Managing Systemic Treatment in Liver Cancer

Richard S. Finn, MD:I think both regorafenib and nivolumab have a role to play in patients with advanced liver cancer. We are now seeing, in the past year and a half, that we’ve had 3 positive phase III studies with lenvatinib, regorafenib, and then cabozantinib. And as far as approvals, as we sit here today, we have sorafenib for frontline therapy and regorafenib and nivolumab for second-line therapy.

The challenge for us is to figure out how we’re going to sequence these drugs with the given data and when they are approved. At this point in the second-line setting, we’ve certainly seen patients who get nivolumab and appear to be cured. It’s early to say that, but there are patients who many of us have seen have complete responses. It’s not common but when it happens, it’s significant.

At the same time though, that has to be balanced against the fact that we have strong phase III data currently with regorafenib that improved survival, and certainly, we’ve seen patients who have responses with regorafenib. The response rate with that drug is higher than we see with sorafenib. So, it’s a good problem to have several agents to choose from. And I think critical in choosing a choice of therapy is the condition of your patient, specifically in regard to their liver disease and life expectancy, so that we can optimize their chance of getting all active agents.

It’s very important to keep in mind that in order to get patients the option of second-line therapy, we need to get them the option of frontline therapy. And, therefore, it’s important for us to transition patients who are getting locoregional therapy to systemic treatment at the right time. If patients are not in good shape when they present for frontline treatment, they’ll never get the option to get the sequence of treatments that we think is improving overall survival and changing the natural history of advanced HCC.

I think after a decade of managing patients with sorafenib in this clinical situation, meaning advanced HCC, I think many doctors are comfortable with the toxicities that we see. Comparing sorafenib and regorafenib, regorafenib does appear to be more potent. We see a higher frequency of hypertension. But as far as hand-foot skin reaction, diarrhea, and GI toxicity, I think the management protocols are not that dissimilar from what we’ve seen with sorafenib. Keep in mind just because it’s an oral drug does not mean we just let patients take it and go away for several weeks.

Patients need to be seen early and regularly, and educated on being proactive about managing hand-foot skin reaction using the urea-based creams and emollients, being informed on how to manage diarrhea and managing it early with antidiarrhea agents. And also calling the doctor. It’s very important that patients keep in touch with the office should they have problems. Regorafenib is dosed differently than sorafenib. It’s dosed 160 mg once daily but 3 weeks on and 1 week off.

The dose studied in the RESORCE study was this 160 mg dose and I think we should aim at always trying to recapitulate what is done in research studies. Therefore, starting at 160 mg daily is not inappropriate for someone who is well compensated and has good performance status. And then dose adjusting if they have toxicities. I think all of us have some experience with sorafenib that for patients who appear a little more frail, we do start at a lower dose but try to dose escalate as soon as possible.

We’ve also seen from the RESORCE study that the patients benefit from regorafenib is really not related to the dose intensity of prior sorafenib. So, even if a patient was on a lower dose of sorafenib for some period of time, and then gets regorafenib full dose, we still expect to see a similar benefit as if they were on a full dose of sorafenib prior.

Transcript edited for clarity.

February 2017

• A 59-year-old man with presented with RUQ pain and fatigue.
• PMH: Cirrhosis, HCV infection
• SH: lives alone, drinks alcohol daily (~15 drinks/week)
• ECOG, 0
• Laboratory findings:
  • AFP: 677 IU/mL
  • Platelets: 144,000 cells/mm³
  • INR, 1.7
  • Bilirubin: 1.8 mg/dL
  • Albumin: 3.9 g/dL
  • Hepatic encephalopathy: none
  • Ascites: mild
• Child-Pugh A
• Abdominal CT scan showed a large mass (8.6 cm) involving hepatic segments IV and VIII with portal vein infiltration, diffuse 1.0-cm to 1.5-cm nodules in the right hepatic lobe; 1.5-cm left portal vein thrombosis
• Surgical consult, unresectable based on tumor size and portal vein invasion
• Biopsy findings showed grade 3 hepatocellular carcinoma, marked fibrosis  
• The patient was treated with TACE; dynamic liver computed tomography at 1 month showed a partial response; repeat TACE showed no additional response
• The patient was started on sorafenib
• Imaging at 2 and 6 months showed a partial response with marked regression of the hepatic mass and smaller nodules.

February 2018

• The patient reports feeling fatigue, requiring rest during the day, but continues to work full-time
• CT of chest, abdomen, and pelvis showed new pulmonary nodules (2.0 cm and 3.1 cm) consistent with metastatic disease
• ECOG, 1
• He was started on regorafenib 160 mg daily
• After 2 weeks on therapy he developed grade 2 hand-foot syndrome which resolved after dose reduction to 120 mg daily
• After 3 months the patient has stable disease and improvement of symptoms