Therapeutic Advancements Changing Liver Cancer Paradigm

Steven R. Alberts, MD

For nearly a decade after the 2007 approval of sorafenib (Nexavar), there were no new therapies approved for HCC. However, there are now new drugs showing promise, according to Steven R. Alberts, MD.

In April 2017, the FDA approved regorafenib (Stivarga), a small-molecule multikinase inhibitor, as a second-line treatment for patients with HCC who had previously received sorafenib.

Just recently, the FDA granted an accelerated approval to nivolumab (Opdivo) for the treatment of patients with HCC following prior sorafenib, regardless of PD-L1 status. The decision is based on results of the phase I/II CheckMate-040 trial, in which the checkpoint blockade agent provided durable responses along with a manageable safety profile.1

Lenvatinib (Lenvima) is another multikinase inhibitor that has the potential to be promising in this landscape. First-line treatment with lenvatinib improved progression-free survival by 3.7 months and was noninferior for overall survival compared with sorafenib for patients with unresectable HCC, according to phase III results of the REFLECT study.2 Lenvatinib is not yet FDA-approved in this setting.

OncLive: Please provide an overview of your presentation.

What regimens are looking promising for advanced liver cancer?

In an interview with OncLive^® at the 2017 State of the Science Summit^TM on GI Malignancies, Alberts, a professor of oncology in the College of Medicine, consultant in the Division of Medical Oncology at Mayo Clinic, discussed current advancements being made for patients with advanced liver cancer.Alberts: I went over some updates regarding the treatment of patients with advanced liver cancer. I spent some time reviewing the management of smaller, localized tumors that may be treated with embolization. However, the bulk of the talk was focused on systemic therapy for advanced disease. It is an interesting time in liver cancer. For many years, it was sorafenib and not much else. There were a lot of trials that had been conducted in early phases that showed promising results, but none of those made it to FDA approval until regorafenib. Since then, there have been several drugs heading toward hopefully successful trials.

Is lenvatinib being looked at in combination or only as a single agent?

What other ongoing trials are you interested in?

Where are we with biomarker research?

One of those promising drugs was presented this year at the 2017 ASCO Annual Meeting with a drug called lenvatinib, which is mainly used for thyroid cancer, but, compared with sorafenib, showed comparable outcomes. That is a drug that likely will gain FDA approval.Right now, it is being looked at as a single agent. It has some unique toxicities. Until there is a better understanding of how that drug is working in HCC and what populations of patients might benefit from it, the main focus of it will be single-agent therapy. One of the trials right now is with the drug cabozantinib (Cabometyx) that has been ongoing for a while looking at the use of cabozantinib versus placebo. The trial should be near its final accrual with the hope that there may be some results coming out of that in the near future. Biomarker research continues to be a very active area. A lot of interest has been focused on markers that could be used for antiangiogenic agents. To date, across most types of cancer, the VEGF receptors, VEGF levels, or other markers of angiogenesis have not worked out as well as we thought.

What are the most prominent challenges that you would like to see addressed?

c-MET inhibition has been of interest, mainly because of cabozantinib, and had been of interest with another drug that was a c-MET inhibitor but, unfortunately, did not move forward. As an oncologist, we’re always interested in what is the best possible drug for somebody with advanced disease. When you think about a lot of cancers, and HCC certainly one of those, a good portion of the cancers are preventable. With better treatments for viral hepatitis, whether it is the vaccination for hepatitis B or some newer treatment for hepatitis C that has been making impact.

Unfortunately, looming on the horizon right now is nonalcoholic steatohepatitis. That is leading to liver disease, is rapidly increasing in the United States, and will become a dominant cause of HCC in the future.

What are the main takeaways from your talk?

It is an area that would be nice to see a focus on from the public health standpoint to try to prevent cancers rather than focus on newer treatments. My main hope is that as we’re moving in to a new era of targeted therapies and immunotherapy. We really are starting to see breakthroughs in multiple cancers. HCC is finally one of those areas where we are seeing some new drugs coming forward that show benefit for our patients who had previously had a very limited number of treatment options.

References

1. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2.
2. Chen AL, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC) [ASCO abstract 4001]. J Clin Oncol. 2017;35(suppl).