Therapeutic Approach for HCC Progression

Richard S. Finn, MD:We are now a year later and the patient has been managed on sorafenib with what appears to be a good response initially but now has evidence of progression. The patient has apparently tolerated sorafenib during this period of time, and imaging shows new lesions in the lung. It would not be unreasonable to consider biopsying these lesions to document extrahepatic disease. While I think most likely this is liver cancer, sometimes at the first sight of progression, I tend to do a biopsy. This patient did have a biopsy at presentation so maybe that would be necessary. But, again, that would be something to do.

As far as therapeutically, we are now in the era of second-line treatment, and there are several treatments available. One would be regorafenib, which has been shown to improve survival versus placebo. The RESORCE study was the first phase III study to show a survival benefit of a systemic treatment after progression on sorafenib. And in the United States, we now have the availability to use nivolumab. Nivolumab received accelerated approval based on a moderately-sized single-arm phase II study, which showed response rates of around 15%. And very intriguingly for the patients who did respond, they had a very long duration of response, at least 16 months.

So, these are 2 options that are currently available. Also, a clinical trial would be appropriate. And recently, we saw data at GI ASCO with cabozantinib in a similar setting. Patients who progressed on sorafenib were randomized to cabozantinib, the multikinase inhibitor against VEGF, as well as c-MET, and AXL versus placebo and this also showed a survival advantage, though at this time, that’s not FDA approved.

This patient was started on regorafenib and as we discussed, there’s strong eye-level evidence that regorafenib improves survival in patients treated with sorafenib. The patient tolerated sorafenib. The patient had some response to sorafenib. And if we looked at the data from the RESORCE study, we see that there’s a clear survival advantage with a decrease in the risk of death of about 35% with the addition of regorafenib after progression. The patient tolerated sorafenib well, which makes us think that they could tolerate regorafenib as well. We’ve seen data that for patients who go on the sequence of sorafenib to regorafenib in the context of the RESORCE study, survival was out over 24 months, which is very intriguing because that is a very big number. It’s not a number we’ve seen in the setting of advanced liver cancer. And I think it’s a very reasonable approach.

Similarly, nivolumab is approved for a patient like this. We know that immunotherapy agents are really changing the landscape of oncology and cancer medicine. And the hope with the immunotherapy agents is that when patients respond, that they respond very well. But still, we are not able to identify the patients who do respond. I think it’s important that patients have the option to get this drug sometime during their care while we’re waiting for the phase III results to read out with pembrolizumab as well as nivolumab in the frontline setting.

For inclusion into the RESORCE study, patients had to tolerate a minimum dose of sorafenib for a minimum period of time. The feeling is that by selecting patients with those characteristics, regorafenib is more tolerable in this patient population. This patient was on full-dose sorafenib for almost a year and appears to have tolerated it well with good disease control. So, I think I can expect this patient to tolerate regorafenib similarly. That’s not to say that if a patient does not tolerate sorafenib that they won’t tolerate regorafenib, but you would probably approach that patient a little more cautiously.

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