Norris Comprehensive Cancer Center, discussed the promising HCC treatment paradigm.El-Khoueiry: It has been an exciting time for the treatment of [patients with] HCC. There was a 10-year period where only 1 drug was FDA approved: sorafenib. We now have multiple treatment options across multiple lines of therapy.

We now have a compound, lenvatinib, which was noninferior to sorafenib. We are all awaiting the phase III results comparing the anti—PD-1 agent nivolumab with sorafenib in the first-line setting. Those results have not come out yet. We then discussed the various options in the second-line setting, where we have approval for regorafenib (Stivarga) for patients who were previously treated with sorafenib. Regorafenib was compared with placebo and showed a survival benefit.

In addition to that, we have data with cabozantinib. Patients who had failed 1 or 2 prior lines of therapy had a survival benefit with cabozantinib. Last year, we also saw an accelerated approval for nivolumab. This approval could relate to second- or third-line treatment. We also have exciting data with ramucirumab (Cyramza).

What were the most exciting data out of the 2018 International Liver Cancer Association meeting?

In a nutshell, we have multiple new options. The next challenge is figuring out to how to sequence these. We are also heading in the direction of combination therapies.There was a lot of discussion about some of the evolving early trials, including some looking at combinations. They were mostly looking at anti—PD-1/PD-L1 agents with either tyrosine kinase inhibitors like sorafenib or lenvatinib, or VEGF inhibitors. We saw a trial of bevacizumab with atezolizumab that showed a very intriguing response rate of 60%. This was in a small number of patients, so we'll interpret that with caution. Certainly, there is excitement for the potential of these combinations in general.

How do you decide between frontline lenvatinib and sorafenib?

There was also a lot of great discussion about the biology of HCC because the challenge of the future is how to best select therapies for specific patients. Another challenge that was addressed was how to go from locoregional therapy to systemic therapy. When is the perfect time? Naturally, we don't have consensus on this. Now that we have more agents, this transition is becoming more critical.The REFLECT study was a noninferiority study, and it was positive in the sense that it showed lenvatinib was noninferior to sorafenib in terms of survival. The OS numerically was comparable. Lenvatinib had a superior PFS to sorafenib. How meaningful is that? It's a challenge. You would think that physicians could choose them interchangeably.

Pending phase III data, if nivolumab received FDA approval in the frontline setting, how would that also impact sequencing?

The only major difference in toxicity was that sorafenib had higher cases of hand-foot skin reaction, while lenvatinib had a higher frequency of hypertension. Therefore, that is something to consider. In practice, a higher response rate may be relevant to patients who are symptomatic and who need their tumor burden reduced quicker. The higher PFS seen in lenvatinib may be useful for patients who are at high-risk disease, or who we are worried won't make it to second- or third-line therapy. To get a higher and deeper response for these patients is important. Now, this is all interpretation of the data. It's not yet based on solid evidence.We're awaiting the results of the phase III nivolumab versus sorafenib phase III study [CheckMate-459]. If that trial is positive, naturally it moves nivolumab into the first-line setting. Given the popularity of immunotherapy and its general tolerability, it would probably become the preferred treatment. If that trial is negative, immunotherapy will likely remain in the second- or third-line setting.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.