Second-Line Therapy in Advanced HCC

Anthony El-Khoueiry, MD: Let’s discuss the second-line treatment in general and specifically of this patient. More and more, we have the ability to sequence therapies for patients with advanced hepatocellular carcinoma. Of course, the ability to do sequential therapy depends on underlying liver function. If the liver function continues to be well preserved and the performance status is preserved, we are able to go from first- to second- and potentially even third-line treatment for these patients. A lot of the second- and third-line treatment options had been evaluated, studied, and approved in the post-sorafenib era. Many of these studies were completed and designed to be post-sorafenib treatment options.

As we start using the atezolizumab-bevacizumab combination, there are limited data on the best second- and third-line treatment options and how to sequence these options. So we are going to be extrapolating and using available data, but we do not have definitive studies about the ideal second- and third-line treatment options and sequences post-ATEZO [atezolizumab] and bevacizumab.

If you notice, this patient was treated with cabozantinib. This is based on the clinical trial that led to the approval of cabozantinib; that was a post-sorafenib study. What was unique about that study is it allowed up to 2 prior systemic therapy regimens, and a third of the patients had had 2 prior systemic therapies. It randomized patients to receive cabozantinib or placebo in a 2-to-1 fashion, and that study was positive. The median overall survival for cabozantinib was in the 10-month range, versus the 7- to 8-month range with placebo. It showed superior overall survival as well as superior for PFS [progression-free survival] with cabozantinib. The adverse-effect profile for cabozantinib is quite typical of tyrosine kinase inhibitors—some fatigue, anorexia, skin toxicity including hand-foot skin reaction, diarrhea, and rashes. It’s typical of other TKIs and things that we are getting used to managing as medical oncologists.

There is 1 thing to note about cabozantinib and its mechanism of action. This is an oral tyrosine kinase inhibitor that does target VEGF receptor 2. Additionally, it also targets the MET receptor, which is the receptor for hepatocyte growth factor, and that plays an important role in hepatocellular carcinoma. It also targets AXL and some other targets. Some of them actually are considered to have immunomodulatory effects, which may contribute to its mechanism of action.

Other second-line options include regorafenib. Regorafenib was studied in the RESORCE trial, post sorafenib. The patients must have had verified radiological progression on sorafenib and must have tolerated sorafenib at the dosage of 400 mg daily or higher for 20 of the last 28 days. These were arbitrary eligibility criteria. Then patients were randomized to receive regorafenib versus placebo. The trial met its primary end point of improvement in median OS [overall survival] again to the 10-month range with regorafenib versus 7 to 8 months with placebo. The limitation of this trial is that it required that patients must have tolerated sorafenib and must have had radiological progression on sorafenib.

Other treatment options that have approval in the second- and third-line space include ramucirumab, which is a monoclonal antibody to the vascular endothelial growth factor receptor 2. This is based on the REACH-2 study. Ramucirumab had been evaluated initially in what’s called the REACH trial, which was a negative study when they compared ramucirumab with placebo post sorafenib. However, in a retrospective subgroup analysis, patients with elevated AFP [alpha fetoprotein] above 400 ng/mL appeared to benefit. Based on this, a prospective trial, REACH-2, was conducted. In REACH-2, patients were required to have had an AFP of 400 ng/mL or higher to qualify for the study. They all had received prior sorafenib, and they were randomized to ramucirumab versus placebo. All these patients had Child-Pugh stage A cirrhosis. This study met its primary end point of improvement in median overall survival with ramucirumab compared with placebo. The median overall survival of ramucirumab was in the 8-to-9-month range versus the 7-month range for placebo, and the PFS improved as well with ramucirumab.

What’s unique about ramucirumab is it’s a monoclonal antibody, so it does not have the common adverse effects of the TKIs [tyrosine kinase inhibitors]. We do not see the classic skin toxicity and classic diarrhea, but we see more proteinuria and more hypertension because of the nature of the drug-targeting VEGF receptor 2.

Transcript edited for clarity.

Case: A 69-Year-Old Man with Stage 4 Hepatocellular Carcinoma

Initial presentation

• A 69-year-old man presented with vague right upper quadrant abdominal discomfort, decreased appetite and occasional nausea and vomiting
• PMH: diabetes, medially controlled; hepatitis B virus diagnosed and treated 8 years ago
• SH: moderate amount of alcohol use (2-3 drinks a day)
• PE: abdominal discomfort on palpation
  
  

Clinical workup

• Labs: AFP 425 ng/mL, bilirubin 1.2 mg/dL, AST 102 U/L, ALT 116 U/L, ALP 380 U/L, INR 1.6, albumin 3.6 g/dL, BUN 15 mg/dL, creatinine 1.5 mg/dL, plt 205,000
• HBV+, HCV-
• Abdominal ultrasound revealed 2 hepatic lesions
• Chest/abdominal/pelvic CT scan confirmed 2 lesions in the right hepatic lobe measuring 3.2 cm and 5.5 cm, a suspicious lesion in the left lung lobe, and wide-spread lymphadenopathy noted
• Biopsy findings showed grade 3 HCC with marked fibrosis
• Surgical consult: unresectable due to tumor size and location
• Child-Pugh A; BCLC stage C
• ECOG 1
  
  

Treatment and Follow-Up

• Treatment with atezolizumab + bevacizumab was initiated
  • First imaging shows stable disease at 2 months; imaging at 4-month follow-up showed 2 new lung lesions
  • Treatment was subsequently changed to cabozantinib 60 mg PO qDay