Minsig Choi, MD: Looking at refractory treatment options for hepatocellular cancer, just 3 years ago we didn't have any second-line treatment options for liver cancer. But over the last 3 years, large phase 3 trials have shown that there are good second-line treatment options for liver cancer.

I’m going to begin chronologically, in 2017, with regorafenib, which was approved after patients who failed sorafenib. This was based on a resource study showing that regorafenib is effective in patients with refractory HCC [hepatocellular carcinoma] who failed sorafenib. They showed an overall survival of 10 points, 6 months compared with about 8 months in the placebo group. The hazard ratio here was 0.63. Regorafenib is an NCCN [National Comprehensive Cancer Center]–approved indication in the second-line treatment of liver cancer.

Another TKI [tyrosine kinase inhibitor], cabozantinib, which looked at both the VEGF receptor as well as MEK and AXL pathway, has also shown to be an effective agent in refractory hepatocellular cancer. It was a large study comparing cabozantinib with placebo, and overall survival in cabozantinib was almost 10.2 months compared with 8 months in the placebo group. Here the hazard ratio was 0.76, and the PFS [progression-free survival] improved from 2 months to 5.2 months as well. Both regorafenib and cabozantinib are approved agents, and these are category 1 recommendations from NCCN in the treatment of refractory hepatocellular cancer.

However, I told you about lenvatinib and sorafenib in the first-line treatment of liver cancer. If you have actually gotten lenvatinib, you might consider sorafenib as a second-line treatment option. And if you got sorafenib, lenvatinib could be an option in the second-line setting. However, there are currently no studies conducted in those settings, so both of these options are recommended by the NCCN but not category 1 recommendations.

Now there are other monoclonal antibodies and immune checkpoint inhibitors that were approved in the second-line setting. One of these drugs is ramucirumab based on the REACH-2 clinical trials. In the previous REACH trial, ramucirumab was effective but was not clinically significant. But when they looked at alpha-fetoprotein, which is an important biomarker for liver cancer, they noted that people with alpha-fetoprotein above 400 ng/mL benefited from ramucirumab. In the REACH-2 study they looked at patients with alpha-fetoprotein above 400 ng/mL, and ramucirumab was an effective agent in this patient population.

Now both nivolumab and pembrolizumab are approved agents after sorafenib failure, so these are immune checkpoint inhibitors. Just last week we heard that nivolumab-and-ipilimumab combination was a fast track by the FDA for approval in the refractory HCC patients.

Nowadays we have so many options—regorafenib, cabozantinib, other TKIs, ramucirumab, nivolumab, and pembrolizumab—in our treatment for refractory HCC. But the NCCN category 1 recommendations are regorafenib, cabozantinib, and ramucirumab. One of the caveats here is that these are for patients who have failed on sorafenib, so people who progressed on sorafenib. If you use lenvatinib as your first-line treatment because this drug has shown to improve PFS and overall survival—and about 75% of the community oncologists and academic clinicians use lenvatinib as a first-line treatment—then what you do in the second-line setting is really not evidence based. These are based on your clinical experience and how you use the current data available.

Transcript Edited for Clarity