Expert Explores Second-Line Treatment Options for Hepatocellular Carcinoma

When it comes to treating patients with hepatocellular carcinoma (HCC), doctors have a handful of options at their disposal. But how do they decide what’s best? In an interview with OncLive®, CURE®’s sister publication, Dr. Tanios S. Bekaii-Saab, explained his thought process on what therapies are best in the second-line setting, after patients’ disease has progressed after initial treatment.

Bekaii-Saab, the leader of the Gastrointestinal Cancer Program at Mayo Clinic Cancer Center, walked through his choices for the treatment of HCC once a patient has completed one line of therapy but still experiences disease progression.

“When we think about all these first line options now, (like) atezolizumab (Tecentriq) and bevacizumab (Avastin), the question that of course comes next to mind is how do I pick my second line?” posed Bekaii-Saab. “We’ve had a number of options in the second line, they all came at the heels of sorafenib (Nexavar). We don't have much data that informs us about what to do following atezolizumab and bevacizumab. So, we have to go with what we have.”

To start, he explained, the basic options for second-line treatment are Stivarga (regorafenib) and Cabometyx (cabozantinib). If a patient’s alpha-fetoprotein level is 400 ng/mL or more, Cyramza (ramucirumab) is another option, along with Yervoy (ipilimumab) and Opdivo (nivolumab) as well as Keytruda (pembrolizumab).

Some may argue, Bekaii-Saab noted, that Nexavar and Lenvima (lenvatinib) could move to the second line as well, but he doesn’t believe enough data exist to support the use of these drugs beyond the first line. “Frankly, I don't consider them as options,” he said, “but even for the sake of argument, let's put them in that bucket and let's one-by-one eliminate which one makes sense and which one doesn't, until we have further data.”

When looking at Keytruda, Bekaii-Saab cites the results of the Keynote 224 study that found it to be no better than placebo before eliminating it from his options.

The next option for patients whose alpha-fetoprotein level is 400 ng/mL or more, is Cyramza. “The challenge with this is, following exposure to an agent like bevacizumab, which is a pure VEGF inhibitor, is ramucirumab going to be able to (demonstrate) activity?” Bekaii-Saab asks. “The answer is unlikely. And the challenge is that pure VEGF following VEGF may have its own challenges, and I’d say that ramucirumab may not continue to be an option anymore following atezolizumab and bevacizumab.”

Lenvima, according to Bekaii-Saab, “suffers the same fate that ramucirumab does, as it's a very potent VEGF inhibitor with less activity across other targets, and so it becomes less favored.”

When examining the use of Yervoy and Opdivo, Bekaii-Saab explained that following failure with a PD-L1 inhibitor like Tecentriq or Avastin, can a doctor justify using another immunotherapy combination? “The answer is we just don't know. It's very difficult to justify it, and I'd say at this point of time, granted that we don't have phase 3 data on any dual immune checkpoint inhibitors, I'd say it probably is a lesser level and I would not consider it.”

Bekaii-Saab considers Nexavar a “non-player”, since Stivarga has established itself in the second line, and is likely to be “at least as effective, or one can argue, perhaps a little bit better than sorafenib.”

With these eliminations made, Bekaii-Saab says his choices are much simpler. “I have atezo/bev (atezolizumab or bevacizumab) in the first line, and my second line really is limited to cabozantinib or regorafenib. And so those are the two agents I would go with.”

As for how he would choose between one or the other, Bekaii-Saab said the data supports either therapy right now. “There's not much data to tell you,” he said. “Some folks have been favoring regorafenib, and others (prefer) cabozantinib. I think you're justified to use one or the other. But these would be the two agents of choice following atezolizumab and bevacizumab.”