Richard S. Finn, MD: I think these concepts are critical for the community physicians to have an understanding of, especially now that we not only have new front line, second line, but even drugs beyond that, third line, fourth line. And historically speaking, Katie, 10 years ago, who would have even thought we’d be having this discussion? And so it’s a very exciting time for liver cancer. With that in mind, I think we should delve into some of the data that are driving a lot of this excitement.

Historically speaking, before we had sorafenib’s approval in 2007/2008, as you’ve touched on, Katie, locoregional treatment filled a void, right? We had patients who had progression in the liver despite vascular invasion. Even patients who might have small extrahepatic disease would continue to get locoregional treatment. And the approval of sorafenib in 2008, which I think many people are familiar with now, that data, the SHARP study which showed a 31% decrease in the risk of death with sorafenib versus placebo. At that time, a placebo-controlled study could be done because no systemic treatment had been shown to improve survival. And we saw that for the first time, median survival was improved with a systemic drug with an adverse effect profile that is manageable, I would argue. VEGF adverse effects such as hypertension and proteinuria were not so severe with sorafenib, but more commonly, GI toxicity as well as hand-foot-skin syndrome were typically the dose-limiting toxicities. And we learned how to manage sorafenib, the full dose being 400 mg twice a day. And many of us have learned to dose adjust or use supportive care measures to keep patients on sorafenib.

The approval of sorafenib left us with a lot of unmet needs, I think. Specifically, we wanted something that did better than sorafenib. We needed something to do when sorafenib wasn’t working. We needed something when patients could not tolerate sorafenib, despite supportive care measures. I remember giving interviews in 2008 about what does the next 4, 5 years of liver cancer look like. And I said, "Sorafenib’s ushered in the golden age. We’re going to have so many new approvals.” I was off by about a decade. But we tried for a long time and had numerous negative studies. And this was not because of lack of trying. But I think our insight into how these drugs work and our expectations in clinical trial design just were not mature enough. Sometimes, you need to fail a few times to learn.

That changed in 2018 with the REFLECT study, which was the lenvatinib approval. We saw with lenvatinib that we had a new drug, a new option for liver cancer. When we looked at the survival data, it was noninferior, so it was no better and no worse, essentially, for its effect on overall survival. But it did delay progression. It did have a little different adverse effect profile as far as a lower incidence of hand-foot-skin syndrome, a higher incidence of hypertension. And it did have higher response rates. By RECIST, we saw response rates of around 18%, 19%. That was new, because sorafenib, while it improved survival, which all of us, I think, would agree is the most important end point in our liver cancer studies, it didn’t give us a high response rate. I think it was challenging for other physicians in the space to appreciate the importance of a drug that can improve survival but doesn’t necessarily shrink tumors.

Since that time, we’ve had a number of TKIs [tyrosine kinase inhibitors] approved, mostly in the second-line space, which we’ll talk about. Recently at ASCO [the American Society of Clinical Oncology annual meeting], we saw some interesting data with a novel TKI, donafenib. And this was the first time we saw a small molecule beat sorafenib. This study was done essentially in China, so its applicability to the Western population that we see, I think, is still lacking. But interestingly, this was one of the first TKIs that beat sorafenib and had a little more favorable adverse effect profile for TKIs.

Transcript Edited for Clarity