Optimal Sequencing Next Step Following Rapid Progress in HCC

Gazala N. Khan, MD

Now that the treatment armamentarium for advanced hepatocellular carcinoma (HCC) has expanded, investigators are channeling their efforts into defining what the optimal sequencing of these agents will look like, said Gazala N. Khan, MD.

Data from the phase III REFLECT trial, which led to the August 2018 FDA approval of lenvatinib (Lenvima) for the frontline treatment of patients with unresectable HCC, led to a new era of advances in the space. Until that breakthrough, the field had gone a decade without seeing any progress made in the frontline setting, with sorafenib (Nexavar) as the lone available agent.

Results showed that lenvatinib demonstrated noninferiority to sorafenib in the first-line setting. The median overall survival (OS) was 13.6 months in the lenvatinib arm compared with 12.3 months in the sorafenib arm. Additionally, the median progression-free survival (PFS) was 7.4 months in those who received lenvatinib versus 3.7 months in patients treated with sorafenib. Between the 2 agents, lenvatinib appeared to be better tolerated, added Khan, who is a gastrointestinal medical oncologist in the Henry Ford Health System.

Beyond TKIs, the monoclonal antibody ramucirumab (Cyramza), and the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) are also approved in the second-line setting. The challenge with having all of these options to choose from is that there are little data available to inform how to approach sequencing, said Khan.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Khan highlighted the recent headway made in HCC and discussed the remaining challenges.

OncLive: What was it that led to such an explosion of new treatments in HCC after having been a relatively stagnant field?

Khan: Ever since sorafenib was approved by the FDA in 2007, we really didn't have any positive trials until 2017. It was not for a lack of trials; there have been many different phase III trials looking at multikinase inhibitors, but these trials have been mostly negative. The recent advent of these new agents speaks to their improved efficacy and our capability to design newer molecules that act on these specific targets. This success is also based, in part, on a better understanding of the disease biology.

What should the community know about the REFLECT trial?

The REFLECT trial was a large, randomized, phase III, noninferiority trial looking at lenvatinib versus sorafenib [in the frontline setting] of advanced HCC. This was a positive study in that lenvatinib met all of its noninferiority endpoints compared with the standard of care, sorafenib. I would say lenvatinib is as efficacious as sorafenib in all of the parameters. In this trial, investigators did look at secondary endpoints, such as PFS and time to progression. Lenvatinib appeared to be superior in PFS, time to progression, and it appeared to have a higher response rate. All of these data led to lenvatinib getting FDA approved last year.

What data have we seen with cabozantinib (Cabometyx)?

Cabozantinib is a newer TKI that is now FDA approved in the second-line setting for patients who progress on sorafenib. This agent was studied in CELESTIAL, which was a large, randomized phase III trial of cabozantinib versus placebo. The drug did appear to be associated with a statistically significant improvement in OS. It was also fairly well tolerated in this patient population, leading to its approval.

With all these available therapies, how much of a challenge will sequencing be?

It will definitely be difficult since we have so many new agents available now in the span of a 1.5 years. In the frontline setting, based on data from the REFLECT study, we saw a superior response rate and improved time to progression. As such, lenvatinib is a very reasonable frontline option to consider. In terms of second-line treatments, we have many different options out there now. We have cabozantinib, and we [now] have ramucirumab as well, based on data from the REACH-2 trial. Either of these would be a reasonable option to consider.

Agents like nivolumab, as well, for patients who are candidates for immunotherapy, is also an interesting choice. The short answer to your question is that in the second-line setting, it's not clear how to best sequence these drugs. Personally, I would base this decision on the individual patient's profile and characteristics until more data become available.

Where will ramucirumab fit into the paradigm?

Ramucirumab was tested in the REACH-2 trial in a specific patient population. This was a biomarker-selected trial looking at the specific cohort of HCC with alpha-fetoprotein levels of greater than 400. In this specific cohort, ramucirumab did appear to have a survival benefit.

Could you expand on the promise seen with immunotherapy in HCC?

We have data with nivolumab and data with pembrolizumab. Both trials [evaluating these agents] were positive, showing response rates of around 20%. There were also improvements in median OS. In the nivolumab trial, median OS has not been reached. As such, both of these are great options to consider as well.

What does this all mean for the outlook of patients?

Compared with a decade ago, when we only had 1 FDA-approved drug, the outlook for patients with HCC is very promising. We have 2 approved drugs in the frontline setting and multiple other drugs in the second-line setting. There are also emerging data on the use of combined immunotherapy with anti—CTLA-4 and anti–PD-L1 using durvalumab (Imfinzi) and tremelimumab. The preliminary data from that research appear to be promising.

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.