Options Following Sorafenib in HCC

Anthony El-Khoueiry, MD:She continued on this treatment of sorafenib with a dose reduction from January 2017 until April 2017, when she had definitive progression with evidence of extrahepatic disease in the lungs. The question of what to treat patients with after progression on sorafenib remains a challenge. We’ve recently seen in the RESORCE trial that there is a benefit from regorafenib post progression on sorafenib, but the trial was limited in its patient selection to patients who had tolerated sorafenib. And the definition in that trial was 400 mg/daily as a minimum dose for 20 of the last 28 days. So, generally, the RESORCE trial targeted patients who tolerated sorafenib reasonably well and had documented radiologic progression.

The challenge in this case is that the patient had required 2 dose reductions—the second dose reduction to 400 mg/every other day—and had significant toxicity on sorafenib. So, this is not a typical patient that meets the RESORCE eligibility criteria. In general practice, as always, the usage of regorafenib may be expanded beyond the RESORCE trial, but that should be done carefully and based on physician discretion. We should always remember that there are other options being investigated in clinical trials. I think it is critical that we continue clinical trial activity for additional treatment options, in first-, second-, and third-line settings for hepatocellular carcinoma patients.

Actually, in this case, this is a patient who could be considered for second-line clinical trials. And there are a variety of options always being evaluated, such as targeted therapies. For example, an ongoing trial with cabozantinib, which targets the vascular endothelial growth factor receptor 2 as well as MET, would be an option. There are clinical trials using checkpoint inhibitors, such as those that target PD-1 or PD-L1. Such clinical trials, certainly, would be reasonable options, and there are others always coming on board.

There’s recently a large number of clinical trials being conducted for the treatment of advanced hepatocellular carcinoma. There’s a large proportion of them that are in the immunotherapy space, and these include, again, checkpoint inhibitors, such as those that target PD-1 or PD-L1. Many of these are being used as a single agent, but there are also trials looking at the combination of PD-1 and CTLA-4 targeting agents. There are other immunotherapy agents being evaluated, such as those that target agonists, such as OX40, alone or in combination as well. There are emerging early phase clinical trials looking at T cell receptor therapy as well as cell therapy in this setting.

There are clinical trials incorporating combination approaches with oncolytic viral therapy and immune checkpoints. We also should not forget other modalities such as, again, targeted therapies with various targets, including the classic VEGF axis or MET as well. There are also clinical trials that are using novel approaches, such as epigenetic therapy, which is really intended to re-express certain tumor suppressor genes in the tumor. Epigenetic therapy has been shown to potentially condition the tumor and enhance the potential response to immunotherapy by the upregulation of certain immune pathways in the tumor, including the interferon pathway. So, there are some clinical trials planned to combine epigenetic therapy with immune therapy. There’s a large level of activity in clinical trials, and I encourage treating physicians to consider these for their patients in order to allow us to advance the treatment for this disease further.

Transcript edited for clarity.

January 2017

• A 74-year old female with a history of HCV-infection
• Prior treatment with interferon, achieving sustained virologic response
• Had recurrence of HCV
• CT scan showed a 6.5-cm single liver mass with arterial enhancement, venous phase washout, and main portal vein invasion
• ECOG=1
• Child-Pugh A
• Therapy was initiated with sorafenib at 400 BID
• Patient experienced grade 3 hand-foot skin reaction; dose reduction to 400 QD
• Patient experienced grade 3 diarrhea; dose reduction to 400 QOD

April 2017

• Follow-up scans show radiographic progression with lung metastases