Case 2: Second-Line Therapy Options for HCC



Ghassan Abou-Alfa, MD, MBA:What are you going to do with second-line therapy?

Farshid Dayyani, MD:Now it gets a little complicated. If you look at the NCCN [National Comprehensive Cancer Network] Guidelines, there are 7 agents listed. We have to pay attention between: is it from the NCCN Guidelines, or is it based on randomized phase III data? That’s where the different categories come in, category 1 versus 3. In terms of tyrosine kinase inhibitor [TKI]—based or anti-VEGF second-line-plus agents, we have regorafenib, cabozantinib, and ramucirumab for patients withAFPhigher than 400 IU/mL in the second line based on category 1 data. But we also have checkpoint inhibitors, nivolumab and pembrolizumab, at category 2. Actually, sorafenib was also listed for patients who progressed on lenvatinib.

When it comes to choosing the treatment, if you want to be going by data, you can see what the eligibility criteria were in the respective trials and let those guide you. For regorafenib, which was the first TKI that was approved in the second-line setting based on the RESORCE trial, those were only patients who were able to tolerate sorafenib, as defined by at least 400 mg a day for the last 3 or 4 weeks of treatment before progressing. Those patients were randomized to placebo or full-dose regorafenib, 160 mg. And that showed positive outcomes in all primary and secondary end points: overall survival, progression-free survival [PFS], and time to progression.

Ghassan Abou-Alfa, MD, MBA:In other words, what you’re telling us here is that, if I’m not mistaken, for the approval of the regorafenib prior exposure to sorafenib is necessary, and it should have been well tolerated. In other words, if a patient doesn’t get sorafenib beforehand, you are not technically eligible for getting regorafenib, correct?

Farshid Dayyani, MD:That’s correct. Technically, even if they received it and then had toxicities and then came off, they wouldn’t be eligible to go on RESORCE.

Ghassan Abou-Alfa, MD, MBA:Fair enough. What are the other choices besides regorafenib?

Farshid Dayyani, MD:The second one is cabozantinib, a combined VEGF/AXL inhibitor, based on the CELESTIAL trial, a large study of second-line-plus. They must have all had received sorafenib, independently of if they progressed or were intolerant. But there were about 20%, 25% of third-line patients on that trial as well. There were not a lot of exclusion criteria in terms of disease volume in the liver portal vein, thrombosis, etc.

The primary end point was overall survival. It was a randomized trial of 60 mg of cabozantinib versus placebo. Again, that was a positive trial with a hazard ratio of 0.76 for overall survival superiority, 10.2 months. But importantly, for the first time, we see with cabozantinib in the second-line setting—despite the inclusion of second- and third-line patients—with PFS that extends beyond 5 months; 5.1 months in all-comers. If you look at second-line patients only, it actually goes up to 5.5 months. That clearly puts it as a category 1 in second-line plus after sorafenib.

More recently, based on the REACH-2 trial, we have ramucirumab, an anti-VEGF receptor 2 monoclonal antibody, which was tested in patients with anAFPof 400 IU/mL and greater. Based on the randomized placebo-controlled trial—again, that trial also showed patients with highAFP—overall survival is improved with the addition of ramucirumab versus placebo, with a significant improvement of progression-free survival.

Ghassan Abou-Alfa, MD, MBA:In the second line, we have regorafenib with prior exposure to sorafenib as a condition: if anything, good tolerance and progression of sorafenib. No. 2, we have cabozantinib, which can be used in the third line, as you mentioned. And third, you have ramucirumab but with the requirement of alpha-fetoprotein. Let’s talk about the other options in the second line. Let me turn to Amit. Amit, of course we have to talk about immunotherapy. Why don’t you start?

Amit Singal, MD:Checkpoint inhibitors essentially are a medication that can help use your body’s immune system to actually fight the tumor. A tumor basically will express PD-L1 [programmed death-ligand 1] that will then ramp down your immune system. It’s a way for the tumors to escape immune surveillance, and these medications are basically able to ramp up your T-cell response and actually fight the tumor.

There have been 2 that have been evaluated in terms of HCC [hepatocellular carcinoma]: nivolumab and pembrolizumab. Both actually showed very durable and deep responses, about 15% to 20%, in large phase II studies. Both have gone on to phase III randomized trials. Unfortunately, both of those phase III trials did not replicate or provide a survival benefit compared with the comparator arm. But the 1 thing we can say is that I think both of these trials, as we’ve talked about before, have advanced the field in terms of really showing responses—deep, durable responses—with systemic therapy.

Ghassan Abou-Alfa, MD, MBA:Fair enough. In addition to what we heard about the TKIs, we also have 2 checkpoint inhibitors that are approved currently in the United States in the second line, despite limitations based on phase II data that we mentioned in the beginning, being nivolumab and pembrolizumab. This is despite the phase III trials both being negative, nivolumab versus sorafenib in the first line and pembrolizumab versus placebo in the second line.

I’m going to go back to that discussion. But there’s 1 more important point—by the way, I’m sure we’re going to have colleagues ask this, or we might even ask the question ourselves. I’m going to Riad for this. Recurrence with adrenal metastases. Can’t you do anything with IR [interventional radiology] for these adrenal metastases?

Riad Salem, MD:You’d be surprised what we can do. Sure.

Ghassan Abou-Alfa, MD, MBA:That’s why I’m asking.

Riad Salem, MD:There’s no doubt that the manifestation of metastatic disease of HCC is diverse. You can have bone metastases, lung metastases, etc. An adrenal metastasis is a unique form of metastatic disease, and 1 of the ways we can treat some of these sometimes is with an ablative therapy, usually a cryoablative-type therapy if it’s accessible.

We’ve seen some of that. I think there’s been some radiotherapy. Stereotactic body radiation therapy [SBRT] has been applied with these solitary lesions as well. Those tend to be rare, and I think those tend to be the patients where that’s the only site of disease. In fact, in some patients, if the time from disease treatment to recurrence is long, they’ve been resected because they’re better biology patients. In fact, this is an opportunity to think outside the box in the right patient in terms of applying these types of options. There are options for these patients. The reality, however, is they still have metastatic disease, or BCLC [Barcelona Clinic Liver Cancer] stage C, and systemic therapy is still the gold standard. Certainly when you manage patients, they’re looking for individualized care, as you mentioned at the beginning of this broadcast. We need to individualize that. There are patients who presented very late who went on to resection, went on to ablation, and lived even longer. Certainly this multidisciplinary tumor board team is what allows you to have this kind of discussion.

Ghassan Abou-Alfa, MD, MBA:That’s why I really very much like to work with Dr Salem. We’re good friends. But at the same time, I’m always fascinated, and it really is important as a multidisciplinary team to understand what are the choices that are on the table, not only from your own specialty but from all other specialties.

I very much like the thinking process that, yes, we can technically do what needs to be done. Of course, we do acknowledge that. But it’s fascinating, and look at the attention in regard to biology, that we have to wait for a long period of time to really prove that there’s only disease that’s still there, and then we can consider a local approach on top of the systemic therapy. But this is really what would require a close and long observation per se.

More important, Dr Salem was talking to us from a rather historical perspective as well. Remember, as Farshid just mentioned to us, we were just at 1 choice a few years ago, and now we’re at 7 choices. No doubt things are opening up in regard to more opportunities that we can help patients with. Usually what I tell patients is that it’s good to keep everything on the table, and we never say no to anything. At the same time, there is a certain methodical and systemic way to really think about the process exactly as Dr Salem said. Technically he can take care of it, and I’m sure he will do an excellent job in regard to an adrenal metastasis. Nonetheless, systemic therapy is the essence over here in regard to management of this patient.

Transcript edited for clarity.

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